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Lec:3 Biochemistry Dr. Anwar almzaiel GLYCOLYSIS Glycolysis is a cytoplasmic pathway that converts glucose into two pyruvates, releasing a modest amount of energy captured in two substrate-level phosphorylations and one oxidation reaction. If a cell has mitochondria and oxygen, glycolysis is aerobic. If either mitochondria or oxygen is lacking, glycolysis may occur anaerobically (erythrocytes, exercising skeletal muscle),although some of the available energy is lost glycogen glucoseamine G.1.P Hexokinease Glucokinase 1) Glucose G.6.P +2 Mg , Mn+2 ADP ATP Insulin glycolysis Phosphohexo isomerase Hexose mono phosphate pathway It is an allosteric enzyme. 2) G 6.P F.6.P (the reaction is reversible because the energy is equal on sides (equilibrium) so if the level of G.6.P increases or exceeds the F.6.P the G 6.P is converted to F.6.P and vice versa). 3) F.6.P then phosphorylated and converted to fructose1,6 –diphosphate (F.1,6 diphosphate or F.1,6 bis phosphate), by action of phosphofructokinase which need energy so ATP ADP and also Mg+2 +2 and MnPhosphofructokinase are needed F.6.P. lactate ATP F.1,6 diphosphate -, it continue until Goes to pyruvate or Mg+2, Mn+2 ADP 1 Lec:3 Biochemistry Dr. Anwar almzaiel -Its regulatory enzyme (allosteric) enzyme), inhibited by ATP and citrate, and activated by AMP. and long chain fatty acid also inhibited P enzyme Insulin stimulates and glucagon inhibits hosphofructokinase PFK in hepatocytes Phosphofructokinase is another allosteric enzyme of glycolysis and catalyzes rate limiting reaction of glycolysis. 4) F.1,6 diphosphate now split into 2 triose: glyceraldyde-3-phosphate and dihydroxy aceton phosphate, the reaction is reversible carried out by aldolase Aldolase F.1,6 diphosphate glyceraldeyde-3-phosphate Dihydroxy aceton phosphate -dihydroxy aceton phosphate is metabolised in glycolysis unless its converted to glyceraldehyde-3 -phosphate by phosphotriose isomerase (This reaction is reversible) -Two molecules of glyceraldeyde-3-phosphate is formed, molecule from glyceraldehyde-3 phosphate and other from dihydroxy aceto phosphate, so from this point the next rea will be for 2 molecules Dihydroxy aceton phosphate may be converted into glycerol and F.A. Glycerol can be oxidized to give dihydroxy aceton phosphate, while fatty acids are oxidised to acetyl COA which enters Citric acid cycle For example, when someone eats any rice, he will be a fat due to accumulation of fat, rice is a carbohydrate which is converted into glycerol and F.A and stored as fat. During fasting fat is changed into glycerol and F.A to supply energy by conversion to aceton dihydroxy phosphate (pioint of junction with fat metabolism) 2 Lec:3 Biochemistry Dr. Anwar almzaiel 5) glyceraldeyde-3-phosphate is converted into glyceric acid 1,3 diphosphate by the action of glyceraldehyde 3 phosphate dehydrogenase. The reaction is reversible and involves the conversion of NAD+ into NADH, the removal of hydrogen (oxidation) causes dehydrogenation and we have also energy released in the form of Pi group, glyceric acid 1,3 diphosphate high energy compound. If glycolysis is aerobic, the NADH can be reoxidized (indirectly) by the mitochondrial electron transport chain, providing energy for ATP synthesis by oxidative phosphorylation . glyceraldehyde 3 phosphate dehydrogenase Pi glyceraldeyde-3-phosphate NAD+ NADH+H glyceric acid 1,3 diphosphate glyceraldehyde 3 phosphate dehydrogenase enzyme made of 4 subunits contains sulfhydro group, it is inhibited by mercury (Hg), iodoacetate and arsenate How does NAD work? The active form NAD+ draws 2 hydrogen atoms, one of them attached to NAD+ and the other will loss an electron causing the NAD+ to be neutrilized and this hydrogen atom will be positively charged because it loses an electron the NAD+ as result will be NADH. H+ NADH. H+ can be reoxidized by converting pyruvic acid into lactic acid, for this reason, glycolysis