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Chemistry and Functions of Hemoglobin and Myoglobin

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Chemistry and Functions of Hemoglobin and Myoglobin Chemistry And Functions Of Hemoglobin and Myoglobin Dr Bela Goyal • What are Hemoproteins? • What is Hemoglobin? • Structure of Hemoglobin • Functions of Hemoglobin • ODC and Factors affecting it • Normal Hb Variants • Hemoglobin Derivatives • Hemoglobinopathies Learning objectives What are Hemoproteins? What is Hemoglobin? Structure of Hemoglobin What Are Hemoproteins? • Hemoproteins are Conjugated Proteins • With Heme as a Prosthetic group in their structures. Heme Containing Proteins 1. Hemoglobin (Hb) 2. Myoglobin (Mb) 3. Cytochromes (ETC Components) Heme Containing Enzymes 1. Catalase 2. Peroxidase 3. Tryptophan Dioxygenase/ Tryptophan Pyrrolase What Is Hemoglobin? • Hemoglobin(Hb) is a major Hemoprotein of Human body • Hemoglobin Chemically is: • Conjugated Protein • In Hemoglobin • Heme is a Prosthetic group • Globin is a Protein part (Hemoglobin = Heme + Globin) • Hemoglobin(Hb) is Red color pigment • Location Of Hemoglobin- Inside Red blood cells/Erythrocytes of blood. • Hemoglobin In RBCs Occupies: • 33% of the RBC volume (1/3) • 90-95% of the dry weight of RBC is by Hb. • Normal concentration of Hemoglobin in the Human Blood: Adult Males- 13.5–17.5 gm/dL Adult Females- 12.5–16.5 gm/dL Terminologies of Hemoglobin • Hemoprotein -Heme is a prosthetic group • Chromoprotein - Red in color • Metalloprotein - Metal Iron (Fe) present • Respiratory Protein- Connected to Respiration process and Respiratory Chain(Electron Transport Chain) • Oxygen Binding Protein-Binds with molecular Oxygen and transports it. Structure of hemoglobin • Iron containing pigment heme is attached to protein globin • Heme is iron porphyrin complex called Iron protoporphyrin IX • Globin is a protein Iron in Heme • Functional form Iron in Heme is- • Ferrous form(Fe++) • Reduced state • Fe++ located centrally in Protoporphyrin ring system. • Fe of Heme is Hexavalent • 4 bonds linked with each Nitrogen of 4 Pyrrole rings. • 5th bond linked with Proximal Histidine (F8) of Globin chain • 6th bond is with Oxygen. Structure Of Protoporphyrin IX- • Cyclic substituted Tetrapyrrole ring structure (I,II,III and IV Tetrapyrrole ). • Tetrapyrrole rings has substituted groups in systematic manner- MV,MV,MP,PM (M=Methyl ,V=Vinyl, P=Propionyl) Structure of Globin Adult Hemoglobin has 4 Polypeptide chains : 2α and 2β • In Hb 4 polypeptide chains are visualized as two identical dimers, (αβ)1 and (αβ)2. • Two dimers are linked to each other by weak polar bonds- movement at the interface of these two occurs more freely. • Two polypeptide chains within a dimer are held together tightly by: • Ionic bonds and Hydrophobic interactions, which prevent their movement relative to each other. Heme Pocket • Heme Pocket is a crevice/ hollow hydrophobic area • Formed in the interior of Globin subunits • Heme group is tucked between E and F helices of Globin subunit. • Amino acids in Globin chain are identified by • The helix name and position of a.a in that helix. • E7 His ( Distal His) • F8 His ( Proximal His) • Fe++ of Heme is linked to Proximal Histidine (F8) • O2 is linked to Distal Histidine(E7). • Thus to attain stability Oxygen is bound to both Heme and Globin . Learning objectives Functions of hemoglobin Features of oxygenation of Hb Functions of Hemoglobin • Hemoglobin has important role in Respiration mechanism- Hb Majorly Transports- Oxygen (97% -100%) Hb Minorly Transports – Carbon dioxide (15% -25 %) Deoxy Hemoglobin Transports-Protons(H+) • Oxygen transported by Hb and reached to every cell is used up in Mitochondrial ETC (Respiratory Chain/Cellular respiration) • To generate ATP (Oxidative Phosphorylation) • Hemoglobin Plays Role as Buffer- • (Hb/Hb-H+) in the Erythrocytes • Resists change in pH • Imidazole group of amino acid Histidine of Hb molecule – • Participates in buffering mechanism of Hb. SALIENT FEATURES OF OXYGENATION AND DEOXYGENATION OF HEMOGLOBIN • Hemoglobin gets Oxygenated • At Lungs • At increased pO2 concentration (100-120 mm Hg) • At decreased pCO2 • Hemoglobin gets deoxygenated • At Tissues • With Increased pCO2 • Decreased pO2 levels (40 mm Hg) • Hemoglobin is 97 % saturated with Oxygen when it leaves the Lungs- (Arterial Blood-Oxy Hb). • Under resting conditions Hb is about 75% saturated with Oxygen when it returns-(Venous blood- Deoxy Hb). Pulse Oximeter Is An Instrument That Measures The Percentage Hb Fully Saturated With Oxygen In Arterial Blood Features of Oxygenation of Hb • Oxygen binds with Hb to form HbO2 • Oxygen links to Ferrous form of Iron, of Heme • Non enzymatically, loosely and reversibly. • During oxygenation One Hb molecule with 4 Heme can bind to four O2 molecules • During Oxygenation Ferrous of Heme is not oxidized to Ferric. Oxygenation of Hemoglobin causes Considerable structural conformational change in Globin