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Welcome Dear Students, Welcome to the second year medicine. As you have already started in the Faculty curriculum (System- Based Curriculum), this year you are in Phase II of the program. Phase I : Premedical Year (First Year) Phase II : Second and Third Years Phase III : Fourth, Fifth and Sixth Years Congratulations, you passed phase I. But what about phase II? Phase II includes many core modules and also System-Based Modules. The aim of this phase is to lay down a solid foundation for the subsequent full-time clinical study in stage III of the MBBS program. It will also integrate the basic sciences knowledge with the clinical sciences. This include knowledge, skill and attitudes, particularly attitudes towards the learning process. The curriculum philosophy in stage II is enforcing the development of a mixture of teaching approaches including System-Based Learning, Problem-Based Learning and also stressing on the idea of "Student Self-Directed Learning". The department has the honor to introduce this study guide to you hoping that it may be helpful in making you oriented with the aims, objectives, contents of our courses, and through it, you will find the answers of the frequently asked questions. All the Best Department Chairman V TABLE OF CONTENTS TOPIC INTRODUCTION COURSE DESCRIPTION AND ORGANIZATION MAJOR COURSE OBJECTIVES STUDY STRATEGIES AND CLASS PARTICIPATION EXPECTATIONS INSTRUCTIONAL METHODS ASSESSMENT & EVALUATION TIME ALLOCATION CLINICAL BIOCHEMISTRY DEPARTMENT STAFF LISTING DEPARTMENT WEB SITE ICONS TOPIC OUTLINES NO. LECTURES (NAMES) 01 02 03 04 05 06 07 08 VII Page 09 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 VIII NO. PRACTICAL (Names) 01 02 03 04 05 06 07 08 09 10 11 12 13 14 TUTORIALS 01 Anatomy of the Heart and Big Vessels 02 03 04 05 07 08 09 10 IX Introduction Welcome to the Department of Clinical Biochemistry. The aim of this course guide is to provide you with clear description of the course objectives, contents of each topic together with its lectures, tutorials and practicals, which are presented in a sequential manner. Also it states clearly what is expected from you to achieve together with the evaluation procedures. There is no reason to suppose that Biochemistry is intrinsically uninteresting, difficult to understand or an obstacle to be overcome during your progress to a professional qualifications. In the contrary you can enjoy its study if you remember the simple biological principals that the body is formed from organs and tissues and these are formed from aggregates of cells. The cell is build up from sub-cellular structures which by itself is an aggregate of molecules. Every human actively, like walking, breathing and even thinking are the result of the interactions of these molecules. Defective molecular processes result in disease state. Moreover Biochemistry has become a background subject for a great family of medical sciences. Understanding Biochemistry will build for you a good foundation for understanding disease states, their prevention, diagnosis and treatment. We advice you to read the objectives of each topic before the start of its lectures and focus your attention on the important points. Take another look after the end of the lecture to make sure that these points have been understood. Dr. Zainy Mohammed Abdullah Banjar Chairman, Department of Clinical Biochemistry 1 Faculty of Medicine Biochemical Basis of Medicine I COURSE DESCRIPTION AND ORGANIZATION The aim of Clinical Biochemistry II course for second year student is to introduce you to the basic concepts of structure and metabolism in relation to the mechanisms by which primary foodstuffs, proteins, carbohydrates and lipids, are manipulated by the body in order to provide energy and to allow for biosynthesis of cellular material. Also you will have a good view of storage, transmission and expression of genetic information. Clinically relevant examples will be discussed. Biochemical basis of medicine I course includes and covers the following topics: allosteric proteins, enzymes, membrane and transport, bioenergetics and oxidative metabolism, anaerobic metabolism, tricarboxylic acid cycle, carbohydrate storage and synthesis in liver and muscle, oxidative metabolism of lipid in liver and muscle, biosynthesis and storage of fatty acids, lipid and lipoproteins, and cholesterol metabolism. The course consists of lectures, practical classes and tutorials. Core Course Code/No Course Units Credit Hours Lectures Practical Tutorial 30 15 15 Biochemical Basis Of Medicine I 2 3 Faculty of Medicine Biochemical Basis of Medicine I MAJOR COURSE OBJECTIVES On completion of the course in Clinical Biochemistry I student will: 1. Evaluate the biochemical logic of the human cell. 2. Explain the maintenance of cellular life in the term of energy production and biosynthetic ability. 3. Apply biochemical knowledge to solve problems of human health and disease. 4. Practice basic skills in applying laboratory techniques encountered in hospital's clinical biochemistry laboratories. 5. Appreciate the functional role of membrane proteins as pumps, gates and channels 3 Faculty of Medicine Biochemical Basis of Medicine I STUDY STRATEGIES AND CLASS PARTICIPATION EXPECTATIONS The course offered to 2nd year medical students in clinical biochemistry consists of scheduled lectures, tutorials and practicals which ensure smooth flow of the scientific material, in a controlled manner, through several pathways to achieve our objectives. There is some suggestion for optimal utilization of these classes by the students. A. Lectures: The aim of the lecture is not to give information but to frame up the subject, pointing out its relation to other parts of the course, its relevance to clinical situations and to explain difficult points. To prepare your self for the lecture: 1. Give a thorough look to the course objectives and the topic outline delivered by the department and try to read the topic from the recommended textbook. 2. Note taking in lectures keeps the student in track during studying the subject. 3. If is recommended to study the topic of the lecture, if possible, in the same day, to prevent fading of knowledge. You can utilize different ways of self-testing in order to assess your grasping of the subject. B. Practicals: For optimal utilization of the practical class time it is advisable to: 1. Read your practical worksheet so as to have view of what is expected from you to perform, observe and draw conclusions on your practical work. 2. A record of the practicals should be used according to instructions. 3. The practical time can also be used for discussing difficult theoretical or practical points with the instructor. C. Tutorials: For optimal benefit of the tutorial, the tutorial will be reserved for open discussion about the subjects listed in the tutorial schedule. The students will be assigned these topics and will be asked to present them and be ready to change the most recent knowledge about these topics and how to defend their thoughts on scientific bases 4 Faculty of Medicine Biochemical Basis of Medicine I Instructional Methods The main instructional material includes lectures, practicals to steamline the applied and clinical aspects of the lectures and tutorials session to stimulate the students to participate in the teaching/learning activities. Instructional Materials And Resources 1. Required Texts And Resources a. Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey b. Baynes, Medical Biochemistry, Mosby, London. 2. Supplementary Texts And Resources a. Thomas M. Devlin, Textbook of Biochemistry with Clinical Correlations, Jon Willey & sons, New York. b. Lubert Stryer, Biochemistry, W.H. Freeman and Company, San Francisco. c. Pamela C. Champe, Biochemistry, Lippincott Raven. 5 Faculty of Medicine Biochemical Basis of Medicine I ASSESSMENT 1. Formative: This form of assessment is designed to give you feedback to help you to identify areas for improvement. It includes a mixture of MCQs, short answer-questions (SAQs), extended matching questions (EMQs), problems-solving exercises and independent learning activities in all subjects. These will be given during tutorial sessions and practicals. The Answers are presented and discussed immediately with you after the assessment. The results will be made available to you. 2. Summative This type of assessment is used for judgment or decisions to be made about your performance. It serves as: a. Verification of achievement for the student satisfying requirement b. Motivation of the student to maintain or improve performance c. Certification of performance d. Grades In this Course your performance will be assessed according to the following: 1. Continuous Assessment 20 Marks 2. Assignment 20 Marks 3. OSPE 20 Marks 4. Final End of Semester Exam (Two Hours) 40 Marks Total = 100 Marks 6 Faculty of Medicine Biochemical Basis of Medicine I All grades will be assigned as follows: 85 - 100 A Excellent 75 - 84 B Very good 65 - 74 C Good 60 - 64 D Pass Less than 60 F Fail Exams: Exams will include short answer and multiple choice questions (MCQs). They will cover material presented in lecture, readings, and discussion. All exams must be taken on the date scheduled. In case of an emergency, the coordinator must be notified. No make-up exams will be provided if you fail to notify and discuss your situation with the coordinator. Assignment paper: The purpose of the work is to provide you with the opportunity to explore an area of basic medical sciences or medical education in depth. The paper is to be a 10-15 page literature review of the topic will constitute 20% of your final grade. Policy: Topics must be approved in writing by the coordinator. Directions for topic submission will be discussed during the first week of class. Topics that have not been approved will not be accepted. All papers must reference a minimum of eight references from refereed journals. All papers must be typed, double-spaced, have 1 inch margins. Note: We will be making the journey from "womb to tomb" in 15 weeks. Therefore, this course requires an intensive coursework load. Class attendance and participation are extremely important to your learning and as such are considered in the evaluation of your course grade. This course is recommended for students that can make the required time and energy commitment. If there is anything that the coordinator can do to assist you during the course, please feel free to contact him. 7 Faculty of Medicine Biochemical Basis of Medicine I Time Allocations BIOCHEMICAL BASIS OF MEDICINE Topic Lecture Practical Tutorial BIOCHEMICAL BASIS OF MEDICINE I: 1. Allosteric proteins 3 1 1 2. Collagen 1 3. Catalytic proteins - Enzymes 7 3 4 3. Membrane and transport 2 4- Cellular transduction 1 5. Introduction to Metabolism, Bioenergetics, 2 1 1 6. Glycolysis 2 1 1 7. The tricarboxylic acid cycle 1 1 1 8. Gluconeogenesis 1 1 1 9. Glycogen metabolism 2 1 1 10. Pentose phosphate pathway 1 1 11. Metabolism of Monosaccharides and Disaccharides 1 1 12. Fatty acid oxidation 1 1 13. Fatty acid synthesis 1 1 1 14. Lipogenesis 2 1 1 15. Ketone bodies metabolism 1 1 1 16. Lipolysis 1 and the Role of ATP Total 8 30 1 1 15 15 Faculty of Medicine Biochemical Basis of Medicine I CLINICAL BIOCHEMISTRY DEPARTMENT STAFF LISTING The following is a list of the faculty members and staff of the Department of Clinical Biochemistry. Students are welcome to contact any of the members of the department to answer any of their inquiries. Male Section: Men Medical Complex Name/Status Room No Phone No Dr. Zainy M. A. Banjar 2/945 51-048, 22-116 B.Pharm., M.Sc., Ph.D. 2/948 22-101, 22-176 E-Mail Address [email protected] Office Hours Daily 11.00-12.00 Associate Professor Chairman Prof. Adil Abdel Rafee 2/946 22-112, 22-194 M.B., B.ch., D.M.Sc.,Ph.D. 2/924 22-102, 22-173 [email protected] Daily 12.00-1.00 Professor Prof. Mohammed Ali Ajabnoor 2/942 22-100, 22-174 [email protected] B.Pharm.,M.S., Ph.D. Sat, Mon, Wed 1.00-2.00 Professor Prof. Mohammed Saleh Ardawi 2/925 22-103, 22-177 [email protected] B.Med. Sc., M.A., Ph.D. Professor Prof. Zohair M. H. Marzouki B.Pharm., M.Sc., Ph.D. G/640 51-701 zmarzouki@ Kau .edu .sa 12.00-1.00 2/853 22-099, 22-170 Professor Prof. Abdulwahab A. Noorwali Daily Dean Off., Faculty of Pharmacy 2/911 22-097, 22-172 [email protected] 2/852 22-098, 22-169 [email protected] B. Phar., Ph.D. Professor Prof. Mohammed Zelai A. Abdu B.Sc., M.Sc., Ph.D. Associate Professor Sat, Sun, Mon 1.00-2.00 9 Faculty of Medicine Biochemical Basis of Medicine I drmamdouhyoussef Prof. Mamdouh Youssef Souaida 2/940 Sat, Sun, Mon 22-128 @yahoo.com M.B.ch., M.Sc.,Ph.D. Associate Professor Dr Osama Abdul Aziz M.B., B.ch., M.D. 1.00-2.00 2/910 22-096 2/941 22-118 [email protected] Daily 8.00-10.00 mohammedhassanien700 Daily @hotmail.com WWW.kaau.edu. 8.00-10.00 Associate Professor Dr Mohammed A Hassanien M.B., B.ch., M.D. sa/mhassanien Assistant Professor Dr. Mohammed Shoaib Jarullah B.Sc., M.Sc., Ph.D. 2/912 22-130 Lab 22-120, 22-121 2/914 22-129 Lab 22-120, 22-121 2/922 22-117 Lab 22-120, 22-121 [email protected] Technician Mr. Khalil Fadul Al-Moula B.Sc. Technician. Mr. Ahmad Al-Shamrani B.Sc. Technician 10 [email protected] Faculty of Medicine Biochemical Basis of Medicine I Female Section: Women Medical Complex Name/Status Prof Suhad Matoug Bahijri B.Sc.,M.Sc., Ph.D. Professor Prof Enayat Mohd. Hashem M.B., B.ch., h.D. Professor Dr Amina Mohd. Al-Ghareeb M.B., B.ch., h.D. Associate Professor Dr Huda Gad M.B., B.ch., h.D. Assistant Professor Dr. Eman Mokbel Alissa(BSc MSc PhD) Assistant Professor Dr. Fayza F Al Fayez (BSc MSc PhD ) Assistant Professor Ms. Areej Al-Turki B.Sc. Technician. Zain Mohd.AL-Shareef B.Sc. Technician. Hana Abdullah Basaffar B.Sc. Technician. Rehab Aboobakar Al-Aydoos B.Sc. Technician. Nada Saleh Al-Saykhan B.Sc. Technician. Reem Foad Ghazali B.Sc. Technician. Room No 2/510 Phone No E-Mail Address 23-429 [email protected] 2/513 23-441 [email protected] 2/551 23-448 [email protected] 2/550 23-447 [email protected] Office Hours [email protected] 23-432 Webpage: www.kau.edu.sa/ealissa 23-431 [email protected] 2/514 23-442 [email protected] 2/613 23-433 2/620 23-436 2/618 23-437 [email protected] 2/618 23-437 [email protected] 2/622 23-601 [email protected] Department Web Site www.kau.edu.sa/faculties/medicine/dcbcweb 11 Faculty of Medicine Biochemical Basis of Medicine I Icons The following icons have been used to help you identify the various experiences you will be exposed to. Learning objectives Content of the lecture Independent learning from textbooks Independent learning from the CD-ROM. Independent learning from the Internet Home Work Problem-Based Learning Self- Assessment (the answer to self-assessment exercises will be discussed in tutorial sessions) The main concepts 12 Faculty of Medicine Biochemical Basis of Medicine I Lectures 13 Faculty of Medicine Biochemical Basis of Medicine I Lectures # (1-3) : Allosteric protein Student Notes: . DEPARTMENT: Clinical Biochemistry Tutor: Dr. TEACHING LOCATION: Auditorium By the end of this lecture, you will be able to: 1. Relate the structural properties of particular proteins such as hemoglobin and myoglobin to their functions in human health and disease. 2. Discuss the genetic bases of protein structure and how molecular defects lead to diseases such as sickle cell anemia. 3. Be able to recognize the structure of the commonly found amino acids in specific proteins and explain the their importance. • Hemoglobin: • Quaternary structure of hemoglobin, cooperative binding of oxygen, effect of hydrogen ion and carbon dioxide (Bohr effect) • Functional significance of DPG, fetal hemoglobin, abnormal hemoglobin, (sickle cell anemia). • Myoglobin: • Globular proteins, myoglobin configuration and conformation. 14 Faculty of Medicine Biochemical Basis of Medicine I • Oxygen binding site. • Microenvironment and reversible oxygen binding. Myoglobin and hemoglobin are two oxygen – binding proteins with a very similar primary structure. However, myoglobin is a globular protein composed of a single polypeptide chain that has one O2 binding site. Hemoglobin is a tetramer composed of two different types of subunits. Each subunit has a strong sequence homology to myoglobin and contains an O2 binding site. A comparison between myoglobin and hemoglobin illustrates some of the advantages of a multisubuniut quaternary structure. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P : 25 - 42 2. Reading Handouts will be distributed 3- Lectures and power point presentation will be published on department website: www.kaau.edu.sa/faculties/medicine/dcbcweb • • • You have the opportunity to watch the CDROM about Hemoglobin. You can access the CD-ROM during your spare time. 15 Faculty of Medicine Biochemical Basis of Medicine I 1- Haemoglobin http://www.ebi.ac.uk/interpro/potm/2005_10/Page1.h 2- Haemoglobin http://www.iscid.org/encyclopedia/Haemoglobin 3- Haemoglobin animations http://www.umass.edu/microbio/chime/hemoglob/2fr t.htm 4- Oxygen dissociation curve http://www.bio.davidson.edu/Courses/anphys/1999/D s/Oxygendissociation.htm 5- Oxygen dissociation curve 2 http://www.ventworld.com/resources/oxydisso/dissoc 6- Haemoglobin dissociation curve 3 http://www.manbit.com/Hbdiss.htm 7- Carbon dioxide and Oxygen transport http://cal.man.ac.uk/student_projects/2001/MNQC7N omepage.htm 1- In a table form compare between Hemoglobin and Myoglobin including the difference in the : Structure, Function, Oxygen binding and Oxygen dissociation curve. Clinical Question A 67 – year old man presented to the emergency department with one week history of angina and shortness of breath. He complained that his face and extremities had a "blue color" . His medical history included chronic stable angina trated with isosorbide dinitrate and nitroglycerin. Blood obtained for analysis was chocolate – colored. What is the possible diagnosis 16 Faculty of Medicine Biochemical Basis of Medicine I I- Short Questions: a- What of the effects of the following on oxygen dissociation curve of Hemoglobin 1- 2,3 – BPG 2- CO2 3- pH b- What is the molecular defect which leads to the following? 1- Sickle cell disease 2- Methemoglobinemia 3- Thalassemias II- MCQ: 1- Hemoglobin is A. A tetramer of 4 myoglobin proteins. B. A tetramer of four globin chains and one heme prosthetic group. C. A dimer of subunits each with two distinct protein chains (alpha and beta). D. A dimer of subunits each with two myoglobin proteins. 