Abstract

Hemoglobin acts as a receptor for a variety of drugs and other compounds. Some of these have potential as antisickling agents or agents that promote delivery of oxygen to infarcted tissue or tumors, but so far their clinical application has foundered on their strong affinity for serum albumin. Their stereochemistry of binding to the recently solved structure of serum albumin will be explored with a view to lowering their affinity for it without lowering that for hemoglobin. Human globin can now be made in E.coli. This has opened the way to directed mutagenesis of hemoglobin, capable of exploring the evolution of its structure and of its specialized functions in different species, and of modifications designed to make it usable as a blood substitute. One possible strategy towards the prevention of sickling would be inhibition of the phosphoglyceromutase that converts 1,3- to 2,3- diphosphoglycerate. Horseradish peroxidase is widely used in diagnostic tests and could be adapted to more uses by directed mutagenesis, but its structure is unknown. Efforts are under way to determine the structure of both these proteins.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL031461-09
Application #
3342593
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1983-12-01
Project End
1992-11-30
Budget Start
1992-01-01
Budget End
1992-11-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Medical Research Council Lab of Molec Biol
Department
Type
DUNS #
232560263
City
Cambridge
State
Country
United Kingdom
Zip Code
CB2 0-QH

  Publications

Boyle, W A; Muralidharan, S; Maher, G M et al. (1997) Vascular actions of 'caged' phenylephrine analogs depend on the structure and site of attachment of the 2-nitrobenzyl group. J Photochem Photobiol B 41:233-44
Stott, K; Blackburn, J M; Butler, P J et al. (1995) Incorporation of glutamine repeats makes protein oligomerize: implications for neurodegenerative diseases. Proc Natl Acad Sci U S A 92:6509-13
Whitaker, T L; Berry, M B; Ho, E L et al. (1995) The D-helix in myoglobin and in the beta subunit of hemoglobin is required for the retention of heme. Biochemistry 34:8221-6
Gilles-Gonzalez, M A; Gonzalez, G; Perutz, M F (1995) Kinase activity of oxygen sensor FixL depends on the spin state of its heme iron. Biochemistry 34:232-6
Perutz, M F (1995) Polar zippers: their role in human disease. Pharm Acta Helv 69:213-24
De Baere, I; Perutz, M F; Kiger, L et al. (1994) Formation of two hydrogen bonds from the globin to the heme-linked oxygen molecule in Ascaris hemoglobin. Proc Natl Acad Sci U S A 91:1594-7
Gilles-Gonzalez, M A; Gonzalez, G; Perutz, M F et al. (1994) Heme-based sensors, exemplified by the kinase FixL, are a new class of heme protein with distinctive ligand binding and autoxidation. Biochemistry 33:8067-73
Perutz, M (1994) Polar zippers: their role in human disease. Protein Sci 3:1629-37
Perutz, M F; Fermi, G; Poyart, C et al. (1993) A novel allosteric mechanism in haemoglobin. Structure of bovine deoxyhaemoglobin, absence of specific chloride-binding sites and origin of the chloride-linked Bohr effect in bovine and human haemoglobin. J Mol Biol 233:536-45
Gilles-Gonzalez, M A; Gonzalez, G (1993) Regulation of the kinase activity of heme protein FixL from the two-component system FixL/FixJ of Rhizobium meliloti. J Biol Chem 268:16293-7

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