ch05pt2 - Sigmoidal Curves deoxy-Hb Oxy-Hb 5-10 Salt...

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Unformatted text preview: Sigmoidal Curves deoxy-Hb Oxy-Hb 5-10 Salt bridges in deoxyhemoglobin 5-9b What is this red group? A. Ile B. His -NH3+ C. His -COO- 5-9 5-11 V&V10-16 Blue = deoxy; red = oxy deoxyHb X-ray structure = tense (T) form (more salt bridges) oxyHb X-ray structure = relaxed (R) form (fewer salt bridges) T vs. R can be used to describe all allosteric proteins (enzymes, etc). T is lower affinity; R is higher affinity form. T and R in equilibrium, regardless of whether O2 present or not: T R Anything that stabilizes T relative to R decreases O2 affinity of population (R) (T) 5-12 Plot log( 1- ) vs. log[L] = Hill plot; slope, n = degree of interaction between sites 5-14 Hb also carries other ligands: H+ and CO2 - end products of tissue respiration. Formation of CO2 in cells causes an increase in H+ conc: Equilibrium processes of the bicarbonate buffering system: hydration of CO2 (catalyzed by carbonic anhydrase): CO2 + H2O H2CO3 (weak acid) What happens to this weak acid? It dissociates: H2CO3 H+ + HCO3- Hb carries about 20% total CO2 and 40% of H+ formed in tissues to lung and kidneys, where they are excreted. At which pH does Hb have the highest affinity for O2? A. 7.2 B. 7.4 C. 7.6 C. pH 7.6 effect of pH and CO2 on affinity = Bohr effect Recall, 1 kPa ~ 8 Torr 5-16 To account for H+ effect, rewrite reaction: HHb+ + O2 HbO2 + H+ (HHb+ = protonated Hb) O2 and H+ are bound by Hb inverse manner, i.e. Hb releases protons upon binding O2. However, not bound at same sites. H+ are bound to R group of His146 in chain and to N-terminal amino groups of chains. Why does proximity to aspartate (in T state) raise pKa of histidine? Asp FG1 H+ binding decreases O2 affinity 5-10 stabilizes T state CO2 is bound by -amino group at N-term end of each of the 4 chains to form carbamino-Hb. CO2 binding decreases the affinity for O2. Note that carbamate formation releases H+ as well, which can also be bound by Hb: p.166 CO2 binding decreases O2 affinity stabilizes T state CO2 is bound by -amino group at N-term end of each of the 4 chains to form a carbamate: converts uncharged group to negative charge - new salt bridge can form p.166 Bohr effect: O2Hb + H+ + CO2 tissues lungs H+ Hb CO2 Note: Mb does not show any Bohr effect. + O2 2,3-bisphosphoglycerate (BPG) -O C H H C C O -O P OO O H O O P OO- HbBPG + O2 p.167 HbO2 + BPG Binding of 2,3-bisphosphoglycerate (BPG) to Hb Mvh7.18 What are these amino acids? 5-17 HbF A B Which curve is HbF? HbA Fetal erythrocytes contain different Hb = HbF (fetal Hb) = 22 HbF has higher O2 affinity than HbA. All of these cooperative phenomena involve interactions between ligands which bind at different sites on the Hb from the O2 binding site. Implies that the molecule must be capable of transmitting the signal that another ligand has bound to a different portion of the molecule. Remember that Mb shows none of these effects, even though the tertiary structure of the substituent chains is almost identical. What is it about the structure of Hb that allows these effects? Quaternary structure! oligomeric proteins that exhibit cooperativity = allosteric MWC (Concerted) Sequential Model 5-15 Sickle Cell Anemia 5-19 5-20 V&V10-26 V&V10-26 Distribution of mutations in human hemoglobin Sickle-cell mutation Pathological mutation (red) Nonpathological mutation (blue) Mvh7.25 ...
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