2- Hydrophobic amino acid sequences in myoglobin are responsible for A. Covalent bonding to the heme prosthetic group B. The folding of the polypeptide chain C. The reversible binding of oxygen D. b and c above 3- Cooperative binding of oxygen by hemoglobin A. Is induced by hemoglobin B. Is a result of different affinities for oxygen by each subunit protein C. Is induced by oxygenation D. Is a result of interaction with myoglobin 17 Faculty of Medicine Biochemical Basis of Medicine I III- True / False a. Proteins often consist of multiple subunits so that they may have different functions under different conditions. b. The porphyrin prosthetic group is held into the interior of globin molecules by covalent bonds to specific amino acid residues c. Myoglobin has a greater affinity for oxygen than hemoglobin. d. Cooperative binding and allosterism of hemoglobin allow oxygen to be unloaded at low partial pressures of oxygen in the tissues. e. The Bohr effect is a description of the effect of pH on hemoglobin, oxygen bound more tightly at f. low pH (in tissues) and less tightly at higher pH values. 18 Faculty of Medicine Biochemical Basis of Medicine I Lecture #(4) : Collagen DEPARTMENT: Clinical Biochemistry Tutor: Dr. TEACHING LOCATION: Auditorium By the end of this topic the student shall be able to: 1. Understand the role of the extracellular matrix 2. Understand the components of the extracellular matrix 3. Understand the structure and synthesis of collagen fibers • Collagen. • Synthesis and post-translational modification of collagens. • Noncollagenous proteins extracellular matrix. in the Collagen is on of the components of the extracellular matrix (ECM), which present outside of the cell. This matrix, even from a basic list of its components; proteins, glycoproteins, glycosaminoglycans, and many other large and small biological molecules, can 19 Faculty of Medicine Biochemical Basis of Medicine I been seen as complex. Furthermore there is no one specific ECM with great variation from tissue to tissue and also specific functional specializations. This lecture will attempt therefore to only cover a Collagen as a part of ECM. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P : 2. Reading Handouts will be distributed 3- Lectures and power point presentation will be published on department website: www.kaau.edu.sa/faculties/medicine/dcbcweb • • • You have the opportunity to watch the CDROM about Collagen You can access the CDROM during your spare time. 1-Extracellular matrix (Collagen)1 http://cellbiology.med.unsw.edu.au/units/science/l e0508.htm 2 –Extracellular matrix (Collagen) 2 http://cellbiology.med.unsw.edu.au/units/pdf/anat L8s4.pdf 3-Extracellular Matrix lecture http://www.owlnet.rice.edu/~bioc341/notes/lec23.p Do the proline side groups (rings) point inward (to the center of the axis of the triple helix), or do they point out? You can change the "display" to "backbone" then back to "sticks" to see where the side groups of proline are. 20 Faculty of Medicine Biochemical Basis of Medicine I 1- Explain how collagen structure serves its function in different body tissues I- Short Questions: 1- How many amino acid chains are present in this model of collagen? 2- Of the 20 possible amino acids, how many are present in this model of collagen? 3- What is the repeating pattern of these amino acids? II- MCQ: 1- Substitution of Gly in the primary sequence of collagen with almost any other amino acid results in defective collagen assembly because: A. collagen is glycosylated on Gly residues. B. Gly forms critical hydrogen bonds with neighboring glycines. C. the contact points of the triple helix are so close that only the Gly side chain fits well into the space available. D. Gly is crosslinked to allysine residues in the mature protein. 2- The collagen defect present in scurvy is A. substitution of gly for pro and lys residues in the collagen sequence. B. decreased protein stability due to decreased hydroxylation of pro and lys residues. C. conversion of the collagen helix from a right- to a left-handed triple supercoil. D. decreased protein stability due to increased glycosylation. 21 Faculty of Medicine Biochemical Basis of Medicine I III- True / False a- Ascorbic acid is necessary for the formation of hydroxyproline and hydroxylysine residues before they are incorporated into the collagen protein molecule. b- All collagen types have a triple helical structure. c- In Collagen molecules, Hydroxyproline is formed by the posttranslational hydroxylation of peptide-bound proline residues catalyzed by the enzyme prolyl transferase. 22 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (5) : Introduction to the enzymes DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1. Summarize the importance of enzymes in many aspects in health and disease 2. Describe general properties of enzyme molecule and the process of enzyme catalysis 3. Define terms used in enzymology 4. Compare and contrast between enzymes and inorganic catalysts 5. Identify the nomenclature of enzymes 6. Outline the classification of enzymes 7. Distinguish the different types of enzyme specificity • Enzymes are important for medical students for diagnosis and treatment • Enzymes are typically large globular proteins that accelerate reactions by million folds 23 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I • Substrate, product, apoenzyme, holoenzyme, cofactor, coenzyme, active site and catalytic site, all are terms used in study of enzymes • There are many differences between enzymes and inorganic catalysts as reversibility and specificity of enzyme action • Naming of enzymes is either convenient for everyday use, or more complete systematic name divided into six major classes • Enzyme specificity are absolute, relative, stereochemical and group Remember that all reactions in the body are mediated by enzymes, which are protein catalysts that increase the rate of reactions without being changed in the overall process. Enzymology is important as inborn errors of metabolism are due to deficiency of some enzymes. Also assay of particular enzymes can help in diagnosis of many diseases. The most striking characteristics of enzymes are their catalytic power and specificity which is of many types. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey , chapter 27 ( pp:365-367) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. Chapter 18 (pp:217-218) • 24 Faculty of Medicine Biochemical Basis of Medicine I • • You have the opportunity to watch the CDROM about enzymes. You can access the CD-ROM during your spare time. 1- http://web.indstate.edu/thcme/mwkin g/enzyme-kinetics.html 2- http://www.stolaf.edu/people/qiannin i/fashanimat/enzymes 3- http:// www.reachoutmichigan.org/funexpe riments/quick/eric/enzymes 4- http://www.pubmedcentral.nih.gov/a rticlerender.fcgi?artid 5- http://www.ncbi.nlm.nih.ov/entrez/qu ery/fcgi?cmd 6- http://www.wiley.com/legacy/college/ boyer/0470003790 7- http:/www.siu.edu/departments/bioc hem/som_pbl/ms_ppt_anim.html 8- http://www.lewport.wnyric.org/wana maker/animations/Enzymes%20activ ity. ** Enzymes are biological catalysts that accelerate the rate of reaction, by using the library and the internet try to explain how this occurs. Clinical Case: A 52-year-old-man presented at ER of a hospital with severe chest pain which had present for the past hour. He had 25 Faculty of Medicine Biochemical Basis of Medicine I a 2-year history of angina of efforts. How can you use enzymes in?: a. Diagnosis of this case b. Treatment of it I- Short Questions: 1- Enumerate enzyme specificity 2- Differentiate between enzymes and inorganic catalysts II- MCQ: 1.Enzymes are: a) Proteins b) Chloroplasts c) Genes d) Mitochondria 2. Enzymes are catalysts. They increase the rate of chemical reactions by: a) Raising the activation energy b) Temporarily increasing the temperature c) Covalently binding the substrate d) Lowering the activation energy 3. Enzymes are classified by the: a) Size of the enzyme b) Size of the substrate c) Type of reaction d) Rate of reaction 4. Shown below is a graph describing energy versus reaction coordinate for a catalyzed and uncatalyzed reaction. Fill in the blanks with the letter that corresponds to each stage of the graph. 26 Faculty of Medicine Biochemical Basis of Medicine I _____ ES _____ S (substrate) _____ P (product) _____ Uncatalyzed reaction III- Complete the following: Some enzymes require another chemical to function. These helper compounds are called __________. If a cofactor is covalently bound to the enzyme, it is called a __________ group. An enzyme with its cofactor attached is called a __________, while an enzyme minus its extra component is called an __________. 27 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (6) : Mechanism of enzymatic catalysis DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1. Describe the two models of binding the enzyme to its substrate 2. Identify what is meant by transition state 3. Understand the difference between ∆G and ∆G‡ 4. Explain the mechanism of enzymatic catalysis by acid-base catalysis, covalent catalysis, substrate strain and entropy effect • Two models have been proposed to explain how an enzyme binds its substrate; lock-and-key model and induced-fit model • Lock-and-key model assumes that an enzyme active site will accept a specific substrate • Induced-fit model recognizes that there is much flexibility in an enzyme’s substrate . Accordingly, an enzyme is able to conform to a 28 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I substrate • Transition state is state of maximum energy through which the enzymatic reaction proceeds. It is not an intermediate compound. • The differences in free energy (∆G) between the transition state and substrate is the free energy of activation (∆G‡) • Enzyme can enhance the rate of reaction by four processes: general/acid base catalysis, covalent catalysis, substrate strain and entropy effect When correctly positioned and bound on the enzyme surface, the substrate may be “strained” toward the transition state. At this point the substrate has been “set up” for acid-base and/or covalent catalysis. Proper and the nearness of the substrate with respect to the catalytic groups (proximity effect) contribute to decrease in entropy and so enhance the rate of enzymatic reaction. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey , chapter 27 ( pp:365-367) 2.Supplementary Texts And Resources: Medical Biochemistry, Baynes and st Dominiczek, 1 edition, Mosby. Chapter 18 (pp:217-218) • • • You have the opportunity to watch the CDROM about enzymes. You can access the CD-ROM during your spare time. 29 Faculty of Medicine Biochemical Basis of Medicine I 1http://web.indstate.edu/thcme/mwking/e nzyme-kinetics.html 2http://www.stolaf.edu/people/qiannini/fash animat/enzymes 3- http:// www.reachoutmichigan.org/funexperiment s/quick/eric/enzymes 4http://www.pubmedcentral.nih.gov/articler ender.fcgi?artid 5http://www.ncbi.nlm.nih.ov/entrez/query/ fcgi?cmd 6http://www.wiley.com/legacy/college/boy er/0470003790 7http:/www.siu.edu/departments/biochem/s om_pbl/ms_ppt_anim.html 8http://www.lewport.wnyric.org/wanamaker/ animations/Enzymes%20activity 9http://www.bio.winona.edu/berg/308/oldex am/308exam1.txt ** How does the enzyme bind its substrate? By using the library and the internet try to answer this question. I- Short Questions: 1. What is meant by transition state 30 Faculty of Medicine Biochemical Basis of Medicine I 2. Enzymes can enhance the rate of reaction. Enumerate the processes by which this occurs. II- MCQ: 1. The minimum amount of energy necessary for a molecule(s) to react is the: a) Activation energy b) Free energy c) Thermal energy d) Potential energy 2. The state produced when two or more molecules collide with just the right energy and just the right orientation so that a chemical reaction might occur is: a) Catalytic state b) Transition state c) Activation state d) Transient state 3. One of the following statement describing the mechanism of enzyme action is INCORRECT: a) Many enzymes have flexible structures that allow them to enfold their substrate b) The substrate is often distorted when it enters an enzyme-substrate complex c) Amino acid side chains involved in the formation of the active site center are usually close together in the amino acid sequence of the enzyme protein d) Amino acid side chain near the active site center often have a role in the catalytic process 4.Which of the following statement about enzyme catalyzed reaction is NOT TRUE: a) Enzymes form complexes with their substrate b) Enzymes increase the activation energy for chemical reaction c) Many enzymes change shape slightly when substrate binds d) Reactions occur at the “active site” of enzymes, where a precise quaternary orientation of amino acids is an important feature of catalysis 31 Faculty of Medicine Biochemical Basis of Medicine I III- Complete the following: Enzymes carry out different chemical reactions in catalysis. Fill in the blanks with the name of the mechanism that matches with the example described in each line. Mechanism names to choose from are: covalent catalysis, acid-base catalysis, and metal ion catalysis. __________ catalysis may involve Glu, Asp, His, Lys, or Arg residues. __________ catalysis may involve Na+, K+ or Mg2+, Ca2+. __________ catalysis may involve serine proteases. 32 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (7) : Enzyme kinetics DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1. Distinguish the several terms used in enzyme kinetics as rate or velocity, rate constant, order of a reaction, turnover number ..etc 2. Identify Michaelis-Menten equation and Linweaver-Burk equation 3. Recognize the factors affecting enzyme activity as substrate concentration, pH and temperature • The enzyme (E) combines with its substrate (S) to form an enzymesubstrate complex (ES). • The ES complex can dissociate again to form E + S, or can proceed chemically to form E and the product P. • The rate constants k1, k2 and k3 describe the rates associated with each step of the catalytic process. 33 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I • The initial velocity (Vo) at low substrate concentration is directly proportional to [S], while at high substrate concentration the velocity tends towards a maximum value (Vmax) which is independent of [S]. • Michaelis-Menten equation describes a “hyperbolic curve” of the relationship between [S] and velocity of the reaction • Lineweaver-Burk plot (double reciprocal plot) gives a straight line if Vo is measured at different substrate concentration • Not only substrate concentration , but also pH and temperature can affect enzymatic activity • Kinetics is a study of the rate of changes of substrates to products. Kinetics properties for many enzymes reveals that, the rate of catalysis V varies with [S] in a hyperbolic manner which is expressed in Michaelis-Menten equation. Lineweaver-Burk plot gives a straight line of relationship between [S] and the rate of reaction.. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey , chapter 27 ( pp:365-367) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. Chapter 18 (pp:217-218) • • • You have the opportunity to watch the CDROM about enzymes. You can access the CD-ROM during your spare time. 34 Faculty of Medicine Biochemical Basis of Medicine I 1.http://web.indstate.edu/thcme/mwking /enzyme-kinetics 2.htmlhttp://www.stolaf.edu/people/qian nini/fashanimat/enzymes 3.http:// www.reachoutmichigan.org/funexperim ents/quick/eric/enzymes 4.http://www.pubmedcentral.nih.gov/art iclerender.fcgi?artid 5.http://www.ncbi.nlm.nih.ov/entrez/que ry/fcgi?cmd 6.http://www.wiley.com/legacy/college/ boyer/0470003790 7.http:/www.siu.edu/departments/bioch em/som_pbl/ms_ppt_anim.html 8. http://www.lewport.wnyric.org/wanama ker/animations/Enzymes%20activity. By using the library and the internet try to illustrate the relationship between substrate concentration and reaction velocity. I- Short Questions: a) Would you think that all enzyme assays need the same pH? Why? b) What is the meaning of optimum temperature? II- MCQ: 1. Which of the following does not influence enzyme activity? a) pH b) Temperature c) Product degradation d) Substrate concentration 35 Faculty of Medicine Biochemical Basis of Medicine I 2. The Michaelis constant Km is: a) Numerically equal to ½ Vmax b) Dependent on the enzyme concentration c) Independent on pH d) Numerically equal to the substrate concentration that gives half-maximal velocity What effect does temperature have on enzymes? a) Boiling will denature them, as will being too cold b) Boiling will not harm them, but being too cold will denature them c) Boiling and cooling will both reduce the speed of their rate d) Boiling will denature them, but cooling will only slow down their work 4. The Michaelis-Menten equation is Vo=Vmax [S]/(Km+[S]). Fill in the blanks with the letters shown to correctly label each part of the graph _____ Vmax _____ [S] _____ Vo _____ Point used to determine the Km III- Complete the following: Often the kinetic values of an enzyme are plotted using the Lineweaver-Burk equation: 1/vo=Km/Vmax·1/[S] +1/Vmax Enter "yes" or "no" to indicate if the equation and graphical terms match in each statement. _____ Y-intercept and -1/Km _____ X-intercept and 1/Vmax _____ Slope and Km/Vmax 36 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (8) : Enzyme inhibitors DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1. Outline the importance of enzyme inhibition studies 2. Discriminate the two broad classes of enzyme inhibitors that based on the extent of inhibition 3. Compare the mechanisms of enzyme inhibition 4. Interpret the use of enzyme inhibition as drugs in the treatment of diseases • There are two broad classes of enzyme inhibitors: reversible and irreversible • Reversible inhibitors interact with an enzyme via noncovalent association • Irreversible inhibitors interact with an enzyme via covalent association • Competitive inhibitors binds only to enzyme (E) and not to enzymesubstrate complex (ES) • Noncompetitive inhibitors binds either to (E) and/or to (ES) • Uncompetitive inhibitors binds only 37 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I to (ES) and not to (E) • Enzyme inhibition may affect Vmax or Km or both • Many natural occurring and manmade compounds are irreversible enzyme inhibitors • There are therapeutic application for enzyme inhibition A competitive inhibitor prevents the substrate from binding to its enzyme, while noncompetitive or uncompetitive do not. Competitive inhibitor increases Km without change Vmax. Noncompetitive inhibitor decreases Vmax without change in Km. But uncompetitive inhibitor decreases both Vmax and Km . 