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PMID: 9307009 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Review

Comparative anatomy of the aldo-keto reductase superfamily.

The Biochemical journal ·Vol. 326 ( Pt 3) ·1997-09-15 ·Pages 625-36

Jez JM, Bennett MJ, Schlegel BP, Lewis M, Penning TM

Abstract

The aldo-keto reductases metabolize a wide range of substrates and are potential drug targets. This protein superfamily includes aldose reductases, aldehyde reductases, hydroxysteroid dehydrogenases and dihydrodiol dehydrogenases. By combining multiple sequence alignments with known three-dimensional structures and the results of site-directed mutagenesis studies, we have developed a structure/function analysis of this superfamily. Our studies suggest that the (alpha/beta)8-barrel fold provides a common scaffold for an NAD(P)(H)-dependent catalytic activity, with substrate specificity determined by variation of loops on the C-terminal side of the barrel. All the aldo-keto reductases are dependent on nicotinamide cofactors for catalysis and retain a similar cofactor binding site, even among proteins with less than 30% amino acid sequence identity. Likewise, the aldo-keto reductase active site is highly conserved. However, our alignments indicate that variation ofa single residue in the active site may alter the reaction mechanism from carbonyl oxidoreduction to carbon-carbon double-bond reduction, as in the 3-oxo-5beta-steroid 4-dehydrogenases (Delta4-3-ketosteroid 5beta-reductases) of the superfamily. Comparison of the proposed substrate binding pocket suggests residues 54 and 118, near the active site, as possible discriminators between sugar and steroid substrates. In addition, sequence alignment and subsequent homology modelling of mouse liver 17beta-hydroxysteroid dehydrogenase and rat ovary 20alpha-hydroxysteroid dehydrogenase indicate that three loops on the C-terminal side of the barrel play potential roles in determining the positional and stereo-specificity of the hydroxysteroid dehydrogenases. Finally, we propose that the aldo-keto reductase superfamily may represent an example of divergent evolution from an ancestral multifunctional oxidoreductase and an example of convergent evolution to the same active-site constellation as the short-chain dehydrogenase/reductase superfamily.

MeSH Terms
Alcohol Oxidoreductases/chemistry,genetics Aldehyde Reductase Aldo-Keto Reductases Amino Acid Sequence Animals Evolution, Molecular Humans Mice Molecular Sequence Data Mutagenesis, Site-Directed Protein Conformation Rats Sequence Alignment Sequence Analysis Structure-Activity Relationship
Chemicals
Alcohol Oxidoreductases Aldo-Keto Reductases Aldehyde Reductase AKR7A5 protein, mouse
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Jez J M
Department of Biochemistry & Biophysics, University of Pennsylvania Medical School, 3620Hamilton Walk, Philadelphia, PA 19104, USA.
Bennett M J
Schlegel B P
Lewis M
Penning T M
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
DOI
10.1042/bj3260625
Published
1997-09-15
Pages
625-36
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1218714
Subset
IM
Grants
NCI NIH HHS · CA39504 · United States
NIDDK NIH HHS · DK47015 · United States
External Links
PubMed source DOI: 10.1042/bj3260625 PMC Full Text View journal details
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