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المحاضره كامله GLOBULAR HEMOPROTEINS • Hemeproteins are a group of مكون من1- specialized proteins that contain 2-heme as a tightly bound prosthetic group ( non protein part attach fraimly to protein ). • Heme is a complex of protoporphyrin IX ( cyclic tetra (4) birol ring ) ) كربونات ونتروجين واحده ( انظر الرسمه الشريحه التاليه4 حلقه خماسيه بها اللون االصفر نوت اضافي and ferrous iron (Fe2+) مهمه. • The iron is held موجودin the center of the heme molecule by bonds to the four nitrogens of the porphyrin ring كالحديد مرتبط باربع ذرات نتروجين. • The heme Fe2+ can form two additional bonds, one on each side of the planar porphyrin ring واحده ليرتبط بها االكسجين واالخرى روابط6 مكتوبه باالسفل – اذا مجموع روابط الحديد. • In myoglobin and hemoglobin, one of these positions is coordinated to the side chain of a histidine residue of the globin molecule, whereas the other position is available to bind oxygen A .Hemeprotein (cytochrome c( B .Structure of heme هذه الصوره توضح ما Myoglobin : اول نوع من هيموبروتين :الوظيفه يقول الدكتور سؤال استغفر هللاStructure and function • Myoglobin, a hemeprotein present in heart and skeletal muscle, functions both as a reservoir for oxygen, and as an oxygen carrier that increases the rate of transport of oxygen within the muscle cell. )مهمه جدا ( سؤااال خصوصا االخضر • Myoglobin consists of a single polypeptide chain that is structurally similar to the individual subunit polypeptide chains of the hemoglobin molecule. • Myoglobin is a compact مرصوصmolecule, with approximately 80 % ) مهمه جدا ( سؤالof its polypeptide chain folded into 8 stretches of α-helix ) هذي مهمه جدا ( سؤال. These α-helical regions, labeled A to H Myoglobin has more affinity to o2 than hemoglobin mussels and get the o2 from • A-B-C-D-E-F-G-H يعنيMyoglobin located in hemoglobin • The interior الداخليof the myoglobin molecule is composed almost entirely of nonpolar amino acids. • In contrast, polar amino acids are located almost exclusively on the surface of the molecule. • The heme ( non polar ) group of myoglobin is located in a crevice المسافه بينin the molecule between helix E and helix F, مهمه جدا ( سؤال ) – تتوضح من الرسمه القادمهwhich is lined with nonpolar amino acids. Notable exceptions are two histidine residues اسم احماض امينيه قطبيه في المركز غير القطبي تتوضح بالرسمه وسوف تشرح الحقا. الحظ مكان الهيمي بين F and E A. Model of myoglobin showing helices A to H. B. Schematic diagram of the oxygen-binding site of myoglobin هذه االحماض االمينه عباره عن اجزاء قطبيه في مركز غير قطبي Distal : بعيد عن جزيء الحديد Proximal : قريب من جزيء الحديد • One, the proximal histidine (F8), binds directly to the iron of heme. • The second, or distal histidine (E7), does not directly interact with the heme group, وظيفة الديستالbut helps stabilize the binding of oxygen to the ferrous iron. • فائده البروتين: The protein, or globin, portion of myoglobin prevents the oxidation of iron of heme. مهمه نوع الحديد دائما FE++ ferrous سواء كان االكسجين مرتبط به او ال بسبب ارتباط Globin ثانيا: Hemoglobin Structure and function الوظيفه سؤااال: • Hemoglobin is found exclusively in red blood cells, where its main function is to transport oxygen from the lungs to the capillaries of the tissues. • Hemoglobin A, the major hemoglobin in adults, is composed of four عكس السابق المكون من واحده فقطpolypeptide chains - two α chains and two β chains - held together by noncovalent interactions. • Each subunit has stretches of α-helical structure, and a heme-binding pocket similar to that described for myoglobin. • However, the tetrameric hemoglobin molecule is structurally and functionally more complex than myoglobin. • For example, hemoglobin can transport H+ and CO2 from the tissues to the lungs, and can carry four molecules of O2 from the lungs to the cells of the body. • Furthermore, the oxygen-binding properties of hemoglobin are regulated by interaction with allosteric effectors . DIFFREENSES BETWEEN MYOGLOBIN AND HEMOGLOBIN 1- hemoglobin carry 4 o2 atoms while myoglobin carry 1 o2 atom only 2- the affenity of Hb to o2 affected by 5 factors ( which will be expliened later ) while myoglobin not affected by any factor 3- myoglobin carry o2 only while hemoglobin can carry o2 , co2 and