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey , chapter 27 ( pp:365-367) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and st Dominiczek, 1 edition, Mosby. Chapter 18 (pp:217-218) • • • You have the opportunity to watch the CDROM about enzymes. You can access the CD-ROM during your spare time. 1http://web.indstate.edu/thcme/mwking/e nzyme-kinetics.html 2http://www.stolaf.edu/people/qiannini/fa 38 Faculty of Medicine Biochemical Basis of Medicine I shanimat/enzymes 3- http:// www.reachoutmichigan.org/funexperime nts/quick/eric/enzymes 4http://www.pubmedcentral.nih.gov/articl erender.fcgi?artid 5http://www.ncbi.nlm.nih.ov/entrez/query/ fcgi?cmd 6http://www.wiley.com/legacy/college/boy er/0470003790 7http:/www.siu.edu/departments/biochem /som_pbl/ms_ppt_anim.html 8http://www.lewport.wnyric.org/wanamak er/animations/Enzymes%20activity. **How can the irreversible inhibitors bind the active site of the enzyme? By using the library and the internet try to explain how this occurs. Clinical Case: A young girl was brought to the pediatric clinic with infected wound on her knee. The mother was instructed to give the child penicillin. The child had improved after a week. a) What the possible mechanism of action of this antibiotic? b) What is the target enzyme of penicillin? I- Short Questions: 1. Classify enzyme inhibitors 2. Tabulate the effect of competitive, 39 Faculty of Medicine Biochemical Basis of Medicine I noncompetitive and uncompetitive on Vmax and Km II- MCQ: 1. Which type of reversible enzyme inhibitor binds to the free enzyme and the enzymesubstrate complex? a) Noncompetititive b) Competitive c) Uncompetitive d) None of the above 2. In competitive inhibition, one of the following statement is CORRECT: a) Vmax is increased b) The concentration of active enzyme molecule is unchanged c) The apparent Km is increased d) The apparent Km is decreased 3. Enzyme action can be influenced by the presence of inhibitors. Which of the following statements correctly matches the type of inhibitor with its effect on an enzyme. a) Irreversible and Renders the enzyme permanently inactive b) Competitive and Inhibitor binds only to ES complex, only important when[S] high, Vmax lower, Km lower c) Noncompetitive and Can be overcome with high [S], Vmax unchanged, Km higher d) Uncompetitive and Cannot be overcome with high[S], Vmax lower, but Km unchanged 4. In Lineweaver-Burk plot below: a) Mention the type of inhibition of enzymatic reaction b) Which one of the lines of the plot represents the enzymatic reaction without inhibition? 40 Faculty of Medicine Biochemical Basis of Medicine I III- Complete the following: Any molecule that acts directly on an enzyme to lower its catalytic rate is called ---------. Enzyme inhibition may be of --------types. Reversible inhibition can be overcome by-----but this is not possible for ----------inhibition. 41 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (9) : Enzyme regulation DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to 1. Integrate enzymes into metabolic pathways 2. Identify the terms of the rate-limiting enzyme and the committed step in a metabolic pathway 3. Know the different ways of enzyme regulation under physiological and pathological conditions 4. Recognize the allosteric regulation 5. Explain a feedback control mechanism • There are key enzymes in a metabolic pathway which can be regulated and hence control the pathway • The activity of these enzymes can be regulated by: • Changing the amount of enzyme by enzyme induction, enzyme repression, and enzyme degradation • Changing the activity of enzyme by allosteric regulation, feedback control, 42 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I covalent modification, and activation by cleavage • Compartmentation of pathways is also a way of enzyme regulation Control of a pathway occurs through modulation of the activity of one or more key enzymes in the pathway . The rate-limiting enzyme and the committed step enzyme can be regulated by changing the amount (enzyme induction, repression, or degradation), or changing the activity (allosteric regulation, feedback inhibition, covalent modification, or enzyme cleavage) or compartmentation of the pathways. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey , chapter 27 ( pp:365-367) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. Chapter 18 (pp:217-218) • • • You have the opportunity to watch the CDROM about enzymes. You can access the CD-ROM during your spare time. 1http://web.indstate.edu/thcme/mwking/e nzyme-kinetics.html 2http://www.stolaf.edu/people/qiannini/fa shanimat/enzymes 3- http:// www.reachoutmichigan.org/funexperime 43 Faculty of Medicine Biochemical Basis of Medicine I nts/quick/eric/enzymes 4http://www.pubmedcentral.nih.gov/articl erender.fcgi?artid 5http://www.ncbi.nlm.nih.ov/entrez/query/ fcgi?cmd 6http://www.wiley.com/legacy/college/boy er/0470003790 7http:/www.siu.edu/departments/biochem /som_pbl/ms_ppt_anim.html 8http://www.lewport.wnyric.org/wanamak er/animations/Enzymes%20activity. 9- en.wikipedia.org/wik/Enzymes 10.www.elmhurst.edu/~chm/vchembook/ 573 regulate ** By using the library and the internet try to illustrate covalent modification of an enzyme (e.g. glycogen phosphorylase) II- Short Questions: 1. List some of the molecular mechanisms by which the catalytic activity of enzymes is controlled. 2. Using a graph, illustrate the kinetic behavior of an allosteric enzyme II- MCQ: 1. Allosteric enzymes are large, oligomeric proteins that have catalytic sites for binding substrates and regulatory sites that bind effectors. The separate oligomers influence one another; they work cooperatively. This is evidenced by the characteristic rate curves for allosteric enzymes which have: a) Michaelis-Menten kinetics b) Hyperbolic kinetics c) Sigmoidal kinetics 44 Faculty of Medicine Biochemical Basis of Medicine I d) Regulatory kinetics 2. Some enzymes are first synthesized in an inactive form. These zymogens must undergo proteolytic cleavage to produce the active enzyme. Which of the following statements are true of proteolytic cleavage? a) It is reversible b) It is irreversible c) It is random d) It occurs in the region of zymogen synthesis 3. Increased synthesis of an enzyme is known as: a) Activation b) Inhibition c) Induction d) Repression 4. In the graph below a) Which one of the plot explains the behavior of an allosteric enzyme? b) What is the meaning of cooperativity? III- Complete the following: The rate- limiting enzyme in a pathway is the enzyme with the-------Vmax, while the enzyme catalyzing the committed step is -----------. 45 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (10) : Coenzymes and cofactors DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1. Recognize the importance of cofactors and coenzymes for the enzymes 2. Identify vitamin-derived coenzymes 3. Distinguish some coenzymes that are synthesized from common metabolites 4. Relate classes and groups of enzymes to some coenzymes • Cofactors are required by inactive apoenzymes to convert them into active holoenzymes • Cofactors may be metal ions or organic compounds (coenzymes) • Coenzymes may be freely dissociate from the enzyme, or may remain bound to its apoenzyme • Metabolite coenzyme are Sadenosyl methionine, UDP46 Student Notes: . Faculty of Medicine glucose • Vitamin-derived are NAD, NADP, TPP, PLP, CoA • Some coenzymes from fat-soluble vitamin K Biochemical Basis of Medicine I coenzymes FAD, FMN, are derived vitamin as Biological oxidation-reduction reactions need certain hydrogen carriers as NAD, NADP, and FAD. Some transaminases need PLP, transacylases need CoA , transmethylases require SAM, and transketolases need TPP. Biotin is required for certain carboxylases, while THF is needed for transfer of one carbon moiety. Vitamin K is needed for carboxylation of glutamate residue in prothrombin. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey , chapter 27 ( pp:365-367) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. Chapter 18 (pp:217-218) • • • You have the opportunity to watch the CDROM about enzymes. You can access the CD-ROM during your spare time. 47 Faculty of Medicine Biochemical Basis of Medicine I 1http://web.indstate.edu/thcme/mwking/e nzyme-kinetics.html 2http://www.stolaf.edu/people/qiannini/fa shanimat/enzymes 3- http:// www.reachoutmichigan.org/funexperime nts/quick/eric/enzymes 4http://www.pubmedcentral.nih.gov/articl erender.fcgi?artid 5http://www.ncbi.nlm.nih.ov/entrez/query/ fcgi?cmd 6http://www.wiley.com/legacy/college/boy er/0470003790 7http:/www.siu.edu/departments/biochem /som_pbl/ms_ppt_anim.html 8http://www.lewport.wnyric.org/wanamak er/animations/Enzymes%20activity. ** By using the library and the internet try to illustrate the active part in each of the following coenzymes: NAD, FAD, TPP, CoA, PLP and THF Clinical Case: A 37-year-old man had developed enlarged liver that was tender to palpation. AST in serum and total plasma bilirubin were found to be elevated. A diagnosis of 48 Faculty of Medicine Biochemical Basis of Medicine I hepatitis was made. a) What is the coenzyme needed for AST? b) Mention two other enzymes that need this coenzyme. I- Short Questions: 1. Mention the coenzyme needed for each of the following: carboxylases, transaminases, transmethylases, and transacyalses 2. Give examples of some metal ions that are cofactors and mention the enzyme of each. II- MCQ: 1. Many enzymes require cofactors to function. Many of these cofactors are vitamins. Which of the following statements is NOT TRUE? a) Fe, Zn, Cu, Mg, Mn, K, and Mo are classified as vitamins b) Humans have lost the ability to synthesize vitamins c) Vitamins are modified by the body to form coenzymes d) There are two classes of vitamins: water-soluble and fat-soluble 2. From which of the following vitamins, a coenzyme of transketolases is derived ?: a) Vitamin B1 b) Vitamin B2 c) Vitamin B6 d) Vitamin B12 3. A coenzyme derived from Niacin is: a) FAD b) NAD c) CoASH d) PLP 4. Shown below is a coenzyme acts as a 49 Faculty of Medicine Biochemical Basis of Medicine I hydrogen carrier a) Give the full name of it b) What is the name of the vitamin that is derived from? c) How can this coenzyme carry hydrogen atoms? III- Complete the following: Some enzymes require another chemical to function. These helper compounds are called cofactors. Cofactors may be_____, or__________. Examples of vitamin-derived coenzymes are:_____,________, and________. Metabolitederived coenzymes include________and_________ 50 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (11) : Enzymes in clinical practice DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1. Evaluate the use of enzymes and isoenzymes in the diagnosis of diseases 2. Know the use of enzymes in treatment of some diseases 3. Recognize the ribozymes and catalytic antibodies 4. Identify the site-directed mutagenesis • Enzymes are used clinically in three principal ways: - in diagnosis and prognosis of various disease - as analytical reagents in the measurement of activity of other enzyme or non-enzyme substances - as therapeutic agents • RNA enzymes (hammerhead ribozymes) and catalytic antibodies are recently discovered • Site-directed mutagenesis is used for design a new drug therapy 51 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I Isoenzymes are forms of an enzyme which are structurally different but have similar catalytic properties. Measurements of the isoenzymes of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and creatine kinase (CK) are of clinical value. Studies have shown that catalysis for biochemical reactions are not limited to naturally occurring proteins. Sitedirected mutagenesis (modification of amino acid sequence of known enzymes) is used for design new drug therapy. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey , chapter 27 ( pp:365-367) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. Chapter 18 (pp:217-218) • • • You have the opportunity to watch the CDROM about enzymes. You can access the CD-ROM during your spare time. 1http://web.indstate.edu/thcme/mwking/ enzyme-kinetics.html 2http://www.stolaf.edu/people/qiannini/f ashanimat/enzymes 3- http:// 52 Faculty of Medicine Biochemical Basis of Medicine I www.reachoutmichigan.org/funexperi ments/quick/eric/enzymes 4http://www.pubmedcentral.nih.gov/arti clerender.fcgi?artid 5http://www.ncbi.nlm.nih.ov/entrez/quer y/fcgi?cmd 6http://www.wiley.com/legacy/college/b oyer/0470003790 7http:/www.siu.edu/departments/bioche m/som_pbl/ms_ppt_anim.html 8http://www.lewport.wnyric.org/wanama ker/animations/Enzymes%20activity. 9www.dcnutrition.com/Miscellaneous/D etail **It was believed that all enzymes were proteins till a recent discovery , by using the library and the internet try to explain this statement. Clinical Case: A 52-year-old-man presented at ER of a hospital with severe chest pain which had present for the past hour. He had a 2-year history of angina of efforts. a) What specific tests would you request from the biochemistry laboratory? b) How can use of an enzyme share in the treatment of this condition? I- Short Questions: 53 Faculty of Medicine Biochemical Basis of Medicine I 1. Enumerate five enzymes used in clinical diagnosis and mention the major diagnostic use for each 2. What are the causes of presence of non-plasma specific enzymes? II- MCQ: 1. In normal blood, the alkaline phosphatase activ mainly from: a) Bone and small intestine b) Bone and liver c) Small intestine and placenta d) Bone and placenta 2. How many different isoenzymes of normal LDH can be identified by electrophoresis at pH 8.6 a) Two b) Three c) Four d) Five 3. LDH assays are useful in diagnosing diseases of the: a) Heart b) Pancreas c) Liver d) a and c 54 Faculty of Medicine Biochemical Basis of Medicine I Lectures # ( 12 ) : Membrane Structure DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this topic the you will be able to: 1. Comprehend the fluid mosaic model of biologic membrane. 2. Understand how change in membrane composition changes its function. Chemical compositions of membranes: • Separation of cells and intracellular organells into different chemical compartments by membranes. • Lipids of membranes. • Distribution of membrane lipids. • Membrane proteins. • Carbohydrates of membranes. Molecular structure of membranes: • The fluid mosaic model of biologic membranes. • Asymmetry of membrane.Membrane fluidity 55 Faculty of Medicine Biochemical Basis of Medicine I Membranes are highly viscous, plastic structures. Plasma membranes form closed compartments around cellular protoplasm to separate one cell from another and thus permit cellular individuality. The plasma membrane has selective permeabilities and acts as a barrier, thereby maintaining differences in composition between the inside and outside of the cell. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P : 2. Reading Handouts will be distributed 3- Lectures and power point presentation will be published on department website: www.kaau.edu.sa/faculties/medicine/dcbcweb • • • You have the opportunity to watch the CDROM about Membrane structure. You can access the CD-ROM during your spare time. 1- Membrane structure http://cellbio.utmb.edu/cellbio/membrane.htm 2- Biological membrane structure http://www.pnas.org/cgi/content/abstract/66/3/615 3- Biological membrane structure http://www.pnas.org/cgi/content/abstract/66/3/615 4- Membrane Composition http://www.pnas.org/cgi/content/abstract/66/3/615 56 Faculty of Medicine Biochemical Basis of Medicine I 1- Draw a figure for cell membrane, mention the basic composition for the membrane and explain how membrane structure serves its function? I- Short Questions: a- Which component (s) of membranes give it its fluid characteristics? b- Which part of a membrane helps it keep its shape (prevents deformation)? c- How are proteins arranged in a membrane? What is the difference between a transmembrane protein and a peripheral membrane protein? d- What feature in a membrane helps to prevent freezing? Be specific. II- MCQ: 1- Triacylglycerols cannot form lipid bilayers because they A. B. C. D. Have hydrophobic tails Do not have polar heads Cannot associate with cholesterol Have polar heads 2- In a typical eukaryotic plasma membrane A. Proteins can move in and out of the bilayer B. Lipids can move and diffuse through the bilayer C. Some lipids can rotate within the bilayer D. All of the above 3- The arrangement of lipid bilayers and other components is the basis for the currently widely accepted description which is called the A. Lipid bilayer model B. Mosaic model C. Diffusion model D. Fluid mosaic model III- True / False 57 Faculty of Medicine Biochemical Basis of Medicine I A. According to the current model of cell membrane structure, the two layers of lipids in the bilayer are nearly identical B. Cholesterol accounts for 20% to 25% of the mass of lipids in a typical mammalian plasma membrane C. The distribution of peripheral membrane proteins is generally identical on both sides of a given membrane. 58 Faculty of Medicine Biochemical Basis of Medicine I Lectures #(13) : Membrane Transport DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this topic you will be able to: 1. Explain how molecules move through membranes and the forms of energy needed to derive this process and to differentiate between active and passive transport. 2. Appreciate the functional role of membrane proteins as pumps, gates, channels and receptors. Movement of molecules across membranes: • Diffusion across cellular membranes. • Mediated transport passive mediated transport system, active mediated transport system: Na+ K+. • ATpase, Ca2+ translocation and Na+ dependent transport system. • Endocytosis and phagocytosis 59 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I Molecules can passively traverse the lipid bilayer of the membranes down electrochemical gradients by simple diffusion or by facilitated diffusion. This spontaneous movement toward equilibrium contrasts with active transport, which requires energy because it constitutes movement against an electrochemical gradient. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P : 2. Reading Handouts will be distributed 3- Lectures and power point presentation will be published on department website: www.kaau.edu.sa/faculties/medicine/dcbcweb • • • You have the opportunity to watch the CDROM about Membrane transport. You can access the CD-ROM during your spare time. 1-Membrane transport 1 http://www.emc.maricopa.edu/faculty/farabee/bio ioBooktransp.html 2-Transport across cell membrane http://users.rcn.com/jkimball.ma.ultranet/Biology s/D/Diffusion.html 3-Membrane transport mechanisms http://physioweb.med.uvm.edu/bodyfluids/membr htm 4- Cell membrane and transport mechanisms http://staff.jccc.net/PDECELL/cells/transport.htm 60 Faculty of Medicine Biochemical Basis of Medicine I 1- In a table form, describe Major mechanisms used to transfer material, mention the characteristics of each of them including the factor affecting and the need for energy. I- Short Questions: 1- Give the definition for the following: a- Simple diffusion b- Facilitated diffusion c- Uniport, antiport, symport d- Active transport e- Endocytosis II- MCQ: 1- Very large molecules (macromolecules) can be transported across membranes by : E. pores or channels with very large openings through the center F. active transport proteins G. diffusion down a concentration gradient H. endocytosis or exocytosis 2- Another name for facilitated diffusion is E. Active transport F. Transverse diffusion G. Lateral diffusion H. Passive transport 3- Facilitated diffusion (passive transport) through a biological membrane is: A. generally irreversible B. driven by the ATP to ADP conversion C. driven by a concentration gradient D. endergonic 61 Faculty of Medicine Biochemical Basis of Medicine I III- True / False a- Proteins that transport water across cell membranes are called aquaporins. b- Symport and antiport proteins must be active transport proteins. c- Active transport involves the conversion of ADP to ATP. d- Endocytosis is the process by which cells take up large molecules e- In adipocytes and muscle, glucose enters by facilitated diffusion 62 Faculty of Medicine Biochemical Basis of Medicine I Lectures #(14) : Cellular transduction DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this topic you will be able to: 1. The molecular mechanisms for regulation and action of protein kinases, protein phosphatases and G-proteins including small G- proteins of the Ras-superfamily and heterotrimeric G-proteins; 2. The molecular basis for signalling by reversible protein phosphorylation; 3. The molecular basis for targeting in signal transduction. • Kinases & phosphatases • Protein Kinase A (cAMPdependent protein kinase) • G-protein signal cascade • Structure of G-proteins • Small GTP-binding proteins, GAPs & GEFs • Phosphatidylinositol signal cascades • Signal protein complexes 63 Faculty of Medicine Biochemical Basis of Medicine I Cellular transduction is any process by which a cell converts one kind of signal or stimulus into another. Processes referred to as signal transduction often involve a sequence of biochemical reactions inside the cell, which are carried out by enzymes and linked through second messengers. Such processes take place in as little time as a millisecond or as long as a few seconds. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P : 2. Reading Handouts will be distributed 3- Lectures and power point presentation will be published on department website: www.kaau.edu.sa/faculties/medicine/dcbcweb • • • You have the opportunity to watch the CDROM about Cellular transduction. You can access the CD-ROM during your spare time. 1-Signal transduction power point presentation www.smd.qmul.ac.uk/morbidanatomy/Cancerbiolo gy/Cancer-Signal-transduction.ppt 2-Signal transduction lecture powerpoint 2 www.nida.nih.gov/whatsnew/meetings/frontiers/po werpoint/howlett.ppt 3-Signal transduction lecture powerpoint 3 64 Faculty of Medicine Biochemical Basis of Medicine I www.bmb.psu.edu/courses/bmmb598e/signaltrans. pdf 4- Signal transduction in tumor cells www.mdc-berlin.de/signaltransduction 1- Diagram and describe the sequence of events by which a hormone such as epinephrine or glucagon activates production of cyclic AMP within a cell. Include the roles of the receptor (GPCR), the different subunits of the stimulatory G protein, and Adenylate Cyclase. How is the signal turned off at each step? You may be asked to briefly describe the role of one of the following: AKAP, RGS protein. 2- Describe the activation of cAMPDependent Protein Kinase. What causes the enzyme to be inhibited in the absence of cyclic AMP? How is activation by cyclic AMP turned off? Signaling pathways are a balance of positive and negative signals. Cholera toxin, the active agent of Cholera vibrio, causes an increase in protein kinase A activity. From this point of view, Explain how cholera toxins produces its toxic effects? I- Short Questions: 1- Diagram an example of the reaction catalyzed by the activated cAMPDependent Protein Kinase. What reaction is catalyzed by the enzyme Protein Phosphatase. 65 Faculty of Medicine Biochemical Basis of Medicine I 2- Write out (in words) the reaction catalyzed by Phospholipase C. Describe the "second messenger" roles of the two products of the Phospholipase C reaction. II- MCQ: 1- In signal transduction what is an effector enzyme? A. An integral membrane protein that changes conformation upon binding of a ligand to a cell surface receptor. B.A small molecule that diffuses within a cell and carries a signal to its ultimate destination. C.A protein bound on the interior of a cell membrane that generates a second messenger. D.Protein bound on the exterior surface of a cell and is the receptor site for a ligand. 2- Which does not generally use a signal transduction mechanism? A.hydrophilic hormones B.neurotransmitters C.growth factors D.steroids 3- Which of the following enzymes is involved in the activation of the protein kinase C signaling pathway? A- Ca2+-ATPase B.Gβγ C.phospholipase C D. DAG kinase III- True / False a- G proteins are are multisubunit proteins consisting of , and subunits b- In the adenyl cyclase signaling pathway the second messenger is AMP c- The toxins from cholera and whooping cough both interfere with the proper functioning of ATP synthesis. 66 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (15- 16 ): Introduction to Metabolism, Bioenergetics, and the Role of ATP Student Notes: DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture, you will be able to: 1. Compare and contrast catabolism and anabolism 2. Outline the general mechanisms for regulating metabolic pathways through enzymes. 3. Understand the role of ADP/ATP in connecting catabolic and anabolic reactions. How does the structure of these molecules allow them to mediate energy requiring reactions? 4. Compare the two physiological mechanisms for the net synthesis of ATP 5. Be able to determine the direction in which electrons would pass in an oxidation-reduction couple, given either ΔG’ or ΔE’. 6. Be familiar with the relative oxidation reduction potentials of NAD, FAD (FMN), ubiquinone, cytochromes c and a, and oxygen. 7. Understand the importance of various mitochondrial compartments in cellular energy production. 8. Explain the relationship between 67 . Faculty of Medicine Biochemical Basis of Medicine I electron flow and ATP production in the mitochondria (chemiosmotic theory of Peter Mitchell). 9. Describe the components of the electron transport chain, including the points where common inhibitors act. 10. Discuss the mechanism of ATP production in the mitochondria. 11. Understand the concepts of respiratory control and coupling. • Metabolic Pathways 1- Definition, classification (Anabolism & Catabolism) 2- Catabolic phase 3- Low and high energy bonds – ATP – ADP cycle 4- Mechanism of collection of energy • Regulation of Metabolism 1- Signals from within the cells 2- Communication between cells 3- Intracellular messenger systems • Electron transport chain (ETC) 1- Components of ETC 2- Electron transport 3- Chemiosmotic hypothesis 4- ATP synthesis 5- Inhibition of ETC 6- Uncouplers 68 Faculty of Medicine Biochemical Basis of Medicine I In order to survive, humans must meet two basic metabolic requirements: we must be able to synthesize everything our cells need that is not supplied by our diet, and we must be able to protect our internal environment. In order to meet these requirements, we metabolize our dietary components through four basic types of pathways: Fuel oxidative pathways, fuel storage and mobalization pathways, biosynthetic pathways, and detoxification or waste disposal pathways. 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P: 69 – 82 & P: 89 - 94 2. Reading Handouts will be distributed 3- Lectures and power point presentation will be published on department website: www.kaau.edu.sa/faculties/medicine/ dcbcweb • • • You have the opportunity to watch the CDROM about Bioenergetics and introduction to metabolism . You can access the CDROM during your spare time. 1- Overview of metabolism http://www.elmhurst.edu/~chm/vchembook/5900verviewmet .html 2- Introduction to metabolism (PowerPoint) http://www.rit.edu/~pac8612/Biochemistry/503(703)/ppt/Intr 69 Faculty of Medicine Biochemical Basis of Medicine I oduction_to_Metabolism.ppt 3- Electro Transport chain(ECT) http://www.dentistry.leeds.ac.uk/biochem/lecture/etran/etra n.htm 4- Electro Transport chain(ECT) http://vcell.ndsu.nodak.edu/animations/etc/movie.htm 5- ECT Animation http://www.sp.uconn.edu/~terry/images/anim/ETS_slo w.html 6- ATP Synthesis Animation http://www.sp.uconn.edu/~terry/images/anim/ATPmit o.html 7- ECT Movie http://vcell.ndsu.nodak.edu/animations/etc/movie.htm 1- Regulation of metabolism is based on need, from your studying outline the factors regulating metabolism and how they work according to body needs? 2- Summarize the composition of each of the respiratory chain complexes I, III, and IV. Diagram the pathway of electron transfer in the mitochondrial inner membrane from matrix NADH to oxygen, including the smaller electron carriers, coenzyme Q and cytochrome? 1- If sodium ions rather than protons were pumped across the mitochondrial membrane, would there be any energy available to couple to ATP synthesis? 2- Clinical Question The desire for a quick weightloss drug has led to a number of disasters. In the 1930s, dinitrophenol was explored as a possible weight-loss aid, but it had a variety of severe side effects, including 70 Faculty of Medicine Biochemical Basis of Medicine I hyperthermia and death. Why was dinitrophenol a bad idea? Explain how dinitrophenol induces hyperthermia I- Short Questions: 1- Give the definition for the following: a- Anabolic reaction b- Catabolic reaction c- Free Energy Change d- Electron Transport Chain 2. Enumerate components of Electron Transport Chain, How many ATP molecules will be produced from oxidation of One NADH+H+, FADH2 respectively, in the chain? 3- How cAMP activates some metabolic reactions and inhibits others? II- MCQ: 1. In the mitochondria NADH and QH2 are oxidized by ____________. (a) carbon dioxide (b) hydrogen peroxide (c) ozone (d) oxygen 2. The synthesis of one molecule of ATP from ADP requires _________ to be translocated across the inner mitochondrial membrane. (a) one proton (b) about two protons (c) hundreds of protons (d) 1 mole of protons 71 Faculty of Medicine Biochemical Basis of Medicine I 3. The degradation of which class of biochemicals does not significantly contribute to the release of energy to cells? (a) nucleic acids (b) Proteins (c) Lipids (d) carbohydrates III- True / False a. The biochemical reactions that degrade molecules, such as nutrients, are called anabolic reactions b. Metabolic pathways generally have easily distinguished starting and stopping points c. All metabolic reactions occur in the cytosol of cells d. In mammals the enzyme complexes of oxidative phosphorylation are in the inner mitochondrial e. Most of the free energy needed to drive ATP formation in the mitochondria is the result of an electrical contribution from a charge gradient across the inner mitochondrial membrane matrix. 72 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (17- 18) Glycolysis DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1- Define glycolysis, form a working definition knowing the substrates and products involved and any other key intermediates produced. 2- Trace tissue location of glycolysis, particularly tissues or cells in the body where the pathway is most important. 3- Locate the cell site of glycolysis, where in the cell it occurs (cytosol). 4- Describe the sequence of events, the overall reaction sequence and the number of stages and reactions: a. Material Flow:: Trace the fate of labeled carbon or other elements through the pathway b. Energy flow: Trace the production and consumption of ATP 73 : Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I c. Electron flow: trace the production and consumption of reducing power 5- Identify the Key steps, either those which form major control sites or those which are main " branch points" 6- Describe connections to other pathways especially citric acid cycle . • • • • • Overview of Glycolysis Coupled Reactions in Glycolysis First Phase of Glycolysis Second Phase of Glycolysis Metabolic Fates of NADH and Pyruvate • Anaerobic Pathways for Pyruvate • Energetic Elegance of Glycolysis • Other Substrates in Glycolysis The glycolytic pathway is employed by all tissues for the breakdown of glucose to provide energy ( in the form of ATP) and intermediates for other metabolic pathways. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby 74 Faculty of Medicine Biochemical Basis of Medicine I • • • You have the opportunity to watch the CDROM about glycolysis. You can access the CD-ROM during your spare time. 1. Introduction to Glycolysis: http://www.terravivida.com/vivida/glyin 2. Glycolysis Lecture: http://web.indstate.edu/thcme/mwking olysis.html 3. Glycolysis Animation: http://www.johnkyrk.com/glycolysis.ht 4. Glycolysis Home: http://biotech.icmb.utexas.edu/glyco lysis/glycohome.html 3- List the enzymes that convert glucose to glyceraldehyde 3-PO4. Add to your list the substrates, products, and cofactors for each of these enzymes. It might be handy to make up a table for this. 4- List the enzymes that convert glyceraldehyde 3-PO4 to pyruvate. Add to your list the substrates, products, and cofactors for each of these enzymes. It might be handy to make up another table for this. 2- Clinical Question Predict the effect of a GLUT4 knockout (in mice) on the levels 75 Faculty of Medicine Biochemical Basis of Medicine I of blood glucose before and after a meal. Search the Internet and report whether your predictions were confirmed by experiment. Of what use is a GLUT4 knockout mouse? 3- Clinical Case Ahmed entered the stadium for the final lap of his marathon race. He was well ahead of his competitors. In the last few minutes, he became confused. In the stadium, he started running around the track in the wrong direction and then collapsed. What went wrong? I- Short Questions: 1- Give the cellular location of the glycolytic pathway. 2- Where is NADH produced ? 3. Which step produces ATP? Which one of these is considered to be 'substrate level phosphorylation? 4- Name the enzyme that makes anaerobic glycolysis possible by using up the NADH that accumulates. 5 -Consider the ten steps of glycolysis, starting with glucose. What would be the effect on pyruvate concentration (increase, decrease or none) of increasing the concentration of the following? Give a brief (one sentence) explanation for your answer. a) ATP 76 Faculty of Medicine Biochemical Basis of Medicine I b) AMP c) citrate d) fructose-1,6-bisphosphate e) fructose-2,6-bisphosphate II- MCQ: 1- Which of the following metabolites does not regulate glycolysis in liver cells? A. glucose-6-phosphate B. fructose-6-phosphate C. fructose-1-phosphate D. fructose-2,6-bisphosphate 2-During kinase reactions, the role of magnesium ions is to A. be catalytic metals at the active sites of the enzymes. B. interact with the hydroxyl groups of the various sugar molecules. C. interact with the negative charges on phosphate groups. D. provide a bridging atom between substrate and product, stabilizing the transition state. 3- Which of the following is not a substrate for hexokinase? A. glucose B. fructose C. galactose D. mannose 3- How many ATP molecules are produced from glucose during anaerobic glycolysis? A. 0 B. 1 C. 2 77 Faculty of Medicine Biochemical Basis of Medicine I D. 3 III- True / False a. Four molecules of ATP are consumed per glucose during the hexose stage of glycolysis b. The reaction catalyzed by PFK-1 is metabolically reversible c. Mammals can convert pyruvate to either ethanol or lactate depending on the availability of oxygen d. Glucose is normally transported into cells by an active transport protein since the concentration of glucose inside cells is normally higher than that in the blood. e. Two molecules of ATP are consumed per glucose molecule during the hexose stage of glycolysis 78 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (19) : Tricarboxylic Acid Cycle (TCA) DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1. Define TCA, form a working definition knowing the substrates and products involved and any other key intermediates produced. 2. Trace tissue location of TCA, particularly tissues or cells in the body where the pathway is most important. 3. Locate the cell site of TCA, where in the cell it occurs (Mitochondria). 4. Describe the sequence of events, the overall reaction sequence and the number of stages and reactions: a- Material Flow:: Trace the fate of labeled carbon or other elements through the pathway b- Energy flow: Trace the production and consumption of ATP c- Electron flow: trace the production and consumption of reducing power 5. Identify the Key steps, either those which form major control sites or those which are main " branch points" 79 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I 6. Describe connections to other pathways related to carbohydrate, lipid and amino acids metabolism 7. Describe the amphibolic aspects of TCA and the role of its intermediate in various metabolic process. 8. Diagram the shuttles for the transport of cytoplasmic reducing equivalents into the mitochondria • Overview of TCA • Reaction of the TCA cycle a- Oxidative decarboxylation of pyruvate b- The eight sequential reactions of TCA • Energy produced by the cycle • Regulation of the TCA cycle The tricarboxylic acid cycle (TCA) is also called citric acid cycle or Kreb's cycle. It is the major final common pathway of oxidation of carbohydrates, lipids and proteins since their oxidations yield Acetyl Co A. It also plays a major role in lipogenesis,gluconeogenesis, transamination and deamination. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P: 107 – 114 80 Faculty of Medicine Biochemical Basis of Medicine I 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby You have the opportunity to watch the CDROM about TCA. You can access the CDROM during your spare time. 1- TCA animation http://www.science.smith.edu/departments/Biol Bio231/krebs.html 2-TCA animation http://www.wiley.com/legacy/college/boyer/0470 90/animations/tca/tca.htm 3- TCA http://www.sigmaaldrich.com/Area_of_Interest/L Science/Metabolomics/Key_Resources/Meta _Pathways/TCA_Cycle.html 4- Step by step Kreb’s cycle http://www.terravivida.com/vivida/tcasteps/ 5- Biochemistry animations http://www.wiley.com/college/fob/anim/ a. Diagram the Krebs Citric Acid Cycle, beginning with pyruvate, giving the names of all enzyme substrates and products and names of enzymes (no abbreviations). Indicate where NAD+, NADH, FAD, FADH2, GDP, Pi, GTP, coenzyme A, H2O, or CO2 are substrates or products of reactions. 81 Faculty of Medicine Biochemical Basis of Medicine I b. What is the fate of reducing equivalents of FADH2 generated in Krebs Cycle? 1- Clinical Question A patient diagnosed with thiamine deficiency exhibited fatigue and muscle cramps. The muscle cramps have been related to an accumulation of metabolic acid. What is the metabolic product leads to this condition? Explain your answer. I- Short Questions: 1- What is the intercellular location of TCA? 2- What is the sources of Acetyl CoA? 3- What are the products of TCA? 4- Describe the functions of 2 intermediates of TCA? 5- Summarize the functions of TCA. II- MCQ: 1- The citric acid cycle oxidizes pyruvate and some of the pathway intermediates are starting materials for many biosynthetic pathways. This means the citric acid cycle is a/an ______________. A. B. C. D. amplifying pathway strictly catabolic pathway anaerobic pathway amphibolic pathway 82 Faculty of Medicine Biochemical Basis of Medicine I 2- In eukaryotes the enzymes of the citric acid cycle are found in the _________. A. cytosol B. mitochondria C. nucleus D. endoplasmic reticulum 3- The enzyme pyruvate translocase is located ______________. A. in the cytosol B.in the inner mitochondrial membrane C. in the mitochondrial matrix D. in the endoplasmic reticulum III- True / False 1- The overall goal of the citric acid cycle is to oxidize pyruvate, form reduced coenzymes and produce ATP 2- The citric acid cycle is an anaerobic pathway that occurs in the mitochondria of eukaryotes. 3- ATP is consumed by the pyruvate dehydrogenase complex during the synthesis of acetyl CoA 4- The citric acid cycle can be viewed as a multi-step catalyst simply because it returns to its original state after each round of reactions. 5- Isocitrate is more easily oxidized than citrate because it has a secondary alcohol group, whereas citrate's alcohol group is tertiary 83 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (20) : Gluconeogenesis D DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1- Define Gluconeogenesis, form a working definition knowing the substrates and products involved and any other key intermediates produced. 2- Trace tissue location of gluconeogenesis, particularly tissues or cells in the body where the pathway is most important. 3- Locate the cell site of gluconeogenesis, where in the cell it occurs (cytosol) Except for the carboxylation of pyruvate, which occurs in mitochondria. 4- Describe the sequence of events, the overall reaction sequence and the number of stages and reactions: a. Material Flow:: Trace the fate of labeled carbon or other elements through the pathway b. Energy flow: Trace the production and consumption of ATP c. Electron flow: trace the production and consumption of reducing 84 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I power 5- Describe the sequence of events, the overall reaction sequence and the number of stages and reactions 6- Identify the Key steps, either those which form major control sites or those which are main " branch points" 7- Describe connections to other pathways, especially glycolysis and the reciprocal regulation of both pathway 8- Identify the non carbohydrate sources of gluconeogenesis. • Overview of gluconeogenesis • Substrates for gluconeogenesis • Reactions unique to gluconeogenesis • Regulation of gluconeogenesis Gluconeogenesis is ' production of glucose from non – carbohydrate sources' For a period of starvation of longer than about 12 hours. This pathway is very important for tissues which require a continuous supply of glucose as a metabolic fuel such as the brain, red blood cells, kidney medulla, lens and cornea of the eye, testes and exercising muscle. 85 Faculty of Medicine Biochemical Basis of Medicine I 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey p: 115 - 122 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby • • • You have the opportunity to watch the CDROM about gluconeogenessis. You can access the CD-ROM during your spare time. 1- Gluconeogenesis http://web.indstate.edu/thcme/mwking/gluconeogenesi s.html 2- Gluconeogenesis http://www.answers.com/topic/gluconeogenesis 3- Gluconeogenesis animation http://www.wiley.com/college/fob/quiz/quiz15/1522.html 4- Gluconeogenesis powerpoint presentation http://www.sb.fsu.edu/~chapman/Classes/Bch4054/Co ntent/Gluconeogenesis.pdf 1. a. Write out the two sequential reactions catalyzed by Pyruvate Carboxylase, giving names and structures of reactants and products, including the active site prosthetic group. What is the nature and significance of the linkage of the prosthetic group to the Pyruvate Carboxylase enzyme? 86 Faculty of Medicine Biochemical Basis of Medicine I b. Describe and explain the significance of the effect of acetyl coenzyme A on the Pyruvate Carboxylase enzyme. would it be 1- Why disadvantageous to the organism to have Glycolysis and Gluconeogenesis operating simultaneously within a cell? Briefly describe one example of reciprocal regulation of Glycolysis and Gluconeogenesis, involving an allosteric regulator. For the example chosen, write out the reaction catalyzed by the enzyme in each pathway, and indicate the nature of the effect of the regulator (e.g., inhibition or activation). I- Short Questions: 1- Give the cellular location of the gluconeogenesis pathway. 2- Enumerate the sources for gluconeogenesis ? 3. Define futile cycle, relate it to gluconeogenesis? 4- What are the irreversible reactions unique to gluconeogenesis? 5- How many ATP are consumed for synthesis of one molecule glucose from 2 pyruvates 87 Faculty of Medicine Biochemical Basis of Medicine I II- MCQ: 1- Gluconeogenesis is A. The formation of glycogen B.The formation of starches C.The formation of glucose from noncarbohydrates D.The formation of glucose from other carbohydrates 2- Gluconeogenesis uses the same enzymatic reaction of glycolysis except for A. Pyruvate kinase B.4 irreversible reactions in glycolysis C.3 irreversible reactions in glycolysis D.2 irreversible reactions in glycolysis 3- Any compound that can be converted to _____can be a precursor for gluconeogenesis. A. Citrate B.Pyruvate C.Oxaloacetate D.b and c III- True / False 1- Glucagon increases the transcription of the gene for PEP carboxykinase in gluconeogenesis, while insulin decreases it. 2- Fructose 2,6-bisphosphate is a modulator that can stimulate either glycolysis or gluconeogenesis, depending on cellular glucose concentrations. 3- At high glucagon concentrations gluconeogenesis will be favored over glycolysis. 4- The brain normally uses both glucose and fatty acids as energy sources. 5- Glycerol is one of the precursor for gluconeogenesis. 88 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (21 - 22) : Glycogen Metabolism DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1-Define Glycogenesis and Glycogenolysis , form a working definition knowing the substrates and products involved and any other key intermediates produced. 2- Trace tissue location of Glycogenesis and Glycogenolysis, particularly tissues or cells in the body where the pathway is most important. 3- Locate the cell site of Glycogen metabolism, where in the cell it occurs (cytosol). 4- Describe the sequence of events, the overall reaction sequence and the number of stages and reactions: a. Material Flow:: Trace the fate of labeled carbon or other 89 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I elements through the pathway b. Energy flow: Trace the production and consumption of ATP c. Electron flow: trace the production and consumption of reducing power. 5- Identify the Key steps, either those which form major control sites or those which are main " branch points" 6- Describe connections to other pathways and the reciprocal regulation of both glycogenesis and glycogenolysis • Overview of Glycogen metabolism • Structure and function of Glycogen • Synthesis of Glycogen(Glycogenesis) • Degradation of Glycogen (Glycogenolysis) • Regulation of glycogenesis and Glycogenolysis. • Glycogen storage diseases Excess dietary glucose is stored as glycogen. Glucose can be rapidly and easily mobilized from glycogen, when the need arises; for example, between meals or during exercise. A constant supply of glucose is essential for life because it is the main fuel of the brain and the only 90 Faculty of Medicine Biochemical Basis of Medicine I energy source that can be used by cells lacking mitochondria and by contracting skeletal muscle(during anaerobic glycolysis). Glycogen is therefore an excellent short – term storage material that can provide energy immediately. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P: 123 - 134 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby • • • You have the opportunity to watch the CDROM about Glycogen metabolism. You can access the CD-ROM during your spare time. 1- Glycogen metabolism http://web.indstate.edu/thcme/mwking/glycogen.html 2-Glycogen metabolism http://www.med.unibs.it/~marchesi/glycogen.html 3- Glycogen metabolism book http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=stryer. chapter.2911 4- Glycogen metabolism animation http://www.wiley.com/college/fob/quiz/quiz15/1520.html 1- Describe the regulation of the muscle Glycogen Phosphorylase enzyme by local allosteric regulators. 91 Faculty of Medicine Biochemical Basis of Medicine I What is the effect of phosphorylation of the enzyme via Phosphorylase Kinase? A diagram may be helpful. What is the significance of the allosteric regulation with regard to cellular metabolism? 2. a. Diagram and describe the reaction cascade by which cyclic AMP alters activity of the Glycogen Phosphorylase enzyme. (The process by which cyclic AMP production is activated by glucagon or epinephrine may be omitted here.) Include the effects of covalent modification on sensitivity of Glycogen Phosphorylase to allosteric regulators. What is the significance of such a regulatory cascade in liver in relation to the well being of the whole organism? b. How does the rise in cytosolic [Ca++] that occurs during activation of muscle contraction affect glycogen breakdown? How is this significant with regard to metabolism during muscle contraction? 1- Explain how genetic deficiency of each of the following enzymes leads to intracellular glycogen accumulation (glycogen storage disease) along with the specific symptoms listed: • Deficiency of Glucose-6-phosphatase in liver, causing glycogen accumulation plus hypoglycemia (low blood glucose) 92 Faculty of Medicine • • Biochemical Basis of Medicine I when fasting. Deficiency of Glycogen Phosphorylase in muscle, causing glycogen accumulation plus muscle cramps with exercise. Deficiency of Phosphofructokinase in muscle, causing glycogen accumulation plus inability to exercise. I- Short Questions: 1- Give the cellular location of Glycogen metabolism. 2- What are the main stores of Glycogen in body ? 3. Enumerate the enzymes of Glycogenesis and Glycogenolysis. 4- What is the advantage of branched structure of glycogen. 5– What is the difference between glycogenolysis in liver and muscles? 6- Enumerate Glycogen storage diseases. II- MCQ: 1- The enzyme which the key regulatory step in glycogen biosynthesis is A. Glycogen synthase B. Glycogenin C. Branching enzyme D. Phosphoglucomutase 2- Protein kinase A, which stimulates glycogen degradation, is activated directly by A. Glucagon 93 Faculty of Medicine Biochemical Basis of Medicine I B. Insulin C. Epinephrine D. Cyclic AMP 3- Glucose 1-phosphate formed by glycogenolysis is converted to glucose 6-phosphate by phosphoglucomutase because A. Glucose 6-phosphate is more stable B. Glucose 6-phosphate is converted to free glucose C. Glucose 6-phosphate is an intermediate in several pathways, including glycolysis D. Glucose 6-phosphate can be transported to the liver III- True / False 1- Enzymes to regulate glycogen metabolism are always active when phosphorylated by protein kineses. 2- Since caffeine inhibits cAMP phosphodiesterase, too much coffee can result in synthesis of too much glycogen. 3-UDP-glucose is a precursor of glycogen in all cells. 5- Glycogen storage disease results in glycogen accumulation in liver and kidneys. It can be controlled by changing ones diet. 94 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (23) : Pentose phosphate pathway DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1. Define the pentose phosphate pathwaw , form a working definition knowing the substrates and products involved and any other key intermediates produced. 2- Trace tissue location of pentose phosphate pathwaw, particularly tissues or cells in the body where the pathway is most important. 3- Locate the cell site of glycolysis, where in the cell it occurs (cytosol). 4- Describe the sequence of events, the overall reaction sequence and the number of stages and reactions: a. Material Flow:: Trace fate of labeled carbon other elements through pathway b. Energy flow: Trace 95 the or the the Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I production and consumption of ATP c. Electron flow: trace the production and consumption of reducing power 5- Identify the Key steps, either those which form major control sites or those which are main " branch points" 6- Describe connections to other pathways, with the emphasis on the role of NADPH in other biochemical pathways • Overview of pentose phosphate pathwaw • Irreversible oxidative reactions • Reversible nonoxidative reactions • Uses of NADPH • Glucose 6 – phosphate Dehydrogenase Deficiency The pentose phosphate pathway occurs in the cytosol of the cell. The pathway provides a major portion of body's NADPH, which functions as a biochemical reductant. It also produces ribose 5phosphate required for the biosynthesis of nucleotides. 96 Faculty of Medicine Biochemical Basis of Medicine I 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P: 143- 154 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby • • • You have the opportunity to watch the CDROM about pentose phosphate pathway. You can access the CD-ROM during your spare time. 1- Pentose phosphate pathway http://web.indstate.edu/thcme/mwking/pentosephosphate-pathway.html 2- Pentose phosphate pathway http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/m b2/part1/pentose.htm 3- Pentose phosphate pathway (PowerPoint) presentation www.cwu.edu/~geed/543/Pentose%20Phosphate%20Pat hway.ppt 4- Pentose phosphate pathway (poweeroint ) www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/15pentose.ppt 1- Diagram and describe the mechanism of the reaction catalyzed by the enzyme Transaldolase, including structures of major intermediates. 2. Write out the linear (oxidative) portion of the Pentose Phosphate Pathway, giving names and structures of substrates and 97 Faculty of Medicine Biochemical Basis of Medicine I reactants, and the name of each enzyme. Summarize in words what happens at each step. What two products of the linear portion of the Pentose Phosphate Pathway have essential roles in anabolic metabolism? What are these roles? Clinical Question 1- In male patients who are homozygous for glucose 6phosphate dehydrogenase (G6PD) deficiency, pathophysiologic consequence are more apparent in erythrocytes (RBCs) than in other cells, such as in the liver. EXPLAIN. I- Short Questions: 1- Give the cellular location of the pentose phosphate pathway 2- What are the main products of pentose phosphate pathway ? 3. Enumerate sources of NADPH? 4- What are the uses of NADPH in our body. Enumerate? . 5- What are the effects of glucose 6phosphate dehydrogenase deficiency 98 Faculty of Medicine Biochemical Basis of Medicine I II- MCQ: 1- The major regulatory step of the pentose phosphate pathway is catalyzed by which enzyme? A. transaldolase B. phosphofructokinase-1 C. glucose 6-phosphate dehydrogenase D. ribose 5-phosphate isomerase 2- The non-oxidative stage of the pentose phosphate pathway produces substances that are intermediates of ___________. A. glycolysis B. the citric acid cycle C. the Cori cycle D. glycogenolysis 3- Which is not a function of the main products of the pentose phosphate pathway? A. To maintain the reduced form of iron in hemoglobin. B.To provide reducing power for the synthesis of fatty acids. C. To serve as precursors in the biosynthesis of RNA and DNA. D. To raise the concentration of cAMP. III- True / False 1- Glucose 1,6-bisphosphate is the primary starting substrate for the pentose phosphate pathway. 2- Two molecules of NADPH are generated for each molecule of glucose 6-phosphate that enters the pentose phosphate pathway. 99 Faculty of Medicine Biochemical Basis of Medicine I 3- Rapidly dividing cells generally have a high pentose phosphate pathway activity. 4- The enzyme transketolase transfers 2-carbon units from ketose phosphates to aldose phosphates 5- NADH and pentose are the main products of pentose phosphate pathway 100 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (24): Metabolism of Monosaccharides and Disaccharides DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1- Define pathways for fructose, Galactose and Lactose Metabolism , form a working definition knowing the substrates and products involved and any other key intermediates produced. 2- Trace tissue location of these pathways, particularly tissues or cells in the body where the pathway is most important. 3- Locate the cell site of these pathways, where in the cell it occurs (cytosol). 4- Describe the sequence of events, the overall reaction sequence and the number of stages and reactions: a. Material Flow:: Trace the fate of labeled carbon or other elements through the pathway b. Energy flow: Trace the production and consumption of 101 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I ATP c. Electron flow: trace the production and consumption of reducing powerIdentify the Key steps, either those which form major control sites or those which are main " branch points" 5- Describe connections to other pathways especially Glycolysis • • • • Overview Fructose metabolism Galactose metabolism Lactose synthesis Although many monosaccharides have been identified in nature, only a few sugars appear as metabolic intermediates or as structural components in mammals. The major source of fructose is sucrose, while the major dietary source of galactose is lactose, entry of both to cells is insulin - independent both can be metabolized for energy generation through glycolysis. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P: 135 – 142 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby 102 Faculty of Medicine Biochemical Basis of Medicine I • • • You have the opportunity to watch the CDROM about Monosaccharide metabolism. You can access the CD-ROM during your spare time. 1- Fructose Metabolism http://www.gpnotebook.co.uk/cache/1798635578 m 2-Fructosa Web site http://www.drkaslow.com/html/fructose.html 3- Fructose and Galactose Metabolism http://web.indstate.edu/thcme/mwking/non-gluc sugar-metabolism.html 4- Galactose Metabolism http://www.gpnotebook.co.uk/cache/1899298874.htm Describe, how different monosaccharides can be interconverted, Explain the benefits of this interconversion to body metabolism. 1- Clinical Question A newborn baby experienced abdominal distension, severe bowel cramps, and diarrhea after being fed milk. A hydrogen analysis of his exhaled breath discovered an eighty – fold increase in the production of H2 ninety minutes after milk feeding. a- Explain the case 103 Faculty of Medicine Biochemical Basis of Medicine I b- This condition is preventable or not? 2- Clinical Case A galactosemic female is able to produce lactose, How? I- Short Questions: 1- What is the main source of dietary fructose?. 2- What is the main source of dietary galactose?. 3. Although fructose is more sweaty than Glucose it is not recommended to be an exchange to it in our diet 4- What is the effects Galactokinase deficiency. 5- Define fructosuria, what is its cause. II- MCQ: 1- 1- Which is an intermediate formed in the conversion of glucose to fructose? A. glucose-1-phosphate B. sorbitol C. ribose D. aldose reductase 2- What types of reactions are involved in the two-step conversion of glucose to fructose? A. reduction followed by oxidation B. two sequential hydrolysis reactions C. hydrolysis followed by isomerization D. phosphorylation followed by 104 Faculty of Medicine Biochemical Basis of Medicine I dephosphorylation 3- What is a cause of cataracts in the eye lens of individuals with diabetes? A.Accumulation of sorbitol and protein precipitation in the lens. B. Precipitation of glucose not oxidized by glycolysis in the lens. C. The absence of membrane transport proteins for pyruvate in the lens cells. D. Lack of regulation of gluconeogenesis in the lens and the accumulation of fructose. IV- True / False 1- Lactose is the main source of dietary fructose. 2- Absorption of fructose is insulin dependent. 3- Aldose reductase reduces glucose, producing sorbitol 4- Classic galactosemia results from missing of Galactose kinase 5- Lactose is synthesized by lactase synthase from UDP glucose and Galactose. 105 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (25) : Fatty acid oxidation DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1- Sequence the reactions catalyzed by acylCoA synthetase, carnitine palmitoyl transferaseI,carnitine-acylcarnitine translocase, and carnitine palmitoyl transferaseII. 2Indicate which of these enzymes is regulated by malonyl-CoA. 3- Explain the importance of carnitine for the oxidation of long-chain fatty acid but not short- and medium-chain fatty acids. 4- Discuss the steps of beta oxidation of fatty acids. 5- Explain the importance of citric acid cycle for the oxidation of fatty acids . 6- Calculate the yield of ATP that is formed through the complete oxidation of one mole of palmitic acid. 7- Indicate the roles of long chain-, medium chain- and short chain-acyl CoA dehydrogenases in the oxidation of long chain fatty acids. Explain why a defect in the medium chain enzyme results in excretion of dicarboxylic acids and acyl carnitine esters in the urine. 106 Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I • Tissues that are most active in oxidation of fatty acids and its sub cellular location • Conditions which favor the process of oxidation of fatty acids • Role of carnitine in the process of beta oxidation • The difference in oxidation of long, medium and short chain fatty acids • The steps of beta oxidation • Energy gained of beta oxidation • Regulation of beta oxidation • The other types of fatty acid oxidation • Diseases associated with genetic abnormality of fatty acid oxidation Beta oxidation takes place in fed state in certain tissues as a source of energy, in starvation it is stimulated to provide energy for many tissues as liver (which becomes completely dependent on it as a source of energy. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey. (187-193) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. (pp 169173) • • • You have the opportunity to watch the CDROM about fatty acid oxidation. You can access the CD-ROM during your spare time. 107 Faculty of Medicine Biochemical Basis of Medicine I 1http://www.dentistry.leeds.ac.uk/biochem/t hcme/fatty-acid-oxidation.html 2- http://www.biocarta.com/pathfiles/betaoxi dationPathway.asp 3- http://ull.chemistry.uakron.edu/Pathways/ b_oxidation/index.html 4- http://www.biocarta.com/pathfiles/boxnpP athway.asp 5http://www.biocarta.com/pathfiles/h_cptPathway.asp 6http://www.brookscole.com/chemistry_d/temp lates/student_resources/shared_resources/an imations/carnitine/carnitine1.html 7- http://www.biocarta.com/pathfiles/oddnum berchainPathway.asp 8http://www.biocarta.com/pathfiles/polyunsatfa ttyacidPathway.asp 1- Try to explain the sequence of events that takes place in the mitochondria during beta oxidation of fatty acid 2- Write down how beta oxidation is regulated 1- Clinical Question: In diabetic patient type I, do you expect that beta oxidation of fatty acid to be increased, decreased or normal and why? 2Clinical Case: A three month old baby brought to you by his mother, she was complaining that the baby seemed to be lethargic and does not grow well, and he 108 Faculty of Medicine Biochemical Basis of Medicine I was on breast fed only. What possible reason(s) may be the cause of this condition? I- Short Questions: a) Name the different types of oxidation of fatty acid b) List the difference between fatty acid synthesis and beta oxidation regarding hydrogen carrier used and the site they occur II- MCQ: 1- Two high energy bonds are lost during β oxidation of long chain fatty acids in: a) Transport of acyl carnitine inside the mitochondria b) Formation of acyl CoA inside the mitochondria c) Formation of acyl CoA in the cytoplasm d) Release of acetyl CoA from acyl CoA by the action of thiolase enzyme e) Non of the above 2- All the following are intermediate in βoxidation except: a) FADH b) NADPH c) NADH d) Acetyl CoA e) All of the above III- True / False a- The major type of fatty acid oxidation in most of he tissues is omega oxidation b- Beta oxidation takes place in all tissues c- Compared to carbohydrate oxidation of fatty acids generate smaller quantity of ATP 109 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (26) : Fatty acid synthesis DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1- Identify the substrate for the building of fatty acid and where it is made. Explain how this substrate is transferred to the cytoplasm. 2- Describe the importance of glycolysis in the cytosol for fatty acid synthesis. 3- Discuss how the fatty acid synthase enzyme complex works. 4- Explain how stearic acid and oleic acid are synthesized from palmitic acid and in what regions of the cell they are synthesized. 5- Describe the different mechanisms of shortterm control of the formation of fatty acids. 6- Indicate the roles of insulin and glucagon in the regulation. 9- Describe long-term control (enzyme induction) of the formation of fat. Indicate the enzymes that are subject to long term control. 10-Explain what prevents the liver from oxidizing fatty acids at the same time it is synthesizing fatty acids. • Tissue and subcellular location for fatty acid synthesis • Transport of the building block for 110 Student Notes: . Faculty of Medicine • • • • • Biochemical Basis of Medicine I fatty acid synthesis from the mitochondria to the cytoplasm The generation of the substrates for fatty acid synthesis in the cytoplasm The arrangement and structure of fatty acid synthesase enzyme Energy requirement for fatty acid synthesis Regulation of fatty acid synthesis Elongation and unsaturation of fatty acid Fatty acid synthesis is an anabolic process, so it is favored during the fed state and inhibited during starvation through hormonal regulation which also activates fatty acid oxidation, so during starvation fatty acid synthesis is shut down and oxidation is turned on. Acetyl CoA is the substrate for fatty acid synthesis which is produced in the mitochondria and has to be transported to the cytoplasm in the form of citrate. In the cytoplasm the other requirement for fatty acid synthesis are present (NADPH and fatty acid synthesase complex) 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey. (pp 179186) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. (pp 179184) • • • You have the opportunity to watch the CDROM about fatty acid synthesis You can access the CD-ROM during your spare time. 111 Faculty of Medicine Biochemical Basis of Medicine I 1- http://ull.chemistry.uakron.edu/Path ways/FA_synthesis/index.html# 2http://www.genome.ad.jp/kegg/pathway /map/map00561.html 3http://ull.chemistry.uakron.edu/Pathways/FA_ synthesis/index.html 4http://ull.chemistry.uakron.edu/genobc/ Chapter_24/ 5http://www.uic.edu/depts/mcam/mcbc/l ect_2004/lecture_27.pdf 1- Outline and contrast the processes of fatty acid synthesis and oxidation 2- Write down the source(s) of each of the substrate for fatty acid synthesis 1Clinical Case Obesity, which will be covered in the tutorial. I- Short Questions: a) Name the key regulatory enzyme in fatty acid synthesis b) Using a diagram drew how this enzyme is controled 112 Faculty of Medicine Biochemical Basis of Medicine I II- MCQ: 1- Acetyl groups for fatty acid synthesis is derived mainly from: a) b) Only glucose Ketogenic amino acids only c) Beta oxidation of fatty acid d) Glucose and amino acids e) Non of the above 2- Acetyl CoA for fatty acid synthesis is produced in the cytoplasm by the action of: a) Acetyl CoA synthetase b) Citrate lyase c) Pyruvate dehydrogenase d) Thiolase e) Non of the above II- True / False a) The synthesis of fatty acids occurs in the cytoplasm of the cells b) The key regulatory enzyme in fatty acid synthesis is the fatty acid synthesase c) Insulin hormone inhibits fatty acid synthesis d) Citrate lyase enzyme has no role in the process of fatty acid synthesis 113 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (27,28) Lipogenesis DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1. Define lipogenesis and its importance 2. Locate the important sites (tissues) for lipogenesis and its intracellular location 3. Discuss the favorable conditions for lipogenesis 4. Differentiate between lipogenesis in adipose tissues and other tissues and explain this differences 5. Trace the substrate of lipogenesis to its final product • Overview and definition of lipogenesis • Sites of lipogenesis (tissues and subcellular level) • Substrates for lipogenesis • Energy utilization of lipogenesis • Regulation of lipogenesis • Fed and fasting conditions and their effect on lipogenesis 114 : Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I How excess calorie are stored in the form of triglycerides and how this process utilizes excess CHO and protein for its synthesis to be utilized during fasting and starvation conditions. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey. (pp 185187) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. (pp 185187) • • • You have the opportunity to watch the CDROM about lipogenesis. You can access the CD-ROM during your spare time. 1- http://www.lipidsonline.org/ 2- http://ull.chemistry.uakron.edu/Pa thways/FA_synthesis/index.html# 3- http://www.genome.ad.jp/kegg/pa thway/map/map00561.html 4- http://www.biochem.arizona.edu/c lasses/bioc801/power/lec27.ppt#2 56,1,Slide 1 5- http://www.genome.jp/kegg/pathw ay/map/map01130.html 6- http://www.biocarta.com/pathfiles /h_vobesityPathway.asp 115 Faculty of Medicine Biochemical Basis of Medicine I 1. Explain why the liver is able to utilize free glycerol for the synthesis of triglyceride glycerol, but the adipose tissue must have glucose in order to synthesize glycerol 3-phosphate. Give the reaction catalyzed by the enzyme missing in the adipose cell. 2. Write down the role of insulin in lipogenesis Clinical Question: 1. What is BMI and how it is used for classification of obesity? Clinical Case: 2. Obesity, which will be covered in the tutorial. I- Short Questions: 1- State the tissues and the subcellular location of lipogenesis 2- Outline the major difference (s) between lipogenesis in the liver and that in the adipose tissue III- MCQ: 1- In liver lipogenesis, glycerol 3phosphate can be obtained by: a)The action of glycerol kinase enzyme only b) Through glycolysis intermediates only c)Both of the above d)Non of the above 116 Faculty of Medicine Biochemical Basis of Medicine I 2- Adipocytes contain fat droplets which serve to provide to an animal a)Increased cell volume b) Insulation c) provide energy d) a and b e) b and c III- True / False a. Lipogenesis takes place in the cytoplasm of the adipose tissues and the liver b. Glycerol kinase is very active enzyme in lipogenesis in the adipose tissue c. Lipogenesis is stimulated by insulin and inhibited by glucagons 117 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (29) : Ketone bodies metabolism Student Notes: . DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1- Define what is meant by ketogenesis and ketolysis 2- Enumerate the different ketone bodies 3- Evaluate the process of synthesis of ketone bodies 4- Explain the ketogenesis role of the liver in 5- Explain why ketone bodies synthesis is activated during fasting and starvation • Definition of ketogenesis and ketolysis • The central role of the liver in ketogenesis and its inability to utilize them • The steps of ketogenesis in the liver • The steps of ketolysis in extra hepatic tissues • Regulation of ketogenesis and ketolysis • • • 118 Faculty of Medicine Biochemical Basis of Medicine I Remember that ketone bodies are used as a major source of energy during starvation in most of the tissues even the brain to decrease the process of gluconeogenesis from muscle protein and spare the glucose produced from gluconeogenesis mainly to the brain and for the tissues which do not have mitochondria such as RBCs. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey. (pp 193197) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. (pp 173176) • • • You have the opportunity to watch the CDROM about fatty acid oxidation. You can access the CD-ROM during your spare time. 1- http://www.biocarta.com/pathfiles/ke tonebodiesPathway.asp 2- http://ull.chemistry.uakron.edu/genobc/Chapter _24/ 3- http://ull.chemistry.uakron.edu/Pathway s/ketone_bodies/index.html 1- Draw the steps of ketogenesis indicating the steps during which 119 Faculty of Medicine Biochemical Basis of Medicine I CoA-SH is regenerated 2- Drew a graph connecting both beta oxidation and ketogenesis 1- Clinical Question: a) In type I diabetes, ketone bodies tend to increase more than type II, explain why? 2- Clinical Case: A type I diabetic patient delivered to you in a coma in the ER , his blood glucose level was 500 mg/dl (27.8 mmol/L), his breath had the acetone charachtristic odour. a) What other investigation(s) would you like to do? b) What type of coma is it? c) What is the biochemical bases of this coma? I- Short Questions: 1- Explain why ketogenesis is essential for energy production in the liver during starvation 2- Explain why the liver can not utilize ketone bodies II- MCQ: 1- Regarding ketogenesis and ketolysis: a) Ketogenesis takes place in the mitochondria of extrahepatic tissues while ketolysis in the cytoplasm of extrahepatic tissues b) Ketolysis takes place in the cytoplasm of extrahepatic tissues c) Ketogenesis and ketolysis takes place in liver mitochondria d) Ketogenesis takes place in liver mitochondria only 120 Faculty of Medicine Biochemical Basis of Medicine I e) All of the above 2- Regeneration of CoA-SH takes place during ketogenesis in the step (s) of: a) formation of acetoacetyl CoA b) formation of beta hydroxybutyrate from acetoacetate c) formation of hydroxymethylglutaeyl (HMG) CoA d) Both (a) and (c) e) All of the above III- True / False 1- Ketogenesis takes place in all the tissues 2- Ketone body oxidation is the major source of energy for most of the tissues in the absorptive state 3- Ketogenesis takes place in the cytoplasm of the liver only 121 Faculty of Medicine Biochemical Basis of Medicine I LECTURE # (30) Lipolysis DEPARTMENT: Clinical Biochemistry TUTOR: TEACHING LOCATION: Auditorium By the end of this lecture you will be able to: 1- Define lipolysis 2- Locate the site where it happens in he tissue and the subcellular location 3- Explain the importance of this pathway in case of fasting and most important during starvation 4- Trace the starting substrate to its final fate 5- Discuss how this pathway is tightly regulated • • • • Definition of lipolysis Conditions favoring lipolysis Site and subcellular level The importance of lipolysis for energy providing • HSL and its regulation • The effect of fed, fasting and exercise conditions on lipolysis Remember that TG is the major energy store in your body, the calorie content of TG in adipose tissue is about 120000, those calories are mobilized through the process of lipolysis during starvation to provide energy in the form of free fatty acid for oxidation in most 122 : Student Notes: . Faculty of Medicine Biochemical Basis of Medicine I of the tissues especially the liver and muscles. 1. Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey. (pp 187-188) 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby. • • • You have the opportunity to watch the CDROM about lipolysis. You can access the CD-ROM during your spare time. 1- http://www.wiley.com/legacy/college/bo yer/0470003790/animations/fatty_acid_ metabolism/fatty_acid_metabolism.htm 2- http://www.elmhurst.edu/~chm/vchemb ook/620fattyacid.html 3- http://www.webpages.uidaho.edu/~dcole/Lipids %20Lecture%2012.pdf 1- Draw how HSL is hormonally regulated 1a) Clinical Question Can you explain why the marathon runner is fed during the marathon in such a ay that his blood glucose is kept low 2a) Clinical Case A patient was delivered to the ER 123 Faculty of Medicine Biochemical Basis of Medicine I with history of type I DM and he was in coma and you diagnosed him as diabetic keoacidosis coma, what do you expect about his plasma level of free fatty acid (low, normal or high) and why? I- Short Questions: 1- Define lipolysis and mention where it happens IV-MCQ: 1-Regarding lipolysis a) It is mostly active during fed state b) It takes place in the adipose tissue and the released fatty acids are carried by chlomicrons to peripheral tissues for oxidation during fasting condition c) It is stimulated by insulin d) The released fatty acids are carried and transported to peripheral tissues by plasma albumin e) All of the above 2-Regarding hormone-sensitive lipase: a) It is active in the dephosphorylated form b) It is activated by the action of the insulin hormone c) It is activated through the action of c-AMP dependent protein kinase d) Its activity is maximum during the fed state e) Non of the above V- True / False 1- Lipolysis means the mobilization of energy storage in adipose tissue in the form of ketone bodies 124 Faculty of Medicine Biochemical Basis of Medicine I 2- HSL is the key regulatory enzyme in lipolysis 3- Glucagon hormone stimulates the process of lipolysis while it is inhibited by insulin 125 Faculty of Medicine Biochemical Basis of Medicine I PRACTICALS Practical (1) : Enzymes: Amylase activity in serum Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Determine the optimum temperature for enzyme activity o Estimate serum amylase activity in the provided sample o Explain the function of serum amylase o Discuss the diagnostic importance of serum amylase • Determination of serum amylase • Explaining the effect of temperature on enzyme activity • Discuss the role of measurement of serum amylase in disease condition • Evaluating the role of amylase in GIT digestion of nutrients Transferable skills: • Interrelate laboratory data with clinical findings READING: Laboratory Handouts will be distributed 126 Faculty of Medicine Biochemical Basis of Medicine I Practical (2) : Enzymes: Estimation of serum alkaline phosphatase Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Determine serum alkaline phosphatase o Evaluate the effect of enzyme inhibitors on enzymatic activity o Define Km and Vmax o Show how the Lineweaver-Burk plot can be used to evaluate Km and Vmax • Determination of serum alkaline phosphatase • The definition of Km and Vmax and the effect of enzyme inhibitors on both of them • Plotting of Lineweaver-Burk plot and its utilization for evaluation of Km and Vmax • Clinical importance of measurement alkaline phosphatase Transferable skills: • Interrelate laboratory data with clinical findings • Serum alkaline phosphatase as marker for bone and liver diseases READING: Laboratory Handouts will be distributed 127 Faculty of Medicine Biochemical Basis of Medicine I Practical (3) : Enzymes: Serum CK isoenzymes Department: Biochemistry Teaching location: Classrooة By the end of this practical the student will be able to: o Define what is meant by isoenzymes o Separate the different CK isoenzymes using electrophoresis o Evaluate the role of CK in tissues o Discuss the role and importance of measuring CK isoenzymes in different diseases conditions • Separation of serum CK isoenzymes • Function of Ck in different tissues • The different isoenzymes of CK and relation to different diseases Transferable skills: • Interrelate laboratory data with clinical findings • How to use CK isoenzymes in evaluating cardiac and muscle diseases READING: Laboratory Handouts will be distributed 128 Faculty of Medicine Biochemical Basis of Medicine I Practical (4): Biologic Oxidation. Oxidative phosphorylation and effect of uncouplers Department: Biochemistry Teaching location: Classroom By the end of this practical the you will be able to: o Determine the amount of inorganic phosphate consumed in the process of oxidative phosphrylation o Explain the effect of uncouplers on this phosphrylation o Discuss how glycolysis was inhibited in this reaction • Determination of activity of the process of oxidative phosphrylation • Explaining the effect of uncouplers • Differentiation between the mechanism of action of different types of uncouplers Transferable skills: • Interrelate laboratory result with some drugs used as uncouplers READING: Laboratory Handouts will be distributed 129 Faculty of Medicine Biochemical Basis of Medicine I Practical (5) : Serum lactate Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Determine blood lactate o Evaluate the importance of determination of serum lactate o To discuss how one enzyme affects different metabolic pathways • Determination of serum lactate • The importance of measurement blood lactate in evaluating children with hypoglycemia • The relation of lactic acidosis to enzyme deficiency such as glucose 6-phosphatase deficiency Transferable skills: • Interrelate laboratory data with clinical findings READING: Laboratory Handouts will be distributed 130 Faculty of Medicine Biochemical Basis of Medicine I Practical (6) : Serum lactate dehydrogenase isoenzymes Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Use electrophoresis for separation of LDH isoenzymes o Differentiate between the different LDH isoenzymes (sources and function) o Evaluate the role of LDH isoenzyme in disease diagnosis • Determination of serum LDH isoenzymes using cellulose electrophoresis • The role of LDH in different metabolic pathways • The sources of LDH isoenzymes and its role in diagnosis Transferable skills: • Interrelate laboratory data with clinical findings • How to use LDH isoenzymes in evaluating cardiac cases READING: Laboratory Handouts will be distributed 131 Faculty of Medicine Biochemical Basis of Medicine I Practical (7) : OSPE TRAINING Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Be familiar with the OSPE • 8-9 stations will be included, two of them will be related to the previously mentioned tests (determination of the analytes), the other will include questions to evaluate the student benefits of the information given in these practicals. Transferable skills: • Accuracy of performing the test • Utilization of data in the different stations for interpretation of clinical cases READING: Laboratory Handouts will be distributed 132 Faculty of Medicine Biochemical Basis of Medicine I Practical (8) : Liver glucose-6-phosphatase deficiency Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Determine glucose-6-phosphatase in tissue extract o Discussing the different changes in blood glucose, lactate, pyruvate, fatty acids, ketone bodies and uric acid found in this case o Explaining the basis of other glycogen storage diseases • Determination of glucose-6-phosphatase activity in liver tissues Transferable skills: • Interrelate laboratory data with clinical findings • Correlation of lactic acidosis with glucose-6-phosphatase deficiency READING: Laboratory Handouts will be distributed 133 Faculty of Medicine Biochemical Basis of Medicine I Practical (9) : Plasma glucose estimation Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Estimate plasma glucose o Differentiate between the different methods for measuring plasma glucose o Utilize the result of plasma glucose to diagnose a case of hyperglycemia o Discuss how to monitor a diabetic patient • Determination of plasma glucose • Difference between blood glucose and plasma glucose • WHO classification of hyperglycemia Transferable skills: • Interrelate laboratory data with clinical findings • How to utilize plasma glucose for diagnosis and monitoring diabetic patients READING: Laboratory Handouts will be distributed 134 Faculty of Medicine Biochemical Basis of Medicine I Practical (10) : Oral glucose tolerance curve Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Draw glucose tolerance curve o Utilize this curve in diagnosis of hyperglycemic case o Differentiate between the different responses in this test • Drawing the curve using different glucose concentration • Estimation of the different samples (fasting, 60 minutes, 90 minutes and 120 minutes) • The difference between oral glucose and intravenous glucose tolerance curve • Monitoring of diabetic patient Transferable skills: • Interrelate laboratory data with clinical findings • How to utilize plasma glucose for diagnosis and monitoring diabetic patients READING: Laboratory Handouts will be distributed 135 Faculty of Medicine Biochemical Basis of Medicine I Practical (11) : Lipid: Estimation of plasma total cholesterol Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Estimate plasma cholesterol using cholesterol oxidase method o Correlate plasma cholesterol level with cardiac diseases o Utilize biochemical knowledge in treating this patient • Measurement of plasma total cholesterol • Different types of hyperlipidemia • Classification of hypercholesterolemia according to Adult Treatment Panel III (ATP III) provided by National Cholesterol Education Program (NCEP) Transferable skills: • Interrelate laboratory data with clinical findings • Approach a case of hypercholesterolemia READING: Laboratory Handouts will be distributed 136 Faculty of Medicine Biochemical Basis of Medicine I Practical (12) : Lipid: Estimation of plasma Triacylglycerol Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Estimate plasma triacylglycerol o Evaluate the role of lipoprotein lipase in lipid metabolism • Differentiate between the different types of hyperlipidemia • Measurement of plasma triacylglycerol • Different types of hyperlipidemia • Classification of hyperlipidemia according to Adult Treatment Panel III (ATP III) provided by National Cholesterol Education Program (NCEP) • Transferable skills: • Interrelate laboratory data with clinical findings • Approach a case of hyperlipidemia READING: Laboratory Handouts will be distributed 137 Faculty of Medicine Biochemical Basis of Medicine I Practical (13) : Lipid: Estimation of fecal fat Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: • Estimate fecal fat • Discuss lipid absorption and factors affecting absorption • Discuss malabsorption as a defective in digestion or absorption • Estimation of fecal fat • Interference of pancreatic damage with the utilization of dietary fat • State of digestion and absorption of other macronutrients in this case • Different causes that may be encountered in this case for malabsorption Transferable skills: • How to approach a case of steatorrhoea READING: Laboratory Handouts will be distributed 138 Faculty of Medicine Biochemical Basis of Medicine I Practical (14) : OSPE TRAINING Department: Biochemistry Teaching location: Classroom By the end of this practical the student will be able to: o Be familiar with the OSPE • 8-9 stations will be included, two of them will be related to the previously mentioned tests (determination of the analytes), the other will include questions to evaluate the student benefits of the information given in these practicals. Transferable skills: • Accuracy of performing the test • Utilization of data in the different stations for interpretation of clinical cases READING: Laboratory Handouts will be distributed 139 Faculty of Medicine Biochemical Basis of Medicine I 140 Faculty of Medicine Biochemical Basis of Medicine I PBL process • The clinical scenario • Key information • Explore the problem • What you know • What you need to know • Identify learning issues • Self/group study • Share the knowledge • Solve the problem • Give feedback & reflect 141 Faculty of Medicine Introduction Biochemical Basis of Medicine I Tutorial # 1 Paget’s Disease of Bone During this week you will work through the case of a Paget’s Disease of Bone A 74-year old woman presented with a 6-week history of pain localized to the left buttock. It did not radiate down the lateral aspect of her thigh and was not aggravated by stooping. On examination there was full movement of both hip joints and no limitation of forward flexion or extension or lateral rotation. The left buttock was slightly warmer to touch than the right. Her blood pressure was 160/75 mmHg and pulse 84/min. Clinical investigations Plasma Urea Reference Range 5.0 mmol/L 25-7.0 Albumin 39 g/L 27-42 Calcium 2.32 mmol/L 2.15-2.55 Phosphate 1.12 mmol/L 0.60-1.40 955 U/L 90-250 ALP Radiological examination demonstrated extensive Paget’s disease of the pelvis, sacrum and left femur 142 Faculty of Medicine Biochemical Basis of Medicine I By the end of this tutorial the student will be able to: 1. Interpret biochemical abnormalities in clinical cases 2. Comment on the clinical and biochemical findings 3. Learn the diagnostic value of different isozymes 4. Learn the clinical application of enzymes assay in clinical conditions 1. How would you interpret the biochemical investigations? 2. What is the most probably diagnosis of this case? Why? 3. What is the clinical application of ALP assay in such a clinical situation? 4. What is the diagnostic value of different isozymes? 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about enzymes. 1. http://www.nlm.nih.gov/medlineplus/pagetsdiseaseofbone.html 2. http://www.pagetsdisease.com/info/about/diagnosed.jsp?usertrack.filte r_applied=true&NovaId=2229644978497118671 3. http://www.mountauburn.caregroup.org/body.cfm?xyzpdqabc=0&id= 6&action=detail&AEProductID=HW_Knowledgebase&AEArticleID= hw1717&AEArticleType=MedicalTest 143 Faculty of Medicine Biochemical Basis of Medicine I Learning issues At the end of the first session you will be able identify the learning issues which related to the Paget’s Disease of Bone Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ………… …………………………………………………………… 144 Faculty of Medicine Biochemical Basis of Medicine I Tutorial # 2 Chest Pains Introduction During this week you will work through the case of chest pain You are in charge of a coronary care unit. The previous day, there were 2 admissions via the accident and emergency services of patients with suspected MI. both men were in their late 40's and had suffered intense chest pain. Patient (a), a businessman, had been taken ill at a local restaurant, while patient (b), a teacher, had just returned home after a strenuous jogging session. Tow blood samples had been taken from each patient, at ≈ 10hr and 24hr after the onset of chest pains, for assay of serum CK and LDH. Clinical investigations Plasma Patient (A) Patient (B) Reference Range 10hr 24hr 10hr 24hr Total CK 748 850 735 790 20-150 U/L CK-MB 82 75 25 23 0-3 U/L LDH 129 182 106 167 45-90 U/L 145 Faculty of Medicine Biochemical Basis of Medicine I By the end of this tutorial the student will be able to: 1. Interpret biochemical abnormalities in clinical cases 2. Comment on the clinical and biochemical findings 3. Learn the diagnostic application of cardiac enzymes in heart patients 4. Learn the use of anticoagulant therapy in MI 1. How would you interpret the changes in cardiac enzymes in both patients? 2. Did the results of biochemical tests assist in making the diagnosis? 3. Would screening the population at large for serum enzymes such as CK and LDH be of predictive value in identifying people at risk of heart attack? 4. One of the treatments that may be given in this situation is the IV administration of t-PA. What is the basis of this treatment? 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about Enzymes 1. http://en.wikipedia.org/wiki/Myocardial_infarction 2. http://www.guideline.gov/summary/summary.aspx?doc_id=6534 3. http://www.nlm.nih.gov/medlineplus/ency/article/003079.htm 146 Faculty of Medicine Biochemical Basis of Medicine I • Learning issues At the end of the first session you will be able identify the learning issues which related to chest pain cases. Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ………… …………………………………………………………… 147 Faculty of Medicine Biochemical Basis of Medicine I Tutorial # 3 Alcohol-Induced Cirrhosis of The Liver Introduction During this week you will work through the case of Alcohol-Induced Cirrhosis of The Liver A 75-year old woman was admitted to hospital following the sudden onset of a rightsided hemiparesis. She had a history of epilepsy and was on treatment with phenytoin. Clinical examination confirmed a right-sided weakness; her blood pressure was normal. Her speech was slurred and her breath smelt strongly of alcohol. Clinical investigations Plasma Bilirubin Reference Range 12 μmol/L <21 ALP 275 U/L 21-92 GGT 402 U/L 6-32 AST 34 U/L 6-35 Ethanol 133 mg/dl Phenytoin 46 μmol/L 148 40-80 Faculty of Medicine Biochemical Basis of Medicine I By the end of this tutorial the student will be able to: 1. Interpret biochemical abnormalities in clinical cases 2. Comment on the clinical and biochemical findings 3. Learn the changes of plasma enzymes activities in liver diseases 1. How would you interpret the biochemical investigations? 2. What is the most probably diagnosis of this case? Why? 3. What is the clinical application of ALP assay in such a clinical situation? 4. What are the change patterns of plasma enzymes in liver diseases? 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about Enzymes 1. http://www.healthsystem.virginia.edu/uvahealth/adult_liver/alcohol .cfm 2. http://www.umm.edu/liver/alcohol.htm 3. http://www.liverfoundation.org/education/info/alcohol/ 4. http://www.clevelandclinicmeded.com/diseasemanagement/gastro/a ld/ald.htm 149 Faculty of Medicine Biochemical Basis of Medicine I • Learning issues At the end of the first session you will be able identify the learning issues which related to Alcohol-Induced Cirrhosis of The Liver Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ………… …………………………………………………………… 150 Faculty of Medicine Biochemical Basis of Medicine I Tutorial # 4 Genetic defect in the Pyruvate Dehydrogenase Complex Introduction During this week you will work through the case of a Genetic defect in the Pyruvate Dehydrogenase Complex A full-term male infant failed to gain weight, had episodes of vomiting, and showed metabolic acidosis in the neonatal period. A physical examination at 8 months showed failure to thrive, hypotonia, small muscle mass, severe head lag, and a persistent acidosis, pH 7 to 7.2. Blood lactate (9 mmol/L), pyruvate (2.4 mmol/L), and alanine (1.36 mmol/L) were greatly elevated. Since these symptoms suggested a genetic defect in pyruvate metabolism, treatment with thiamine, biotin, bicarbonate, protein restriction, and a ketogenic diet were all tried, but none of the treatment alleviated the lactic acidosis. After informed consent, oral lipoic acid greatly improved the lactic and pyruvic acidemia.The patient was doing well 2 years later. By the end of this tutorial you will be able to: 1. Name the enzyme components of pyruvate dehydrogenase complex and cofactors needed for it. 2. Explain the high plasma concentrations of pyruvate, lactate and alanine in a case with defect in pyruvate dehydrogenase complex. 