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3. (a) ( The equilibria for release of molecular dioxygen (O2) and protons (H+) by human hemo- globin (HbA) are illustrated in the scheme below in which the ionization (Ka, Ka') and ligand binding (K02, Ko2') are given as dissociation constants. The proton ionizations are known to be due to Hisẞ146 and account for a major part of the Bohr effect. A mutant hemoglobin is found for which Ka = 6.6 E-9 (pKa =8.18), Ka= 2.0 E-10 (pKa' = 9.70) and Ko2 = 1.0. What is the value of Ko2' for this mutant hemo- globin? K 02 = 1.0 Κα pka = 6.3 E-7 = 6.2 H*Hb O₂ H* + НЬ 02 HHb 02 Ka' = 2.0 E-8 pKa = 7.7 H+ + Hb + 02 K 02' = 0.032 (b) (' For the mutant hemoglobin described above, illustrate the relative changes that will be observed for the oxygen dissociation curve of Y versus pO2 compared to that of normal hemoglobin where Y represents thefraction of heme sites bound by O2. Explain whether there will be a change in the Bohr effect under physiological conditions, considering the pH of normal arterial and venous blood. (c) ( ) If the hemoglobin has arisen through a mutation, which amino acid substitution Arg, Lys, Cys, or Ser, is most likely to account for the observed change in pKa and pKa'? (The approximate pKa values for these residues are: Arg (12.5), Lys (10.0), Cys (8.4), and Ser(> 16). Explain. (d) ( ) The diagram on the right illustrates the hydrogen bond- ing/electrostatic interaction of the Hisẞ146 residue with the side chain of Aspẞ94 in HbA in the deoxy or T quaternary conformation. With the mutant residue in Question 3(c) replacing the His146 residue in that diagram, explain how your selected mutant residue is consistent with the higher O2 affinity. Which conformation of the mutant hemo- globin R or T is destabilized? α2 Lys 40 C terminus B₁ His 146 Added proton B₁ Asp 94

3. (a) ( The equilibria for release of molecular dioxygen (O2) and protons (H+) by human hemo- globin (HbA) are illustrated in the scheme below in which the ionization (Ka, Ka') and ligand binding (K02, Ko2') are given as dissociation constants. The proton ionizations are known to be due to Hisẞ146 and account for a major part of the Bohr effect. A mutant hemoglobin is found for which Ka = 6.6 E-9 (pKa =8.18), Ka= 2.0 E-10 (pKa' = 9.70) and Ko2 = 1.0. What is the value of Ko2' for this mutant hemo- globin? K 02 = 1.0 Κα pka = 6.3 E-7 = 6.2 H*Hb O₂ H* + НЬ 02 HHb 02 Ka' = 2.0 E-8 pKa = 7.7 H+ + Hb + 02 K 02' = 0.032 (b) (' For the mutant hemoglobin described above, illustrate the relative changes that will be observed for the oxygen dissociation curve of Y versus pO2 compared to that of normal hemoglobin where Y represents thefraction of heme sites bound by O2. Explain whether there will be a change in the Bohr effect under physiological conditions, considering the pH of normal arterial and venous blood. (c) ( ) If the hemoglobin has arisen through a mutation, which amino acid substitution Arg, Lys, Cys, or Ser, is most likely to account for the observed change in pKa and pKa'? (The approximate pKa values for these residues are: Arg (12.5), Lys (10.0), Cys (8.4), and Ser(> 16). Explain. (d) ( ) The diagram on the right illustrates the hydrogen bond- ing/electrostatic interaction of the Hisẞ146 residue with the side chain of Aspẞ94 in HbA in the deoxy or T quaternary conformation. With the mutant residue in Question 3(c) replacing the His146 residue in that diagram, explain how your selected mutant residue is consistent with the higher O2 affinity. Which conformation of the mutant hemo- globin R or T is destabilized? α2 Lys 40 C terminus B₁ His 146 Added proton B₁ Asp 94

Biochemistry
Biochemistry
9th Edition
ISBN:9781319114671
Author:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Publisher:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.