H+ السؤال االول على التركيب شريحه مهمه جدا وعليها سؤالين السؤال االول HbA1c : اصله HbA ولكن ارتبط به جلكوز وهذا االرتباط غير عكسي ( يعني غير ) قابل لالنفصال السؤال الثاني 3–6 % Normal adult human hemoglobins. [Note: The α-chains in these hemo-globins are identical] HbA1c could be used as a monitor for the control of the blood glucose level during the last 2 months for diabetic patients Schematic diagram showing structural changes resulting from oxygenation and deoxygenation of hemoglobin . شريحه مهمه وتشرح في الشرائح االقادمه Quaternary رباعي structure of hemoglobin: • The hemoglobin tetramer البروتين المكون من اربع وحداتcan be envisioned ينقسم لصورتين متطابقتينas being composed of two identical dimers, )αβ(1 and )αβ(2, in which the numbers refer to dimers one and two. كما في الصوره • The two polypeptide chains within each dimer are held tightly together, primarily by hydrophobic interactions • In contrast, the two dimers are able to move with respect to each other, being held together primarily by polar bonds. • The weaker interactions between these mobile dimers result in the two dimers occupying different relative positions in deoxyhemoglobin as compared with oxyhemoglobin • T form ) تكون2 – 1 اذا اقتربوا من بعض ( الديامير: مهمه وتشرح الصورهThe deoxy التحرر من االكسجينform of hemoglobin is called the “T,” or taut (tense )توترform. •In the T form, the two αβ dimers interact through a network of ionic bonds that constrain the movement of the polypeptide chains. The T form is the low-oxygen-affinity form of hemoglobin. • R form : اذا ابتعدوا تكون: سيم سيمThe binding of oxygen to hemoglobin causes the rupture of some of the ionic bonds between the αβ dimers. •This leads to a structure called the “R,” or relaxed form, in which the polypeptide chains have more freedom of movement . The R form is the high- oxygen-affinity form of hemoglobin. Binding of oxygen to myoglobin and hemoglobin • Myoglobin can bind only one molecule of oxygen (O2), because it contains only one heme group. • In contrast, hemoglobin can bind four oxygen molecules—one at each of its four heme groups. • The degree of saturation (Y) of these oxygen-binding sites on all myoglobin or hemoglobin molecules can vary between zero (all sites are empty) and 100% (all sites are full نفس مخطط الفيسيو الحظ ان P50 للMyoglobin اكبر بكثير من الهيموجلوبين الن جداذبيه االول اكبر تجاه االكسجين Myoglobin : له شكل Hyperpolic curve Hemoglobin له شكل S shape بسبب وجود اربع مركبات هيمي ( تفصل الحقا Oxygen dissociation curves for myoglobin and hemoglobin Oxygen dissociation curve: • A plot of Y measured at different partial pressures of oxygen (pO2) is called the oxygen dissociation curve. • The curves for myoglobin and hemoglobin show important differences. • This graph illustrates that myoglobin has a higher oxygen affinity at all pO2 values than does hemoglobin Allosteric effects: التاثير الجانبي على الهيموجلوبين • The ability of hemoglobin to reversibly bind oxygen is affected by the pO2 تتاثر بالعوامل التاليه: (1-through hemeheme interactions , 2-the pH of the environment, 3-the pCO2,4- the availability of 2,3-bisphosphoglycerate and 5- CO. • These are collectively called allosteric (“other site”) effectors, because their interaction at one site on the hemoglobin molecule affects the binding of oxygen to heme groups at other locations on the molecule. • [Note: The binding of oxygen to myoglobin is not influenced by allosteric effectors.] Effect of O2 binding (Heme-heme interactions): The sigmoidal له شكل اسoxygen-binding curve reflects specific structural changes that are initiated at one heme group and transmitted to other heme groups in the hemoglobin tetramer. The net effect is that the affinity of hemoglobin for the last oxygen bound is approximately 300 times greater than its affinity for the first oxygen bound. اذا ارتبط االكسجين بهيمي ( واحده من االربع ) فان هذا االرتباط يحفز الهيمي الباقيه لالرتباط باالكسجين ويزيد جاذبيتها ) ضعف الهيمي ( االول300 ( االخير ) الى4 تجاهه حتى يصل عند الهيمي رقم O2 favors the R- form الشكل االكثر جاذبيه لالكسجينof Hb. ( سؤااال ) مهمه Deoxygenation favors تؤدي الىthe T- form of Hb. Effect of pH and CO2 (Bohr effect): • The release of oxygen from hemoglobin is enhanced when the pH is lowered ( H+) or when the