Determination of the pK values for the alpha-amino groups of human hemoglobin.

Garner, Matthew R.; Bogardt, Richard A.; Gurd, Frank R. N.

doi:10.1016/s0021-9258(19)41315-x

Cited by 106 publications

(26 citation statements)

References 49 publications

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“…If an anion is placed in the tertiary deoxyhemoglobin structure between Val-la and Arg-141 a, electrostatic calculations yield a pAj/2 value of 8.02, at / = 0.10 M, and 1/2 for the quaternary transition becomes 0.73 which is in agreement with the experimental value. Further support for this result is provided by the independent study of terminal valine groups by the cyanate kinetic method which yields a pAfl/2 for Val-la in deoxyhemoglobin of 7.8 and in carbonmonoxyhemoglobin of 7.0 (Garner et al, 1975).…”

Section: Resultsmentioning

confidence: 83%

“…Observed pK values for imidazole ionization in individual histidine residues of hemoglobin have been determined by proton NMR measurements (Ho & Russu, 1978); in some cases the resonances have been assigned by comparison of natural or chemically derived hemoglobin variants. Observed pK values for -amino group ionization have been determined from 13C NMR measurements for Val-la and Val-1/3 (Morrow et al, 1976;Matthew et al, 1977) and from cyanate reaction kinetics (Garner et al, 1975).…”

Section: Resultsmentioning

confidence: 99%

“…d Observed and assigned by carbon-13 NMR (Morrow et al, 1976;Matthew et al, 1977). e Observed by kinetic methods (Garner et al, 1975). f His-146• • -Asp-94 saltbridge distance of 2.8 A may be stretched in solution, yielding a slightly lower pA"l/2.…”

Section: Resultsmentioning

confidence: 99%

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Coordination complexes and catalytic properties of proteins and related substances. 104. Electrostatic effects in hemoglobin: hydrogen ion equilibriums in human deoxy- and oxyhemoglobin A

Matthew¹,

Hanania²,

Gurd³

1979

Biochemistry

188

130

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The modified Tanford-Kirkwood theory of Shire et al. [Shire, S. J., Hanania, G.I.H., & Gurd, F.R.N. (1974) Biochemistry 13, 2967] for electrostatic interactions was applied to the hydrogen ion equilibria of human deoxyhemoglobin and oxyhemoglobin. Atomic coordinates for oxyhemoglobin were generated by the application of the appropriate rigid rotation function to alpha and beta chains of the deoxyhemoglobin structure [Fermi, G. (1975) J. Mol. Biol. 97, 237]. The model employs two sets of parameters derived from the crystalline protein structures, the atomic coordinates of charged amino acid residues and static solvent accessibility factors to reflect their individual degrees of exposure to solvent. Theoretical titration curves based on a consistent set of pKint values compared closely with experimental potentiometric curves. Theoretical pK values at half-titration for individual protein sites corresponded to available observed values for both quaternary states. The results bring out the cumulative effects of numerous electrostatic interactions in the tetrameric structures and the major effects of the quaternary transition that result from changes in static solvent accessibility of certain ionizable groups.

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Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

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Coordination complexes and catalytic properties of proteins and related substances. 104. Electrostatic effects in hemoglobin: hydrogen ion equilibriums in human deoxy- and oxyhemoglobin A

Matthew¹,

Hanania²,

Gurd³

1979

Biochemistry

188

130

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“…From the outset we were aware of the propensity for aldehydes to be metabolized rapidly. While we were also concerned with the possibility that Schiff-base linkages could be formed with exposed amines on any protein, the N-terminal valine on the α chain in Hb, having a pK a = 6.9 12 is primarily unprotonated at physiological pH and hence is more nucleophilic than protonated amines, such as the ω amino group of exposed lysine which has a pK a = 10.5 in polypeptides. 13 This differential pK a of the N-terminal valine offers an in-built possibility for selectivity.…”

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confidence: 99%

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

Metcalf

Chuang

Dufu

et al. 2017

ACS Med. Chem. Lett.

152

142

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We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, binds with a 1:1 stoichiometry. Compound is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of ∼150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 () is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).

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“…This mechanism can account for the reduction in the Bohr effect and in CO 2 binding of RRHb. The ValR1 amino terminus is an important contributor of Bohr protons, since the T state salt-bridge requires protonation (22,23). However, the cross-linking strains the salt-bridge (as evidenced by the H-bond weakening of both TyrR140 and TrpR14), thereby inhibiting protonation.…”

Section: Resultsmentioning

confidence: 99%

UV Resonance Raman Spectra Reveal a Structural Basis for Diminished Proton and CO₂ Binding to α,α-Cross-Linked Hemoglobin

et al. 1999

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UV resonance Raman difference spectra between ligated and deoxyhemoglobin contain tryptophan and tyrosine signals which arise from quaternary H-bonds in the T state, which are broken in the R state. These H-bonds are unaffected by bis(3,5-dibromosalicyl) fumarate cross-linking at the Lys alpha 99 residues, which prevents dissociation of Hb tetramers to dimers. However, when the pH is lowered from 9.0, or when NaCl is added, intensity is diminished for the tyrosine Y8 and tryptophan W3 bands of cross-linked deoxyHb, but not of native deoxyHb. This effect is attributed to weakening of tertiary H-bonds involving Tyr alpha 140 and Trp alpha 14, when the T state salt bridge between Val alpha 1 and Arg alpha 141 is formed via protonation of the terminal amino group and anion binding. The Tyr alpha 140-Val alpha 93 H-bond connects the Arg alpha 141-bearing H helix with the Lys alpha 99-bearing G helix. Weakening of the H-bond reflects a tension between the fumarate linker and the salt-bridge. This tension inhibits protonation of the Val alpha 1 amino terminus, thus accounting for the diminution of both proton [Bohr effect] and CO2 binding in the T state as a result of cross-linking.

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Determination of the pK values for the alpha-amino groups of human hemoglobin.

Cited by 106 publications

References 49 publications

Coordination complexes and catalytic properties of proteins and related substances. 104. Electrostatic effects in hemoglobin: hydrogen ion equilibriums in human deoxy- and oxyhemoglobin A

Coordination complexes and catalytic properties of proteins and related substances. 104. Electrostatic effects in hemoglobin: hydrogen ion equilibriums in human deoxy- and oxyhemoglobin A

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

UV Resonance Raman Spectra Reveal a Structural Basis for Diminished Proton and CO₂ Binding to α,α-Cross-Linked Hemoglobin

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Determination of the pK values for the alpha-amino groups of human hemoglobin.

Cited by 106 publications

References 49 publications

Coordination complexes and catalytic properties of proteins and related substances. 104. Electrostatic effects in hemoglobin: hydrogen ion equilibriums in human deoxy- and oxyhemoglobin A

Coordination complexes and catalytic properties of proteins and related substances. 104. Electrostatic effects in hemoglobin: hydrogen ion equilibriums in human deoxy- and oxyhemoglobin A

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin

UV Resonance Raman Spectra Reveal a Structural Basis for Diminished Proton and CO2 Binding to α,α-Cross-Linked Hemoglobin

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UV Resonance Raman Spectra Reveal a Structural Basis for Diminished Proton and CO₂ Binding to α,α-Cross-Linked Hemoglobin