Chapter1: Biochemistry: An Evolving Science
Section: Chapter Questions
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3. (a) ( The equilibria for release of molecular dioxygen (O2) and protons (H+) by human hemo- globin (HbA) are illustrated in the scheme below in which the ionization (Ka, Ka') and ligand binding (K02, Ko2') are given as dissociation constants. The proton ionizations are known to be due to Hisẞ146 and account for a major part of the Bohr effect. A mutant hemoglobin is found for which Ka = 6.6 E-9 (pKa =8.18), Ka= 2.0 E-10 (pKa' = 9.70) and Ko2 = 1.0. What is the value of Ko2' for this mutant hemo- globin? K 02 = 1.0 Κα pka = 6.3 E-7 = 6.2 H*Hb O₂ H* + НЬ 02 HHb 02 Ka' = 2.0 E-8 pKa = 7.7 H+ + Hb + 02 K 02' = 0.032 (b) (' For the mutant hemoglobin described above, illustrate the relative changes that will be observed for the oxygen dissociation curve of Y versus pO2 compared to that of normal hemoglobin where Y represents thefraction of heme sites bound by O2. Explain whether there will be a change in the Bohr effect under physiological conditions, considering the pH of normal arterial and venous blood. (c) ( ) If the hemoglobin has arisen through a mutation, which amino acid substitution Arg, Lys, Cys, or Ser, is most likely to account for the observed change in pKa and pKa'? (The approximate pKa values for these residues are: Arg (12.5), Lys (10.0), Cys (8.4), and Ser(> 16). Explain. (d) ( ) The diagram on the right illustrates the hydrogen bond- ing/electrostatic interaction of the Hisẞ146 residue with the side chain of Aspẞ94 in HbA in the deoxy or T quaternary conformation. With the mutant residue in Question 3(c) replacing the His146 residue in that diagram, explain how your selected mutant residue is consistent with the higher O2 affinity. Which conformation of the mutant hemo- globin R or T is destabilized? α2 Lys 40 C terminus B₁ His 146 Added proton B₁ Asp 94
Transcribed Image Text:3. (a) ( The equilibria for release of molecular dioxygen (O2) and protons (H+) by human hemo- globin (HbA) are illustrated in the scheme below in which the ionization (Ka, Ka') and ligand binding (K02, Ko2') are given as dissociation constants. The proton ionizations are known to be due to Hisẞ146 and account for a major part of the Bohr effect. A mutant hemoglobin is found for which Ka = 6.6 E-9 (pKa =8.18), Ka= 2.0 E-10 (pKa' = 9.70) and Ko2 = 1.0. What is the value of Ko2' for this mutant hemo- globin? K 02 = 1.0 Κα pka = 6.3 E-7 = 6.2 H*Hb O₂ H* + НЬ 02 HHb 02 Ka' = 2.0 E-8 pKa = 7.7 H+ + Hb + 02 K 02' = 0.032 (b) (' For the mutant hemoglobin described above, illustrate the relative changes that will be observed for the oxygen dissociation curve of Y versus pO2 compared to that of normal hemoglobin where Y represents thefraction of heme sites bound by O2. Explain whether there will be a change in the Bohr effect under physiological conditions, considering the pH of normal arterial and venous blood. (c) ( ) If the hemoglobin has arisen through a mutation, which amino acid substitution Arg, Lys, Cys, or Ser, is most likely to account for the observed change in pKa and pKa'? (The approximate pKa values for these residues are: Arg (12.5), Lys (10.0), Cys (8.4), and Ser(> 16). Explain. (d) ( ) The diagram on the right illustrates the hydrogen bond- ing/electrostatic interaction of the Hisẞ146 residue with the side chain of Aspẞ94 in HbA in the deoxy or T quaternary conformation. With the mutant residue in Question 3(c) replacing the His146 residue in that diagram, explain how your selected mutant residue is consistent with the higher O2 affinity. Which conformation of the mutant hemo- globin R or T is destabilized? α2 Lys 40 C terminus B₁ His 146 Added proton B₁ Asp 94
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