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 (α/β)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 of a 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-5β-steroid 4-dehydrogenases (Δ4-3-ketosteroid 5β-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 17β-hydroxysteroid dehydrogenase and rat ovary 20α-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.
Skip Nav Destination
Follow us on Twitter @Biochem_Journal
Article navigation
September 1997
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
Review Article|
September 15 1997
Comparative anatomy of the aldo–keto reductase superfamily
Joseph M. JEZ;
Joseph M. JEZ
*Departments of Biochemistry & Biophysics, University of Pennsylvania Medical School, 3620 Hamilton Walk, Philadelphia, PA 19104, U.S.A.
Search for other works by this author on:
Melanie J. BENNETT;
Melanie J. BENNETT
*Departments of Biochemistry & Biophysics, University of Pennsylvania Medical School, 3620 Hamilton Walk, Philadelphia, PA 19104, U.S.A.
Search for other works by this author on:
Brian P. SCHLEGEL;
Brian P. SCHLEGEL
†Department of Pharmacology, University of Pennsylvania Medical School, 3620 Hamilton Walk, Philadelphia, PA 19104, U.S.A.
Search for other works by this author on:
Mitchell LEWIS;
Mitchell LEWIS
*Departments of Biochemistry & Biophysics, University of Pennsylvania Medical School, 3620 Hamilton Walk, Philadelphia, PA 19104, U.S.A.
Search for other works by this author on:
Trevor M. PENNING
Trevor M. PENNING
‡
†Department of Pharmacology, University of Pennsylvania Medical School, 3620 Hamilton Walk, Philadelphia, PA 19104, U.S.A.
‡To whom correspondence should be addressed.
Search for other works by this author on:
Publisher: Portland Press Ltd
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1997
1997
Biochem J (1997) 326 (3): 625–636.
Citation
Joseph M. JEZ, Melanie J. BENNETT, Brian P. SCHLEGEL, Mitchell LEWIS, Trevor M. PENNING; Comparative anatomy of the aldo–keto reductase superfamily. Biochem J 15 September 1997; 326 (3): 625–636. doi: https://doi.org/10.1042/bj3260625
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Follow us on Twitter @Biochem_Journal
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() View past webinars > |