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Myoglobin, Hemoglobin, and 2,3 BPG.docx

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R.Roy Baker

Myoglobin and Hemoglobin  Myoglobinis a relatively small monomeric protein that facilitates the diffusion of oxygen in vertebrates.  Responsible for supplying oxygen to muscle tissue in reptiles, birds, and mammals.  Hemoglobin is a larger tetrameric protein that carries oxygen in blood. Heme prosthetic group  Both myoglobin and hemoglobin contains a heme prosthetic group. *Prosthetic group is a protein-bound organic molecule essential for the activity of the protein.  Heme consists of a tetrapyrrole ring system (protoporphyrin IX) complexed with iron.  The four rings of this system are linked by methene (-CH=) bridges  The unsaturated porphyrin is highly conjugated (joined) and planar.  The iron of heme group is a ferrous iron (Fe2+) which is caged inside the porphyrin ring.  This ferrous iron can form a complex with up to 6 ligands around it when myoglobin/hemoglobin is oxygenated and usually with 5 ligands when in deoxygenated form: - 4 ligands are the N atoms- each N is from 1 pyrrole ring. (These are in the same plane)  The coordinated nitrogen atoms help prevent conversion of the heme iron to the ferric state. (restricts accessibility of heme) - The fifth ligand is an imidazole nitrogen of the proximal His-93 or His-F8. (This bond is perpendicular to the porphyrin ring) - The sixth ligand is oxygen. (In deoxymoglobin/deoxyhemoglobin, oxygen is not present so iron only binds to 5 ligands) . (This bond is perpendicular to the porphyrin ring)  Out of 4 sides of the porphyrin ring, the one with propionate side chain ended with the ionized carboxyl groups is hydrophilic and thus reach into the aqueous solution (outside of the polypeptide).  The other 3 sides are nonpolar methyl and vinyl group (-CH=CH2) which are hydrophobic and therefore extend into the hydrophobic interior of the polypeptide.  The whole heme group is in a hydrophobic cleft or pocket formed by three alpha helices and two loops of the polypeptide.  The binding of the porphyrin moiety to the polypeptide is due to number of weak interactions including hydrophobic interactions, van der Waals forces, hydrogen bonds.  The ferrous iron is coordinated to the imidazole nitrogen of His-93. (It offers 2 electrons for this bond while N offers none)  The non-polar side chain of Val-68 and Phe-43 also contributes to the hydrophobicity of the oxygen-binding pocket.  Help to hold theheme in place and also sterically hinder any molecules that are not oxygen trying to bind to heme. Myoglobin  Myoglobin is a relatively small molecule with 153 amino acid residues.  ¾ of its amino acids involve in 8 alpha helices.  These 8 alpha helices are connected by short, disordered coils.  Myoglobin is a member of the all-alpha category.  The interior of myoglobin is made up of hydrophobic amino acid residues like Val, Leu, Iso, Phe, and Met.  The surface of myoglobin is made up of both hydrophilic and hydrophobic residues.  The tertiary structure of myoglobin is stabilized by hydrophobic interactions within the core. Hemoglobin  Is more complex than myoglobin because it is a multisubunit protein.  Hemoglobin is a tetramer composed of 2 alpha subunits and 2 beta subunits.  These subunits face one another across a cavity in the center of the molecule.  Each subunit contains a heme so theoretically hemoglobin can bind four molecule of oxygen.  The alpha subunit contains 7 helices while the beta subunit contains 8 helices.  Each subunit especially the beta subunit is quite alike/almost identical myoglobin.  However, hemoglobin is not simply a tetramer of myoglobin: there is an extensive interaction between alpha and beta subunits in the quaternary structure of hemoglobin reflecting that hemoglobin is actually a dimer of alpha-beta subunits.  This characteristic is responsible for the oxygen-binding property of hemoglobin which is different from that of myoglobin. The way oxygen binds to free heme and to heme in myoglobin/hemoglobin  Free heme binds irreversibly to oxygen in aqueous solution: oxidizing Fe2+ to Fe3+: 2+ 3+ - Fe + O -> F2 + O 2  Oxidation of Fe2+ is resulted from the no steric environment in free heme. (the usual polypeptide chain of myoglobin/a subunit of hemoglobin is not found)  The binding of oxygen to myoglobin/ a subunit of hemoglobin is not an oxidation process but rather an oxygenation process.  Oxygenation only partially oxidizes the Fe2+ ion of the heme group by temporarily giving it one electron instead of permanently giving one electron like in oxidation.  The structure of myoglobin/hemoglobin prevents the permanent transfer of an electron: The globin crevice/ sterically hindered hydrophobic pocket in which the heme is located prevents complete oxidation and enforces the return of the electron to the ferrous iron when Oxygen dissociates. u Methemoglobin (Met-Hb)  The abnormal version of hemoglobin where the ferrous iron in the heme prosthetic group of one or all peptide subunits is converted to ferric iron hence losing its oxygen binding property.  The conversion involves a complete oxidation of ferrous iron by permanently transferring one of its electrons to another substance. (This substance is being reduced)  Methemoglobin cannot function as an oxygen carrier like normal hemoglobin.  Methemoglobin is caused by either decomposition of the blood or by the action of various oxidizing drugs or toxic agents.  Met-Hb can bind to water. Oxygen binding curve for Hemoglobin and Myoglobin  Oxygen binding curve describes the differences between hemoglobin and myoglobin on reversible binding of oxygen to the heme group.  The fractional saturation of myoglobin or hemoglobin is the fraction of the total number of molecules that are oxygenated. Y= [MbO ]/2[MbO ]+[2b]}  In this figure on the left, the fraction saturation (Y) of a fixed amount of protein is plotted against the concentration of oxygen (measured as the partial pressure of gaseous oxygen, pO ) 2  Some analysis: 1. The oxygen-binding curve of myoglobin is hyperbolic .  There is a single equilibrium constant for the binding of oxygen to the macromolecule. (Recall the g
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