Abstract

Transport of oxygen from the lungs to the tissues is fundamental to the functioning of any mammal, and requires the oxygen carrier hemoglobin. Oxygen binds in reversible chemical combination to the prosthetic group, Fe(II) protoporphyrin IX. The mechanism and details of this reaction have been the object of long continued in- vestigations in medicine, physiology, biochemistry, chemistry and biophysics to establish the nature and properties of the reaction at the level of the disciplines mentioned. Recent developments in the kinetics of the hemoglobin-ligand reaction have allowed the binding process to be analyzed in terms of a heme (chemical) component, and a diffusive component describing movement of ligand from the entrance to the heme pocket to the heme. The current objective is to sharpen this analysis, at present in terms of arbitrary kinetic parameters, by linking structure and function, using specifically modified hemoproteins and naturally occurring hemoproteins of known structure to locate the functionally significant residues along the diffusion path. This will advance understanding of the effects of naturally occurring mutations (hemoglobinopathies) of which some 500 are currently known. The main tool will be optical absorbance studies in the nanosecond and picosecond domains.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM014276-28
Application #
3268617
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Project Start
1979-06-01
Project End
1994-05-31
Budget Start
1992-06-01
Budget End
1993-05-31
Support Year
28
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Cornell University
Department
Type
Schools of Arts and Sciences
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850

  Publications

Carlson, M L; Regan, R; Elber, R et al. (1994) Nitric oxide recombination to double mutants of myoglobin: role of ligand diffusion in a fluctuating heme pocket. Biochemistry 33:10597-606
Chiancone, E; Elber, R; Royer Jr, W E et al. (1993) Ligand binding and conformation change in the dimeric hemoglobin of the clam Scapharca inaequivalvis. J Biol Chem 268:5711-8
Gibson, Q H; Regan, R; Olson, J S et al. (1993) Kinetics of ligand binding to Pseudoterranova decipiens and Ascaris suum hemoglobins and to Leu-29-->Tyr sperm whale myoglobin mutant. J Biol Chem 268:16993-8
Bellelli, A; Lendaro, E; Ippoliti, R et al. (1993) Ligand binding and slow structural changes in chlorocruorin from Spirographis spallanzanii. Biochemistry 32:7635-43
Gibson, Q H; Bellelli, A; Regan, R et al. (1992) Ligand binding by the chlorocruorin from Eudistylia vancouverii. J Biol Chem 267:11977-81
Gibson, Q H; Regan, R; Elber, R et al. (1992) Distal pocket residues affect picosecond ligand recombination in myoglobin. An experimental and molecular dynamics study of position 29 mutants. J Biol Chem 267:22022-34
Blackmore, R S; Gibson, Q H; Greenwood, C (1992) The relation of ligand binding to redox state in the hexa-heme nitrite reductase of Wolinella succinogenes. J Biol Chem 267:10950-5
Blackmore, R S; Greenwood, C; Gibson, Q H (1991) Studies of the primary oxygen intermediate in the reaction of fully reduced cytochrome oxidase. J Biol Chem 266:19245-9
Carver, T E; Olson, J S; Smerdon, S J et al. (1991) Contributions of residue 45(CD3) and heme-6-propionate to the biomolecular and geminate recombination reactions of myoglobin. Biochemistry 30:4697-705
Smerdon, S J; Dodson, G G; Wilkinson, A J et al. (1991) Distal pocket polarity in ligand binding to myoglobin: structural and functional characterization of a threonine68(E11) mutant. Biochemistry 30:6252-60

Showing the most recent 10 out of 26 publications