is an anaerobic oxidation process because it does not need energy due to the action of NAD. 5) Fate of 1,3 diphosphoglyceric acid: During glycolysis the 1,3 diphosphoglyceric acid enters two pathways Phosphoglceric kinase a. 1,3 diphosphoglyceric acid + 2ADP phosphoglyceric acid +2ATP 3- 1,3 diphosphoglyceric acid has a high energy can be given to ADP and with Pi group f 2 molecules of ATP will form and then conversion of 3 phosphoglyceric into 2-phosphoglyceric by 3 Lec:3 Biochemistry Dr. Anwar almzaiel phosphoglyceric mutase and then continue glycolysis. The reaction is reversible (no loss of energy) diphosphoglyceric acid mutase b. 1,3 diphosphoglyceric acid 2,3 diphosphoglyceric acid Production of 2,3 diphosphophate glyceric acid by glycolysis by a specific mutase and this found in RBC along the normal glycolysis. Large amount of 2,3 diphosphoglyceric acid are produced in human RBC, it plays an important role in regulation of oxygen binding and release by Hb. It lowers the oxygen tension in RBC and thus causes release of O2 to tissue (no energy was produced). 6) Following conversion of 1,3 diphosphoglyceric acid into glyceric acid 3 phosphate, the latter is converted into glyceric acid 2 phosphate by mutase The reoxidation of NADH.H+ into NAD+ can be accomplished by the following reactions: Pyruvate NADH++H lactate (lactic acid) NAD+ glyceraldeyde-3-phosphate glyceric acid 1,3 diphosphate NAD+ NADH++H 6) Fate of 1,3 diphosphoglyceric acid: During glycolysis the 1,3 diphosphoglyceric acid enters two pathways 4 Lec:3 Biochemistry a. 1,3 diphosphoglyceric acid + 2ADP phosphoglyceric acid +2ATP Dr. Anwar almzaiel 3- 1,3 diphosphoglyceric acid has a high energy can be given to ADP and with Pi group 2 molecules of ATP will form and then conversion of 3 phosphoglyceric into 2-phosphoglyceric by phosphoglyceric mutase and continue glycolysis. The reaction is reversible (no loss of energy) Diphosphoglyceric mutase b. 1,3 diphosphoglyceric acid diphosphoglyceric acid acid mutase 2,3 Production of 2,3 diphosphophate glyceric acid by glycolysis by a specific mutase and this found in RBC along the normal glycolysis. Large amount of 2, 3 diphosphoglyceric acid are produced in human RBC, it plays an important role in regulation of oxygen binding and releasing by Hb. It lowers the oxygen tension in RBC and thus causes release of O2 to tissue (no energy was produced). The 2,3 diphosphate glyceric acid hydrolysed and converted into glyceric 2 phosphate without ATP molecules and thus in this secondary pathway no release of energy occurs since 2 ATP is used in the conversion of glucose into glucose 6 phosphate and fructose into fructose 1,6 diphosphate and 2 ATP are released in the conversional of PEP into pyruvic acid Medical Importance 1. In the erythrocytes 2, 3-diPG aids unloading of oxygen by oxyhaemoglobin. 2. Due to the diversion of 1, 3-BPG to 2, 3-BPG production, energy yield of glycolysis is less in erythrocyte 2,3-di( bis) Phosphoglycerate Cycle 5 Lec:3 Biochemistry Dr. Anwar almzaiel 7) Following conversion of 1,3 diphosphoglyceric acid into glyceric acid 3 phosphate, the latter is converted into glyceric acid 2 phosphate by mutase (mutase mean mutarotation changes the position of phosphate group) mutase Glyceric acid 3 phosphate phosphate Glyceric acid 2 8) Glyceric acid 2 phosphate loss H2O molecule in a reversible reaction and no loss of energy to give phosphoenol pyruvate which has energy can be given to ADP to form ATP in an irreversible reaction to form pyruvic acid. Enolase Glyceric acid 2 phosphate Phosphoenol pyruvate 9) Phosphoenol pyruvate has high energy (1200 cal) can be given to ADP to form ATP in an irreversible reaction to form pyruvic acid Puruvate kinase Phosphoenol pyruvate ADP Pyruvate Mg+2, Mn+2 ATP 6 Lec:3 Biochemistry Dr. Anwar almzaiel 10) In absence of oxygen pyruvic acid converted into lactic acid by action of lactic acid dehydrogenase enzyme and the NADH the reaction gives up