hemoglobin is in the presence of an increased partial pressure of CO2. • Both result in a decreased oxygen affinity of hemoglobin and both, stabilize the T state. • In the tissues, CO2 is converted by carbonic anhydrase (CA) to carbonic acid: CO2 + H2O H2CO3 which spontaneously loses a proton, becoming bicarbonate (the major blood buffer): H2CO3 HCO3¯ + H+ • The H+ produced by this pair of reactions pH • H+ increases the ionic bonds on Hb T-form O2 release to the tissues. • Lactic acid produced during muscular exercise pH Effect of 2,3-bisphosphoglycerate ( ) سالب الشحنه:سؤالon oxygen affinity: • 2,3- Bisphosphoglycerate (2,3-BPG) is an important regulator of the binding of oxygen to hemoglobin. • It is the most abundant organic phosphate in the red blood cell, where its concentration is approximately that of hemoglobin. • 2,3-BPG is synthesized from an intermediate of the glycolysis. Binding of 2,3-BPG to deoxyhemoglobin ( )موحب الشحنه: • 2,3-BPG decreases the oxygen affinity of hemoglobin by binding to deoxyhemoglobin but not to oxyhemoglobin. • This preferential binding stabilizes the T conformation of deoxyhemoglobin.( ) يجعله اكثر سالبيه: سؤال Response of 2,3-BPG levels to chronic مهمهhypoxia or anemia: The concentration of 2,3-BPG in the red blood cell increases in response to chronic hypoxia or anemia. • Elevated 2,3-BPG levels lower the oxygen affinity of hemoglobin, permitting greater unloading of oxygen in the capillaries of the tissues. Binding of CO: • Carbon monoxide (CO) binds tightly (but reversibly) to the hemoglobin iron, forming carboxyhemoglobin. • When carbon monoxide binds to one or more of the four heme sites, hemoglobin shifts to the relaxed conformation (R-form), مهمهcausing the remaining heme sites to bind oxygen with high affinity. • As a result, the affected hemoglobin is unable to release oxygen to the tissues. • [Note: The affinity of hemoglobin for CO is 220 times greater than for oxygen. Co compute with O2 on the binding site ( hemoglobin ) Factors favoring the T-form of Hb. are: • Deoxygenation • Low pH ( H+) • CO2 • Lactic acid • 2,3 bisphosphoglycerate Factors favoring the R-form of Hb. are: • O2 • CO Hemoglobinopathies: • Hemoglobinopathies have traditionally تقليدياbeen defined as a family of genetic disorders caused by سببين: 1- production of a structurally abnormal hemoglobin molecule,2- synthesis of insufficient quantities كميات غير كافيهof normal hemoglobin, or, rarely, both. • االمراض1-Sickle cell anemia (Hb S),2- hemoglobin C disease (Hb C), and 3-the thalassemia قلت كميه الهيموجلوبين syndromes are representative hemoglobinopathies that can have severe clinical consequences. • The first two conditions result from production of hemoglobin with an altered amino acid sequence (qualitative تغيير بالجودهhemoglobinopathy), whereas the thalassemias are caused by decreased production of normal hemoglobin (quantitative تغير الكميه hemoglobinopathy). Sickle cell disease (hemoglobin S disease) (SCD) • Sickle cell disease (also called sickle cell anemia) is a genetic disorder of the blood caused by a single nucleotide alteration )a point mutation( in the β-globin gene. • Sickle cell disease is an autosomal recessive disorder. • It occurs in individuals who have inherited two mutant genes (one from each parent) that code for synthesis of the β chains of the globin molecules. A molecule of Hb S contains two normal α-globin chains and two mutant β-globin chains )βS(, ) مهمه جدا جدا ( سؤاالin which glutamate ذو الشحنه السالبهat position six has been replaced with valine ال يحمل شحنه. Therefore, during electrophoresis جهاز االقطاب الكهربائيat alkaline pH, Hb S migrates more slowly toward the anode (positive electrode) than does Hb A ) مهمه ( سؤال. Electrophoresis of hemoglobin obtained from lysed red blood cells is routinely used in the diagnosis of sickle cell trait and sickle cell disease. طريقه الكشف عن المرض: HbS is slower in electrophoretic motility than HbA at pH 8.6 The lifetime of an erythrocyte in SCD is less than 20 days compared to 120 days in normal RBC, hence causing anemia. HbS is less soluble than HbA and precipitates تترسب specially when in T-form giving the RBCs the sickle shape. ) الن الذوبانيه تعتمد على زياده الشحنه ( كلما زادت الشحنه زادت الذوبانيه