Oxygen_transporters_for_video.pdf

OXYGEN TRANSPORTERS (Part 1) I. Myoglobin II. Hemoglobin structure and function III. Diseases of hemoglobin: methemoglobinemia & sickle-cell anemia Jim Baleja Dept of Medical Education Room MV504C, 136 Harrison Avenue Email: [email protected] I have no commer...

OXYGEN TRANSPORTERS (Part 1) I. Myoglobin II. Hemoglobin structure and function III. Diseases of hemoglobin: methemoglobinemia & sickle-cell anemia Jim Baleja Dept of Medical Education Room MV504C, 136 Harrison Avenue Email: [email protected] I have no commercial relationships relevant to the subject matter of this session  The heme of myoglobin and hemoglobin Source: Stryer, 4th ed., Ch 7  Myoglobin: the oxygen transporter of muscle Myoglobin contains a prosthetic group called a heme molecule proximal (Alternatively the helices are labeled A through H and the residues numbered from 1 to about 24) Source: Stryer, 4th ed., Ch 7  The prosthetic group of myoglobin and hemoglobin, heme, is in a deep, non-polar pocket proximal This sequestering from water helps maintain the Fe in the +2 state Source: Stryer, 4th ed., Ch 7  The Difference between Oxygenation and Oxidation Mb:Fe2+ O2 oxidation oxygenation e- e- O2 Mb:Fe2+:O2 Carbon monoxide (CO) bound heme is also Mb:Fe3+ bright red Jane Ann Boles and Ronald Pegg  Myoglobin changes its structure a little when oxygen (O2) binds Source: Stryer, 4th ed., Ch 7  Myoglobin is a monomer, the change in structure on oxygenation has little consequence Source: Stryer, 4th ed., Ch 7  Main Points (Part 1 of 3) Myoglobin is a monomeric helical protein that contains heme. It transports oxygen in muscle. Oxygenated heme is bright red, oxidized heme is brownish, deoxygenated heme is more blue TRUE FOR BOTH MYOGLOBIN AND HEMOGLOBIN The proximal histidine forms a ligand to the iron that moves on oxygenation (both Myoglobin and Hemoglobin) There is a minor change in the structure upon oxygenation  OXYGEN TRANSPORTERS (Part 2) I. Myoglobin II. Hemoglobin structure and function III. Diseases of hemoglobin:  Hemoglobin comprises 2 a subunits and 2 b subunits Hemoglobin (HbA) is a dimer of ab units Myoglobin, the a globin subunit and the b globin subunit all contain heme and have similar sequences and structures Source:Mark’s Basic Medical Biochemistry  Myoglobin is in muscle and hemoglobin is in blood Hill plot n is the Hill coefficient Stryer, 4th ed. Ch. 7 n>1 means positive cooperativity. binding of one ligand promotes binding of another. n=1 means no cooperativity. n1) CO2, H+, and BPG are negative allosteric effectors Fetal hemoglobin is a2g2 and binds BPG less well  OXYGEN TRANSPORTERS (Part 3) I. Myoglobin II. Hemoglobin structure and function III. Diseases of hemoglobin: methemoglobinemia & sickle-cell anemia  Many mutations in Hemoglobin A have been identified Some mutations have no effect on hemoglobin function (a nonpathological substitution) Others, such Hemoglobin S, disrupt hemoglobin structure or function Stryer, 4th ed. Ch. 7/ Mathews, Ch. 7  Sickle Cell anemia Characterized by sickled appearance of red blood cells due to insoluble Hemoglobin (HbS). Result is clogging of capillaries and general organ damage causing pain. Individuals can either be homozygous (SS) or heterozygous (AS). 1 in 13 African-Americans are heterozygous. 1 in 365 have the disease 100,000 with disease in U.S. HbA HbS Lehninger The molecular defect in HbS is a point mutation converting glutamate to valine on the exterior of the b subunit All symptoms occur after birth & can be diagnosed using electrophoresis of hemoglobin Glutamate is negatively charged; valine is neutral  Sickling is made worse by decreased oxygen A hydrophobic hole is formed in both HbA and HbS when in the deoxy form A hydrophobic knob is present on the b subunit of HbS in both forms Stryer, 4th ed. Ch. 7 The deoxy form of HbS can form long polymers  Figure from Champe et al., 3rd ed. Treatment of Sickle Cell Anemia Antibiotic therapy: (to prevent secondary infections) Hydroxyurea (stimulates the production of HbF) Bone marrow transplantation (replaces HbS with HbA) Gene therapy (Phase I/II) For more information check out the web site: http://www.nlm.nih.gov/medlineplus/sicklecellanemia.html Individuals with heterozygous sickle cell anomia have partial resistance to the parasite that causes malaria. Why? Because in