NAD + which enters the cycle again and used for conversion of glyceraldeyde-3-phosphate into glyceric acid 1,3 diphosphate. In presence of oxygen, pyruvate continues in the mitochondria and burned into CO2, H2O and ATP Lactate dehydrogenase Pyruvate Lactate NADH + H+ Glyceraldeyde-3-phosphate NAD+ Glyceric acid 1, 3 diphosphate This reaction occurs under anaerobic conditions. Formation of lactate using NADH as hydrogen donor is essential for the continuation of glycolysis in rapidly contracting skeletal muscle and erythrocytes because NADH can not be oxidized by respiratory chain O2 been reduced to NADH. By reducing pyruvate to lactate and oxidizing NADH to NAD, lactate dehydrogenase prevents this potential problem from developing. In aerobic tissues, lactate does not normally form in significant amounts. However, when oxygenation is poor (skeletal muscle during strenuous exercise, myocardial infarction), most cellular ATP is generated by anaerobic glycolysis,and lactate production increase Energetics of Glycolysis Generation and consumption of ATP in anaerobic and aerobic glycolysis is given below. In aerobic glycolysis: 1. Number of ATPs generated by phosphoglycerate kinase 2 2. Number of ATPs generated by Pyruvate kinase 2 3. Number of ATPs generated by respiratory chain oxidation of 2 NADH produced in reaction 6 6 4. Number of ATPs consumed in reaction 1 and 3 –2 7 Lec:3 Biochemistry Dr. Anwar almzaiel Net = 8 In anaerobic glycolysis 2 NADH produced in reaction 6 are used to convert pyruvate to lactate. Hence, ATP is not generated. Therefore, the net ATP production in anaerobic glycolysis is only 2 (8 – 6 = 2). Thus, oxidation of glucose to pyruvate (aerobic glycolysis) generates 8 ATP molecules whereas oxidation of glucose to lactate (anaerobic glycolysis) generates 2 ATP molecules. Medical and Biological Importance of Glycolysis 1. Glycolysis provides energy to cells. Anaerobic glycolysis meets energy requirement of rapidly contracting skeletal muscle. 2. Since heart is mainly aerobic organ, myocardial ischemia decreases glycolytic ability of cardiac muscle. As a result energy or ATP production in heart is affected. 3. Deficiency of enzymes of erythrocyte glycolysis (pyruvate kinase) causes haemolytic anemia. This is because erythrocytes gets their energy from glycolysis. 4. Deficiency of muscle phosphofructo kinase causes decreased muscular performance and fatigue. 5. Dietary fructose and galactose are also metabolized by this pathway. 6. Glycolysis has amphibolic role also. It provides precursors for the formation of lipids and aminoacids. For example, pyruvate is converted to alanine by transaminationand dihydroxy acetone phosphate serves as precursor for triglyceride formation. 7. Two glycolytic intermediates pyruvate and glyceraldehydes-3phosphate are used for the synthesis of cholesterol, thiamine and pyridoxine in tuberculosis, malaria and gastritis causing organisms. Regulation of Glycolysis 8 LEC: 3 Dr. Anwar J Almzaiel Usually metabolic pathways are regulated by altering activities of few enzymes of that pathway. Glycolysis is under : -allosteric control - hormonal control. regulatory enzymes of glycolysis Hexokinase , phosphofructokinase and pyruvate kinase are. Their activities are allosterically controlled. Gucokinase, phosphofructokinase-1 and pyruvate kinase are under hormonal control also. Allosteric regulation of glycolysis Phosphofructokinase-1 is the major regulatory enzymes of glycolysis. It is an allosteric enzyme and catalyzes rate limiting reaction of glycolysis. It is inhibited by ATP and citrate. AMP and fructose-6-phosphate are activators of this enzyme. Pyruvate kinase is the second regulatory enzyme. It is inhibited by ATP and phosphoenolpyrvate. Glucose-6-phosphate inhibits activity of hexokinase. So, when ATP (energy) concentration is high glycolysis is inhibited and decrease in ATP level increases rate of glycolysis. Hormonal regulation of glycolysis Insulin increases