subunits. T Form of Hb R Form Of Hb Deoxy Hb is in T form binds Oxy Hb is in R form binds only with CO2,H+ and 2,3BPG with Oxygen T form has 8 salt bridges Salt bridges are broken in linked in between the dimer between the dimer subunits subunits during oxygenation of Hb. More constrained form Less constrained form T form has low affinity for R form has higher affinity for Oxygen Oxygen T form of Hb predominates in R form of Hb predominates at low pO2 high pO2 COOPERATIVE BINDING MECHANISM OF OXYGEN WITH HEMOGLOBIN Allows 100% saturation at po2 much lower than what it actually requires Hemoglobin picks up the largest possible load of Oxygen in the lungs, And delivers the Oxygen where and when needed. The cooperative binding of oxygen • enhances the efficiency of haemoglobin as an oxygen transporter. • Without positive cooperativity, an 81-fold increase of the pO2 would be required to raise the oxygen saturation from 10% to 90%. • However, about Five fold increase is sufficient to do the same. • This means that haemoglobin can rapidly bind oxygen in lungs (where pO2 is high) and then readily liberate it in the tissue capillaries (where pO2 is low). • Hill coefficient is an indicator of cooperative binding • Extent to which the binding of first oxygen molecule to one subunit of Hb increases the subsequent oxygen binding to other subunits. • Max.4, practically 2.5 Learning Objectives Oxygen dissociation curve(ODC) Factors affecting ODC (Allosteric Effectors) Oxygen dissociation curve Factors affecting ODC Bohr effect Role of 2,3 BPG • ? Response of 2,3-BPG levels to chronic hypoxia or anemia • ? Role of 2,3-BPG in transfused blood • ? HbF Mnemonic for Factors causing Right Shift of ODC : CADET • C – CO2 • A – Acid (H+) • D– 2,3-BPG /2,3 DPG • E – Exercise • T – Temperature Binding of CO Learning objectives Minor Hb Myoglobin Minor Hb • Binding of 2,3-BPG to HbF: weak • ? Importance ODC of Fetal Hb F vs. Adult Hb HbA1c WHO Criteria for Diabetes Mellitus HbA1c > 6.5% Myoglobin (Mb) Why is myoglobin unsuitable as an O2 transport protein but well suited for O2 storage? • Myoglobin in Muscle Cells is a: • Oxygen storing Hemoprotein • Reservoir of Oxygen • Myoglobin does not allow Oxygen to remain in free state: • Oxygen diffused in muscle cells is used up in Oxidative phosphorylation. • If Oxygen remained unused in the cells it immediately binds with Mb to form MbO2 • Mb present within muscle cells comes out in blood after damage to muscle cells. • Mb is found abnormally in blood and urine of MI cases. • Thus elevated Myoglobin levels in blood/urine is a marker of Myocardial damage. S.No Hemoglobin (Hb) Myoglobin (Mb) 1. DifferencesHb is Oxygen transport of proteinHb Andin Mb is MbOxygen storing protein in RBCs of blood. muscles. 2. Tetrameric has four Heme and Monomeric has one Heme and binds binds with 4O2 with 1 O2. 3. Oxygenated at Lungs Oxygenated at Muscle Cell Cytosol. 4. HbO2 unloads oxygen at tissues MbO2 unloads oxygen at cell cytosol when pO2 is at 40 mmHg. when pO2 is at 5 mmHg. to rapidly respiring cells P50 for HbA1 is 27 torr. P50 for Mb is 2 torr. 5. ODC is sigmoid shaped ODC is hyperbolic shaped. 6. Hb has 574 amino acids. Mb has 153 amino acids. Mol .wt-67,000 Daltons. Mol wt-17,200 Daltons. Learning Objectives Types of Hemoglobinopathies Sickle cell anemia(Qualitative Hemoglobinopathy) Hemoglobinopathies • group of genetic disorders caused by production of a structurally abnormal hemoglobin molecule; • synthesis of insufficient quantities of normal hemoglobin; • or, rarely, both. Sickle cell disease Hb Electrophoresis Treatment • Hydroxyurea Possible selective advantage of the heterozygous state • high frequency of the bS mutation among black Africans Other types of Qualitative Hemoglobinopathies • HbC • HbSC • HbM Conversion Of Methemoglobin To Hemoglobin is NADPH+H+ Dependent H2O2 and Oxidant Drugs Hemoglobin (Fe+2) Methemoglobin (Fe+3) Methemoglobin Reductase NADP+ NADPH+ H+ Methemoglobinemias • Oxidation of the heme iron in hemoglobin to the ferric (Fe3+) state forms methemoglobin, which cannot bind O2. • Causes drugs, such as nitrates endogenous products such as reactive oxygen species inherited defects: HbM, deficiency of NADH-cytochrome b5 reductase, • S/S: chocolate cyanosis • Treatment: methylene blue •Dried blood and old meat have brown color. •Butchers uses Ascorbic acid to reduce Methemoglobin to make the meat look fresh!! Learning Objectives Thalassemia Quiz on hemoglobinopathies ORGANIZATION OF THE GLOBIN GENES Quantitative hemoglobinopathies Thalassemia(α and β) β Thalassemia β Thalassemia Anemia • Anemias, • reductions in the number of red blood cells or of hemoglobin in the blood. • can reflect impaired synthesis of hemoglobin eg, in iron deficiency; • or impaired production of erythrocytes (eg, in folic acid or vitamin B12 deficiency; • Diagnosis of anemias begins with spectroscopic measurement of blood hemoglobin levels. • Thank you.
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