3. Recognize the rationale for attempting therapy with thiamine, biotin, bicarbonate, and protein restriction. 4. Explain why restriction of dietary carbohydrate may not be useful in treating a patient with genetic defect in pyruvate dehydrogenase complex. 1. What are the enzyme components of pyruvate dehydrogenase complex? And what are the cofactors needed for it? 151 Faculty of Medicine Biochemical Basis of Medicine I 2. Why were the plasma concentrations of pyruvate, lactate, and alanine abnormally high? 3. What was the rationale for attempting therapy with thiamine, biotin, bicarbonate, and protein restriction? 4. Restriction of dietary carbohydrate to 40% of the food calories has been fairly effective in alleviating the symptoms of lactic acidosis in patients in whom the genetic defect in the pyruvate dehydrogenase complex is presumably in the E1 subcomplex. In this patient it caused a worsening of the acidosis. Suggest an explanation. 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P: 107 - 114 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about carbohydrate metaboliosm. 1. www.valuemd.com/usmle-step-1-forum/21747-high-yield-biochemistry 2. watcut.uwaterloo.ca/webnotes/PDF/MeatbolismNotes.pdf 3. www.answer.com/topic/pyruvate-dehydrogenase-complex-deficiency 4. www.wikipedia/wiki/pyruvate dehdrogenase complex defect 152 Faculty of Medicine Biochemical Basis of Medicine I • Learning issues At the end of the first session you will be able identify the learning issues which related to the genetic defect in the Pyruvate Dehydrogenase Complex Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ………… …………………………………………………………… 153 Faculty of Medicine Biochemical Basis of Medicine I Tutorial # 5 Pyruvate carboxylase deficiency (Dysfunction of Krebs’ cycle) Introduction During this week you will work through the case of a Pyruvate carboxylase deficiency (Dysfunction of Krebs’ cycle) A 3-month-old female seemed normal until she developed seizures. The infant became progressively worse, showing hypotonia, psychomotor retardation, and poor head control. She had lactic acidosis and an elevated plasma pyruvate level, both more than seven times the normal amount. Plasma alanine concentration was high, and an alanine load failed to induce a normal gluconeogenic response. Pyruvate carboxylase activity was measured using extracts of cultured skin fibroblasts and was found to be less than 1% the normal level. Fibroblasts from the patient accumulated five times greater than normal amounts of lipid. By the end of this tutorial the student will be able to: 1. State the reaction catalyzed by pyruvate carboxylase enzyme. 2. Name the subcellular site of pyruvate carboxylase. 3. Contrast the major biosynthetic function of krebs’ cycle in brain and its main catabolic function in other tissues as skeletal muscle and heart. 4. Relate the failure of alanine load to induce gluconeogenesis in patients with pyruvate carboxylase deficiency. 5. Conclude the benefit of glutamine in stimulation the growth of fibroblasts from a patient with pyruvate carboxylase deficiency disease. 6. Explain the lipid accumulation in cultured fibroblasts in patients with pyruvate carboxylase deficiency. 7. Interpret the use of glutamic acid and aspartic acid in therapy of pyruvate carboxylase deficiency. 1. What reaction is catalyzed by pyruvate carboxylase? Where is the enzyme located in cells? 156 Faculty of Medicine Biochemical Basis of Medicine I 2. What is the metabolic function of pyruvate carboxylase? 3. Explain the failure of the alanine load to induce gluconeogenesis in the patient. 4. Why did lipids accumulate excessively in the patient’s fibroblasts? 5. What treatment would you suggest for a patient with this disease? 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about carbohydrate metaboliosm. ١. www.emedicine.com/Med/topic 1967.htm 2. children.webmd.com/Pyruvate_Carboxylase_deficiency 3. www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?di=226150 4. www.answer.com/topic/pyruvate-carboxylase-deficiency 157 Faculty of Medicine Biochemical Basis of Medicine I • Learning issues At the end of the first session you will be able identify the learning issues which related to the genetic defect in the Pyruvate carboxylase deficiency Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… …………………………………………………………… 158 Faculty of Medicine Introduction Biochemical Basis of Medicine I Tutorial # 6 Von Gierke’s disease During this week you will work through the case of a Von Gierke’s disease The patient was a 12-year-old girl who had a grossly enlarged abdomen. She had a history of frequent episodes of weakness, sweating, and pallor that were eliminated by eating. Her development had been somewhat slow. Her physical examination revealed the following: Blood pressure 110/58 mmHg Temperature 38 ºC Weight 22.4 kg (low) Height 128 cm (low) Lungs clear Heart normal Abdomen prominent with slight venous distention Liver masssively enlarged, firm and smooth Spleen & Kidneys not palpable The following are laboratory findings for a fasting blood sample: Patient Normal values Glucose (mmol/L) 2.8 3.9 – 5.6 Lactate (mmol/L) 6.6 0.56 – 2.0 Pyruvate (mmol/L) 0.43 0.05 – 0.10 Free fatty acids (mmol/L) 1.6 0.3 – 0.8 Triglycerides (g/L) 3.15 1.5 Total ketone bodies (mg/L) 400 30 pH 7.25 7.35 – 7.44 Total CO2 (mmol/L) 12 24 - 30 A liver biopsy specimen revealed bulging and dilated hepatic cells, the portal areas were compressed and shrunken, and no inflammatory reaction.. Glycogen content was 11g/100 g of liver (normal up to 8%), and lipid content was 20.2 g/100 g of liver (normal less than 5g). Hepatic glycogen structure was normal. The following are results of enzyme assays performed on the liver biopsy tissue: Enzyme Patients (units per gram of liver N) Glucose-6- phosphatase 22 Glucose-6- phosphate dehydrogenase 0.07 Phosphoglucomutase 27 Phosphorylase 24 Fructose- 1,6 bisphosphatase 8.4 159 Normal range (units per gram of liver N) 214 ± 45 0.05 ± 0.13 25 ± 4 22 ± 3 10 ± 6 Faculty of Medicine Biochemical Basis of Medicine I By the end of this tutorial the student will be able to: 1. Describe the normal structure of hepatic glycogen. 2. Name the enzyme defect in Von Gierke’s disease. 3. Outline the tissues that might be expected to accumulate excessive amounts of glycogen in Von Gierke’s disease. 4. Match the changes in this structure if there is deficiency in branching enzyme. 5. Explain the reasons for the fasting hypoglycemic episodes in Von Gierke’s disease. 6. Relate the elevated free fatty acids, ketonemia and metabolic acidosis in this disease. 7. Predict and explain the result of continuous parenteral feeding. 8. Recognize the nature of acidosis and its causes in a case of Von Gierke’s disease. 1. What is a normal structure for hepatic glycogen? 2. What changes in this structure would accompany a deficiency in branching enzyme? 3. Which other tissues might be expected to accumulate excessive amounts of glycogen? 4. Explain the reasons for the fasting hypoglycemic episodes. 5. To what might be ascribed (a) the elevated free fatty acid, ketonemia, and (c) the metabolic acidosis? 160 (b) the Faculty of Medicine Biochemical Basis of Medicine I 6. What would you predict would be the result of continuous parenteral feeding? Explain. 7. What is the nature of acidosis 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about carbohydrate metaboliosm. 1. en.wikipedia.org/wiki/Glycogen_storage_disease_type_1 2. www.ncbi.nlm.nih.gov/entrez/dipomim.cgi/id=232200 3. www.merck.com/mmhe/sec 23/ch 282/ ch 282b 4. pediatrics.aappublications.org/cgi/content/abstract/16/6/785 161 Faculty of Medicine Biochemical Basis of Medicine I • Learning issues At the end of the first session you will be able identify the learning issues which related to Von Gierke’s disease Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ………… …………………………………………………………… 162 Faculty of Medicine Introduction Biochemical Basis of Medicine I Tutorial # 7 Galactosemia During this week you will work through the case of Galactosemia A boy patient was the first child of healthy parents without known consanguinity. Delivery was normal and birth weight was 3.78 kg. From the third day of life the child developed an increasing degree of jaundice and at the same time became indolent and difficult to feed. No blood group incompatibility could be demonstrated. At 6 days of age he had a serum bilirubin of 504 µmol/L, and his weight was 15% below normal weight. Muscular tonus was increased, and the patient later began to convulse. Serum bilirubin concentration remained high inspite of frequent exchange blood transfusion. On the the ninth day of life the boy began vomiting, liver enlargement was noted, and the cerebral symptoms became accentuated. A positive test for reducing sugars in urine had already been obtained in the sixth day after birth, which also obtained on the seventh day, while a test for glucose in urine was negative. Hereditary galactosemia was then suspected, and special tests that were performed on the eighth day of life confirmed the diagnosis: Hemoglobin 12.4 mmol/L (200 g/L) AST 299 U/L ALT 202 U/L (normal after seventh day) Bilirubin (max) 549 µmol/L (at seventh day) Glalactose-1-P uridyl transferase 0 (normal 2 – 31 units/g of hemoglobin) (in erythrocytes) Milk feeding was stopped on the ninth day, and it was replaced by intravenous glucose administration. From the tenth day of life, galactose-free diet was introduced. With this treatment the patient improved dramatically. By the end of this tutorial the student will be able to: 1. Summarize the metabolic pathway of galactose in the body. 2. Describe the biochemical defect usually found in galactosemia. 3. Predict the biochemical effects of galactosemia. 4. Illustrate the alternate source of galactose. 5. Explain the ability of galactosemic mother to produce lactose in her milk. 6. Interpret the laboratory results obtained from a galactosemic patient. 7. Distinguish the differences if galactosemia is due to galactokinase deficiency. 163 Faculty of Medicine Biochemical Basis of Medicine I 1. Illustrate the pathway for galactose metabolism 2. What is the biochemical defect in classic galactosemia? 3. What are the biochemical effects of galactosemia? 4. Is there an alternate source of tissue galactose for patient on a galactose-free diet? 5. Would a homozygous galactosemic mother be able to produce lactose in her milk ? 6. How would a D-galactose tolerance curve have appeared if it had (unfortunately) been given to the patient? 7. What are the interpretations of the laboratory results? 8. What differences would have been noted if the deficient enzyme had been galactokinase 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey P: 107 - 114 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about carbohydrate metaboliosm. 1. www.savebabies.org/diseasedescriptions/galactosemia.php 2. www.nlm.nih.gov/medlineplus/ency/article/000366.htm 3.www.wikipedia.org/wiki/galactosemia 4.www.nvbi.nlm.nih.gov/entrez/dispomim.cgi/id=230400 5.www.merck.com/mmpe/sec19/ch296/ch296d.html 6. children.webmd.com/Galactosemia-Test 164 Faculty of Medicine Biochemical Basis of Medicine I • Learning issues At the end of the first session you will be able identify the learning issues which related to Galactosemia Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ………… …………………………………………………………… 165 Faculty of Medicine Introduction Biochemical Basis of Medicine I Tutorial # 8 Hereditary Fructose Intolerance During this week you will work through the case of Hereditary Fructose Intolerance A child had nausea, vomiting, and symptoms of hypoglycemia: sweating, dizziness, and trembling. It was reported that these attacks occurred shortly after eating fruit or cane sugar. This was resulting in a strong aversion to fruits, and the mother was therefore providing large supplementations of multivitamin preparations. The child was below normal weight and was an only child who had been breast fed, during which time none of these symptoms was evident. The clinical findings included some cirrhosis of the liver, a normal glucose tolerance test, and reducing substances in the urine that did not react positively with glucose test papers, in which glucose oxidase was used as the basis for test. A fructose tolerance test was ordered, using 3 g fructose /m2 of surface, given intravenously in a single, rapid push. Within 30 minutes the child displayed the symptoms of hypoglycemia. Blood glucose analysis confirmed this and revealed that the hypoglycemia was greater after 60 to 90 min. Fructose concentration reached a maximum after 15 min and gradually decreased to zero in 2 ½ hr. Phosphate concentration fell 50% and AST and ALT elevation were noted after 1 ½ hr. The urine was positive for fructose. By the end of this tutorial the student will be able to: 1. Summarize the metabolic pathway of fructose in the body. 2. Name the enzyme defect in a patient with hereditary fructose intolerance. 3. recognize the biochemical consequences of deficiency of this enzyme. 4. Explain the elevation noted for AST and ALT in fructose tolerance test. 5. Tell why serum concentration of phosphate drops in fructose intolerance. 6. Explain why the symptoms of hypoglycemia are not found in essential fructosuria. 7. Show the consequences of deficiency of phosphofructokinase in patient with hereditary fructose intolerance. 8. Discover the manifestations of inhibition of fructokinase enzyme caused by fructose-1-phosphate in a patient with hereditary fructose intolerance. 166 Faculty of Medicine Biochemical Basis of Medicine I 1. Illustrate the metabolic pathway of fructose in the body 2. Explain why the fructose concentration in the blood remained elevated for an extended period. 3. Explain the elevation noted for AST and ALT in the fructose tolerance test. 4. Why are the symptoms of hypoglycemia not found in essential fructosuria? 5. What would be the consequences of a deficiency of phosphofructokinase in the patient? 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about carbohydrate metaboliosm. 1. www.pennhealth.com/ency/article/000359.htm 2. www.nlm.nih.gov/medlineplus/ency/article/000359 3. ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=229600 4.www.merck.com/mmpe/sec23/ch282/ch282b.html 167 Faculty of Medicine Biochemical Basis of Medicine I • Learning issues At the end of the first session you will be able identify the learning issues which related to Hereditary Fructose Intolerance Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ………… …………………………………………………………… 168 Faculty of Medicine Introduction Biochemical Basis of Medicine I Tutorial # ٩ Hyperlipidemias During this week you will work through the case of Hyperlipidemias A healthy 25-year-old man presents for a physical examination and is found to have markedly elevated total cholesterol (350 mg/dl), LDL cholesterol (266 mg/dl) and triglycerides (300 mg/dl), and low HDL cholesterol (36 mg/dl). He has an unremarkable physical examination. He is normotensive, a nonsmoker, but with a strong family history of hypercholesterolemia and premature atherosclerotic coronary artery disease By the end of this tutorial the student will be able to: 1. Revise cholesterol metabolism & serum lipoproteins metabolism. 2. Be aware of the types of hereditary hyperlipidemias. 3. Recognize why LDL level is increased with familial hypercholesterolemia. 4. Define the secondary causes of hyperlipidemias 5. Be familiar with the risk factors of coronary artery disease 1. What is the most likely diagnosis? 2. What is the next step after diagnosis? 3. What is the class of medication to be prescribed? 4. What are the possible complications if left untreated? 169 Faculty of Medicine Biochemical Basis of Medicine I 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about Hyperlipidemias . 1. 2. 3. 4. http://ull.chemistry.uakron.edu/biochem/18/ http://www.dentistry.leeds.ac.uk/biochem/thcme/lipoproteins.html http://www.biocarta.com/pathfiles/h_LDLPathway.asp 4- nfs.uvm.edu/nfs-new/activities/tutorials/lipid.html 170 Faculty of Medicine Biochemical Basis of Medicine I • Learning issues At the end of the first session you will be able identify the learning issues which related to Hyperlipidemias Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ………… …………………………………………………………… 171 Faculty of Medicine Introduction Biochemical Basis of Medicine I Tutorial # 10 Gallstones During this week you will work through the case of Gallstones A 45-year-old female presents with midepigastric pain and nausea/vomiting after eating fatty meals. She had been told that she had elevated cholesterol levels, her physical examination is completely normal, but an abdominal ultrasound show few gallstones in the gall bladder By the end of this tutorial the student will be able to: 1. Be familiar with bile salt metabolism and regulation 2. Be able to identify where bile salts are synthesized. 3. Define where bile salts emulsify dietary fats. 4. Differentiate between the types of gallstones 5. Be familiar with the clinical picture, complications & treatment of gallstones 6. Recognize the pathogenetic mechanism of gallstone formation 1. What are gall stones made of? 2. Can gall stones be seen on abdominal X-ray 3. What are the factors needed to consider performing cholecystectomy? 172 Faculty of Medicine Biochemical Basis of Medicine I 1- Required Texts And Resources: Lippincott Illustrated Reviews, 3rd edition, Champe & Harvey 2. Supplementary Texts And Resources: Medical Biochemistry, Baynes and Dominiczek, 1st edition, Mosby Try to access CD-ROM series about Gallstones 1.http://ull.chemistry.uakron.edu/biochem/18/ 2.http://www.uic.edu/depts/mcam/mcbc/handouts/lect26.pdf 3.http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm 4.http://www.dentistry.leeds.ac.uk/biochem/thcme/cholesterol.html 5. http://www.biocarta.com/pathfiles/h_s1pPathway.asp 173 Faculty of Medicine Biochemical Basis of Medicine I • Learning issues At the end of the first session you will be able identify the learning issues which related to Gallstones Try to summarize these learning issues in the table below. We recommend you to learn about these issues. This will help you to solve the problem in the next session. Learning issues Notes ………………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ……………………………………………………………………… ………… …………………………………………………………… 174