rate of glycolysis by increasing concentration of glucokinase, phosphofructokinase-1 and pyruvate kinase Puruvic acid Kinase Its irreversible enzyme under physiological condition and it is regulatory enzyme, it require Mg++, Mn++, Thus it will form complex before bind to substrate this enzyme is activated by by fructose 1,6 diphosphate and phosphoenolpyruvate It is activated by presence of high concentration of fructose 1,6 diphosphate and the reaction will continuous forward and also activated by a high level of phosphoenol pyruvate It is inhibited by the presence of high level of ATP, pyruvic acid, citrate, alanine (alanine is converted into puruvate). 9 LEC: 3 Dr. Anwar J Almzaiel It is 3rd mechanism of regulation, thus mechanism of regulation involve: i) Regulation of hexokinase in the converting of glucose into glucose-6phosphate ii) Regulation phosphofructokinase in the converting of fructose-6phosphate into 1,6 diphosphate iii) Regulation of pyruvate kinase in the formation of pyruvate Biological lesion for pyruvic kinase deficiency The deficiency of pyruvic acid kinase is classified (in RBC) as congenital non spherocytic haemocytic anaemia, it leads to low ATP production in RBC and its prematurated death. The lysis of RBC decreases with an increase in glucose and ATP. By the action of autosomal recessive genes, the enzyme is absent in RBC heterozygous which carry half the normal amount of the enzyme, this is treated by increase the glucose level and ATP level in RBC Lactic acid dehydrogenase It converts pyruvic acid to lactic acid which involves reoxidation of NADH formed in oxidation of glyceraldeyde 3 phosphate. LDH exists in the body as an isoenzyme in the intracellular compartment of pH= 8.6 and molecular weight=130000. It acts as isoenzyme (has different net charge and migrate to different regions in electric field). There are 2 types of this enzymes existing in the tissue and each of them contains sulfahydryl group-SH These 2 types are: 1- HLDH: produced in heart 2- MLDH: produced in liver and skeletal muscle 10 LEC: 3 Dr. Anwar J Almzaiel These 2 will form 5 active enzymes each contain 4subunit LDH isoenzyme LDH1 LDH” LDH3 LDH4 LDH4 HHHH HHHM HHMM HMMM MMMM H4 H3M H2M2 HM3 M4 Heart RBC 60 33 70 Trace<1 Trace<1 42 44 10 4 Trace Skeletal muscle 4 7 17 16 56 Liver 2 6 13 13 64 Tissue contains mixture of these isoenzymes, M subunits are more susceptible to high temperature and other denaturating agents than H subunits, treatment of sample with denaturating agents will destroy M4 and M3H and loss of LDH activity upon heating has been used as an index of relative isoenzyme activities damage in cell permeability or destruction, the serum LDH level is elevated and the Treatment Source of activity Untreated serum LDH1-LDH5 Serum heat to 57 LDH1-LDH4 Serum heat 65 LDH1 Heart muscle works under aerobic condition has primarily isoenzyme made up of 1 subunit (H) so tissue produce very little lactate because : Pyruvic acid formed in glycolysis is oxidised by heart tissue into CO2, H2O and ATP to maintain heart mechanical work. This happens because lactate inhibits (H) isoenzyme of LDH as result the enzyme is used to convert lactate into pyruvate in heart cell acid Immediately used by heart LDH, H1 type Lactate puruvate Energy to continue mechanical work of hart 11 LEC: 3 Dr. Anwar J Almzaiel Fate of Pyruvate Under aerobic conditions, pyruvate is converted to acetyl-CoA in all tissues containing mitochondria. Both pyruvate molecules are oxidized to two acetylCoA molecules. Entry of Pyruvate into Mitochondria In mitochondria, pyruvate undergoes oxidative decarboxylation and remaining two carbon fragment is converted to acetyl-CoA. The reaction is irreversible and multi-step process. This reaction is catalyzed by pyruvate dehydrogenase (PD) multi enzyme complex present in inner mitochondrial membrane. This multi enzyme complex consist of three enzymes. . The conversion of pyruvic acid to acetyl COA involves 5 types of reaction and each reaction is catalysed by different enzyme system these enzymes act as a multi enzyme system (complex).. Regulation of Pyruvate Dehydrogenase Pyruvate dehydrogenase activity is regulated by 1. Feedback inhibition. 