BIOLCHEM 415 1st Edition Lecture 9Outline of Last Lecture I. Basics of Drug actionII. Examples of three different classes of drugs: β-lactam antibiotics, HIV anti-retrovirals, andnon-steroidal anti-inflammatory drugs (NSAIDS)Outline of Current Lecture III. Myoglobin and hemoglobin – crystal structures and oxygen binding propertiesIV. Hemoglobin’s cooperativity in binding O2V. Allosteric regulation of hemoglobin that controls its O2 binding propertiesVI. Sickle Cell Anemia and MalariaCurrent LectureWhy do we need Hemoglobin- delivers O2 throughout body- O2 only soluble to ~200 μM in blood- Hemoglobin soluble to ~50 mM- can also return CO2 to lungsProperties of Oxygen Carrying Protein- bind with O2 with high affinity in lungs- lower affinity for O2 binding in peripheral tissue- here oxygen conc. is low- affinity modulated according to the body’s metabolism- exists in two states with different affinities for O2- equilibrium can be altered according to metabolismMyoglobinThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.- simplest oxygen binding protein- heme group binds to O2- Fe in middle of the ring- single polypeptide chainHemoglobin- 4 polypeptide chains- each has heme groupHeme Group- when O2binded Fe shifts to be in plane of Heme- normally slightly underneath- proximalHistidine – coordinates Fe2+ ion in the heme group- distalHistidine – hydrogen bonds to O2- prevents oxidation of Fe2+ ion- reduces binding affinity of hemoglobin for COOxygen binding by Myoglobin and Hemoglobin- fractional saturation - scale of 0-1- fraction of O2 binding sites bound to protein- pO2- partial pressure O2 binding sites bound to protein- measured in units of torr- myoglobin’s curve is hyperbolic- hemoglobin’s curve is sigmoidal- indicatescooperativityO2 binding comparison- myoglobin is found in muscle- serves as O2 reservoir- hemoglobin found in red blood cells- transport O2 throughout the body- uses both R and T state conformations- R (high binding affinity) state binds to O2 in lungs- T (low binding affinity)state releases O2 in peripheral tissue- O2 binding causes the T to R transition- when bonded in T state- when not bonded in R state- 2,3-BPG binds to T state of Hemoglobin- binding site formed by β1 and β2 subunits of hemoglobin and only existsin the T state- stabilizes T state- allosteric site that regulates the transition between R and T statesFetal hemoglobin binds less 2,3-BPG - binds with O2 with higher affinity than adult hemoglobin- has 2 α subunits and 2 λ subunitsThe Bohr Effect- H+ and CO2 stabilize T state- releases O2- animo terminal groups of subunits react with CO2 to form a carbamate- stabilizes T stateCO2 from peripheral to lungs- carbonic anhydrase converts CO2 and H2O into carbonic acid- lowers pH in red blood cell- hemoglobin releases O2 according to Bohr effectSickle Cell Anemia- Hemoglobin S (HbS) mutation- Glu-6 to Val mutation in β subunit- 2 copies of HbS allele means that person suffers from sickle cell anemia- people with 1 copy show resistance to malaria but no sickle cellQuinine- natural malaria treatment- found in tonic water-
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