MYOGLOBIN STRUCTURE AND FUNCTION Abdul Musasizi MBChB 1.1
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HEMEPROTEINS • Group of specialized proteins that contain heme as a tightly bound prosthetic group • Heme is a complex of protoporphyrin IX and ferrous iron (Fe2+) • Hemoglobin and Myoglobin are the most abundant heme proteins in humans • The heme group group serves to bind reversibly with oxygen.
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10/11/2019 SAIU BIOCHEMISTRY DEPARTMENT 4 Myoglobin • Hemeprotein present in heart and skeletal muscle. • Consists of a single polypeptide chain structurally similar to the a subunit polypeptide chains of the hemoglobin molecule. • It is a reservoir for oxygen by binding it to iron atom. • An oxygen carrier thus increases the rate of transport of oxygen within the muscle cell.
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Myoglobin Structure • Compact molecule, with approximately 80% of its polypeptide chain folded into eight stretches of α-helix • Myoglobin is composed of a single polypeptide chain of 153 amino acid residues. • Interior of the molecule is composed almost entirely of nonpolar amino acids • The structure is stabilized by hydrophobic interactions between these clustered residues • Charged amino acids are located almost exclusively on the surface of the molecule, w • They form hydrogen bonds, both with each other and with water. 10/11/2019 SAIU BIOCHEMISTRY DEPARTMENT 6 10/11/2019 SAIU BIOCHEMISTRY DEPARTMENT 7 Structure and bonding • Heme group is a flat ring molecule containing carbon, nitrogen and hydrogen atoms, with a single Fe2+ ion at the center. • In a heme molecule, the iron is held within the flat plane by four nitrogen ligands from the porphyrin ring. • The globin portion provides an environment for the heme that can bind only one oxygen molecule. • It has eight alpha helices and a hydrophobic core. • There is a proximal histidine group attached directly to the Iron centre. • A distal histidine group exists on the opposite face, not bonded to the iron, but it stabilizes the binding of oxygen to the iron. 10/11/2019 SAIU BIOCHEMISTRY DEPARTMENT 8 Haemoglobin • Found exclusively in red blood cells (RBCs) • Functions to transport oxygen from the lungs to the capillaries of the tissues • Haemoglobin A, the major haemoglobin in adults. • It is a tetrameric protein • Composed of four polypeptide chains ;- two α chains and two β chains held together by non-covalent interactions
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Structure and Bonding • Composed of two identical dimers, (αβ)1 and (αβ)2 • The polypeptide chains within each dimer are held tightly primarily by hydrophobic interactions • Interchain hydrophobic interactions form strong associations between α-subunits and β-subunits in the dimers • Ionic and hydrogen bonds also occur between the members of the dimer
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Forms of Haemoglobin T,” or taut(tense) form R (relaxed) form • Deoxy form of hemoglobin • Oxy form of haemoglobin • The two αβ dimers interact • Binding of oxygen to through ionic bonds and hemoglobin causes the hydrogen bonds. rupture of some of the ionic • T form is the low oxygen- bonds and hydrogen bonds affinity form of hemoglobin. between the αβ dimers. • R form is the highoxygen- affinity form of hemoglobin
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T - form R - form
Deoxy State Oxy state
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Myoglobin
• Myoglobin can bind one molecule of oxygen, because it contains one
heme group.
• The oxygen disassociation curve is Hyperbolic for Mb.
• It means that Mb has high affinity for oxygen at all pO2.
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• pO2 needed to achieve half saturation of the binding site is approx: 1 mm of Hg. ( 26 mm of Hg -Hb).
• Advantage: Mb can bind O2 released by the Hb in the tissues at low
pO2, and then release it within the muscle cell in response to O2 demand.
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• High concentrations of myoglobin in muscle cells allow organisms to hold their breaths longer.
• Oxygen binds to myoglobin and is released only when the hemoglobin
can no longer supply adequate oxygen to muscle cells.
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Differences Haemoglobin Myoglobin Tetrameric protein Monomeric protein 2-alphas 141aas & 2-beta 146aas 153aa residues Four heme groups A single heme group Sigmoid Oxygen dissociation curve Hyperbolic Binds to four Oxygen molecules Binds to a single Oxygen molecule Saturation at high pO2 Saturation at low pO2 Exclusively in RBCs Located mainly in very active tissues
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10/11/2019 SAIU BIOCHEMISTRY DEPARTMENT 17 HEMOGLOBINOPATHIES • Genetic disorders caused by production of a structurally abnormal haemoglobin molecule, synthesis of insufficient quantities of normal haemoglobin. • Sickle cell anemia (Hb S) • Hemoglobin C disease (Hb C) (lysine) • Hemoglobin SC disease (Hb S + Hb C) • Thalassemia syndromes • Qualitative hemoglobinopathy result from production of hemoglobin with an altered amino acid sequence • Quantitative hemoglobinopathy are caused by decreased production of normal haemoglobin e.g. thalassemias
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Hemoglobin S disease • A genetic disorder of the blood caused by a single nucleotide alteration (a point mutation) in the gene for β-globin. • Most common inherited blood disorder in the United States, affecting 80,000 Americans • Sickle cell anaemia is a homozygous, recessive disorder. • 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. Note: The mutant β-globin chain is designated βS, and the resulting hemoglobin, α2βS2, is referred to as Hb S • HbS is characterized by lifelong episodes of pain (“crises”), chronic hemolytic anemia with associated hyperbilirubinemia, and increased susceptibility to infections, usually beginning in early childhood. Note: Lifetime of erythrocyte in sickle cell anemia is less than 20 days, compared with120 days for normal RBCs 10/11/2019 SAIU BIOCHEMISTRY DEPARTMENT 19 Hemoglobin S disease More symptoms…, • A molecule of Hb S contains two • Acute chest syndrome normal α-globin chains and two • Stroke mutant β-globin chains (βS), in which glutamate at position six has • Splenic and renal been replaced with valine. dysfunction, • At low oxygen tension, • Bone changes due to deoxyhemoglobin S polymerizes marrow hyperplasia inside the RBC • A network of fibrous polymers that stiffen and distort the cell, producing rigid, misshapen erythrocytes. 10/11/2019 SAIU BIOCHEMISTRY DEPARTMENT 20 Treatment • Adequate hydration • Analgesics • Aggressive antibiotic therapy if infection is present. • Transfusions in patients at high risk for fatal occlusion of blood vessels. • GENE THERAPY….BONE MARROW TRANSPLANT RESEARCH IS ON! • Intermittent transfusions with packed red cells reduce the risk of stroke • Hydroxyurea, an antitumor drug, is therapeutically useful because it increases circulating levels of Hb F, which decreases RBC sickling Note: A selective advantage exists for heterozygotes for the sickle cell gene that makes them less susceptible to malaria, caused by the parasite Plasmodium falciparum. 10/11/2019 SAIU BIOCHEMISTRY DEPARTMENT 21 Thalassemias • These are hereditary hemolytic diseases in which an imbalance occurs in the synthesis of globin chains • In the thalassemias, the synthesis of either the α- or the β-globin chain is defective • Caused by a variety of mutations; entire gene deletions, substitutions or deletions of one to many nucleotides in the DNA.
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Role in disease • Myoglobin is released from damaged muscle tissue (rhabdomyolysis), which has very high concentrations of myoglobin.
• The released myoglobin is filtered by the kidneys but is toxic to the
renal tubular epithelium and so may cause acute renal failure.