2. Covalent modification. Acetyl-CoA and NADH inhibits activity of pyruvate dehydrogenase. 3.Increase in level of ADP or AMP so the cell needs energy and in order to gain energy citric acid cycle must be activated and this cycle needs acetyl COA which it gets from the activation of pyruvate dehydrogenase This enzyme is found in the cell in two forms:-Inactive (if phosphorylated) -Active (when dephosphorylated) Phosphorylation and dephosphorylation of this enzyme is under hormonal 12 LEC: 3 Dr. Anwar J Almzaiel control Insulin increases its activity by favoring dephosphorylation. Medical Importance 1. Pyruvate dehydrogenase serve as a link between aerobic glycolysis and citric acid cycle. 2. Since the reaction catalyzed by this enzyme is irreversible, acetyl -CoA can not be converted to pyruvate. 3. Lactic acidemia occurs in some individuals due to deficiency of pyruvate dehydrogenase. 4. Arsenic compounds inhibits this enzyme by reacting with-SH of lipoic acid. War gases and pesticides containing arsenic inhibit this enzyme. Deaths due to arsenic poisoning are well documented in history. Fate of Acetyl-CoA -The body used acetyl COA to form fatty acids, so when a person eats any high carbohydrate diet there will be formation of fatty acids which are stored in the form of lipid glycerol and triglycerides, while during fasting triglycerides converted into fatty acids and acetyl COA that enters citric acid cycle - Another fate of Acetyl COA is the formation of cholesterol in liver which is converted into Vit-D, steroid hormones and bile acids and salts that are of great important in the digestive system Citric Acid Cycle 1. Cyclic arrangement of sequence of reactions that convert acetyl-CoA to two molecules of CO2 is called as citric acid cycle. 2. It is also called as Tricarboxylic acid (TCA) cycle or Krebs cycle. 3. This cyclic process starts with oxaloacetate and completes with regeneration of oxaloacetate. 13 LEC: 3 Dr. Anwar J Almzaiel 4. The conversion of acetyl-CoA to CO2 in the citric acid cycle generates reducing equivalents (NADH, FADH2) and GTP. 5. The reduced co-enzymes are finally oxidized in the respiratory chain with concomitant generation of ATP. 6. One acetyl-CoA molecule is oxidized by this cycle at a time. Site Enzymes of citric acid cycle are present in mitochondrial matrix Citric acid cycle pathway 1- Acetyl COA condense with oxaloacetate which can be obtained either from pyruvate or from deamination of aspartate. Citrate is formed by the action of citrate synthase this reaction needs energy and this energy comes from hydrolysis of thioester linkage of acetyl COA. This enzyme can control the citric acid cycle so its inhibited by High level of NADH, because this reaction needs drawing of H and when there is a high level of NADH, no drawing occur and it will stop High level of succinyl COA High level of ATP Long chain fatty acids 1- As citric acid (citrate) is formed, it will be converted into isocitrate this occur by the action of Aconitase enzyme, which draws H2O from citric acid forming Aconitic acid (Cis-aconitate) this compound by the action of the same enzyme will take H2O and thus converting into isocitric acid (isocitrate). This reaction is (reversible) so when level of isocitrate increases, it will return forming citric acid (but usually proceeds forward because of the continuous removal of isocitrate from medium) 2- Once isocitric acid (isocitrate) formed, it will converted into oxalosuccinic acid by the action of isocitrate acid dehydrogenase which needs NAD to draw H and converts it to NADH, then by the action of same enzyme CO2 is removed from oxalosuccinate which is converted 14 LEC: 3 Dr. Anwar J Almzaiel into α ketoglutarate. This enzyme can control the cycle and there are two types of this enzymes. 1st type : - present in the cytoplasm - nonallosteric enzyme - requires different co-factor which is NAPD 2nd type :-a- found in mitochondria (called mitochondrial enzyme) b- allosteric enzyme c- activated by high level of ADP and NAD inhibited by high level of ATP and NADH When α-keto glutarate formed, we have a point of junction with amino acids catabolism, because if α-keto glutarate takes amino group, it will converted into glutamic acid which can loss amino group again and returns to α-keto glutarate (so it can be used in the synthesis of some amino acids (non-essential amino acids)) when α-keto glutarate it will formed by deamination of glutamic acid 3- α-keto glutarate undergoes dehydrogenation and decarboxylation to yield succinyl COA by action of α-keto glutarate dehydrogenase which needs NAD to draw H and form NADH. In this reaction energy is released and stored in succinyl COA. This reaction which is oxidative dehydrogenase is catalysed by multi enzyme complex (like pyruvate dehydrogenase) and needs the same cofactors (TPP, COA, Mg, NAD, FAD). 4- Succinyl COA is converted into succinate by the action of succinate synthase (thiokinase) this results in releasing energy which taken by ADP to give ATP (the 1st ATP formed in the cycle and can be used by the body 5- Now succinate will be undergo molecular arrangement, so it is converted into fumeric acid (fumerate) by action of succinate dehydrogenase which need a carrier of H called FAD that takes H and converts to FADH2 6- Fumarate will take H2O by fumerase enzyme and converted into malate, then malate is converted into oxaloacetate by the action of malate dehydrogenase which need NAD to draw H and give NADH 15 LEC: 3 Dr. Anwar J Almzaiel The citric acid cycle starts with oxaloacetate and acetyl COA and ends with oxaloacetate and acetyl COA which released in the form of CO2, NADH, FAD and ATP Small amount of energy released directly in the form of ATP in citric acid cycle, but in NADH which is produced can oxidized to H2O and produce high energy by respiratory chain through biological oxidation Energetics of Citric Acid Cycle Oxidation of acetyl-CoA in citric acid cycle is expressed as single equation below. Acetyl COA+ GDP +Pi +3NAD+FAD 2CO2 +CoASH+GTP +3NADH+3H+FADH2 Acetyl CoA +2O2+12Pi +12ADP→2CO2 +12ATP+CoASH+13H2O Generation of ATP in Citric Acid Cycle 1. Number of ATP generated by oxidation of 3 NADH 2. Number of ATP generated by oxidation of FADH2 3. Number of ATP generated from GTP 16 9 2 1 12 LEC: 3 Dr. Anwar J Almzaiel For 2 acetyl COA ----------------24ATP Pyruvic acid acetyl COA 2NADH 6ATP The net result 30 ATP from oxidation of acetyl COA ATP produced from metabolism of one molecule of glucose A- Aerobic condition (in presence of O2) Glycolysis per molecule Energy produced reaction 2glyceraldhyde-3-phosphate 2glyceric acid 1,3 diphosphate 2glyceric acid 1,3 diphosphate 2(3 phosphoglycerate) 2phospoenol pyruvate puruvate N of ATP 2NADH(6ATP) 2ATP 2ATP Net 10ATP 2ATP used in Glucose 8ATP glucose-6-phosphate Fructose-6- phosphate Fructose-1,6-diphosphate So that net result will be 8ATP and 2 pyruvate molecules enter citric acid cycle In cireic acid cycle: 30ATP The total ATP molecules from the oxidation of 1 molecule of glucose under aerobic condition is 38 ATP B- Anaereobic condition (anaerobic glycolysis) 17 LEC: 3 Dr. Anwar J Almzaiel Overall reaction: Glucose + 2Pi +ADP 2 Lactate + 2ATP + 2H2O - Two molecules of ATP are generated for each molecule of glucose converted to lactate - In anaerobic glycolysis there is no net production or consumption of NADH formed of NADH - 2 molecules of lactate is produced for each glucose molecule metabolized - Glycolysis in present of O2 give 8ATP Glycolysis in absence of O2 give 18 2ATP LEC: 3 Dr. Anwar J Almzaiel Metabolism of glycogen Glycogen is the major storage form of carbohydrate in animal and corresponds to starch in plant. It occurs mainly in liver (up to 6%) and muscle(up to 1%). However, because of great mass, muscle represents some 3-4 times as much as glycogen store as liver. Like starch it is branched polymer of α- glucose. The function of muscle glycogen is to act as a readily available source of hexose units for glycolysis within the muscle itself. Liver glycogen is largely concerned with storage and export of hexose units for maintenance of the blood glucose, particularly between meals. After (12-18 hours) of fasting, the liver becomes almost totally depleted of glycogen, whereas muscle glycogen is only depleted significantly after prolonged various exercise. Why the cell can store glycogen but not glucose? Because when glucose increased, osmatic pressure in the cell increase, causing water movement toward the cell and leading to burst so when glucose accumulates in the cell, it will convert to glycogen which consists of branched series of glucose. Glycogenesis The process of glycogenesis start when glucose-6-phosphat is changed to glucose1-phosphate by mutase mutas e glucose1,6diphosphate mutas e glucose 1-phosphate glucose-6-phosphat the reaction is reversible and depends on concentration of substrate (glucose-6phosphat), if there is a large amount or quantities of glucose-6-phosphat will lead to formation of glucose 1-phosphate and the opposite is right. No loss in the energy in this reaction As glucose 1-phosphate formed, it will react with high energy compound UTP (uradin triphosphate), which react with glucose to give UDP glucose (uradin diphosphate glucose) and pyrophosphate released glucose 1-phosphate is high energetic compound and called (active glucose molecule), this reaction is carried by (UDP glucose pyrophosphorylase) one UDP glucose is formed ,it can add already to exiting glycogen in the cell (glycogen primer) by addition of α1-4 linkage causing elongation of the chain is carried by glycogen synthase 19 LEC: 3 Dr. Anwar J Almzaiel In the same time (simultaneously) another enzyme will change α1-4 linkage to α1-6 linkage, this enzyme (Amylo α1-4 α1-6 linkage trans glucosidase or branching enzyme. The process continues by addition of more glucose molecules at α1-4 linkage and then changing this to α1-6 linkage as result a large glycogen molecule 20 LEC: 3 Dr. Anwar J Almzaiel Glycogen synthase Found in the cell in active or inactive form Glycogen synthase Inactive form glycogen synthase active form + PO4 - PO4 Glycogen synthase kinase (active) ADP ATP Adenyl cyclase ATP cAMP adrenalin Glycogen synthase kinase (inactive) Glucagon Adenyl cyclase is activated by: 1- Adrenalin hormones 2- Glucagon hormones - So the inactive glycogen synthase is activated by losing phosphate group and gives it to ADP molecule to form ATP - The reaction is carried out by the glycogen synthase phosphatase enzyme which activated by insulin, so high concentration of glucose will cause activation of glycogen synthase - Active glycogen synthase become inactive when it takes phosphate group and thus is converted to ADP - The reaction is carried by the enzyme glycogen synthase kinase (active), this phosphate group is attached to (OH) group of enzyme - Also glycogen synthase kinase is found active or inactive Inactive one is activated by cAMP (cyclic AMP) or 3,5 cyclic AMP that is formed within the cell from ATP by the action of adenyl cyclase enzyme, its activated by adrenalin and glucagon hormones During exercise or emotional stress, adrenalin is released in very high concentration activating the formation of cAMP and then glycogen synthesis is inhibited while a 21 Lec:2 Biochemistry Dr. Anwar almzaiel high amount of glucose will be used by the body to produce high amount of energy, when it necessary for the exercise or emotional stress. H2O cAMP 5AMP Phosphodiesterase Activation by insulin + Inhibited by caffeine Glycogen synthase is activated by glucose-6 phosphate and inhibited by glycogen (allosteric enzyme) 22