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The aldo-keto reductases (AKRs): Overview
1Center of Excellence in Environmental Toxicology, Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Chemico-Biological Interactions
|October 12, 2014
Summary
The aldo-keto reductase (AKR) superfamily, with over 190 members, plays crucial roles in reducing carbonyl substrates and is implicated in various diseases. Understanding AKR variants is key to advancing human health and disease research.
Area of Science:
- Biochemistry and Molecular Biology
- Enzymology
- Genetics
Background:
- The aldo-keto reductase (AKR) protein superfamily comprises over 190 enzymes across 16 families, found in all phyla.
- AKRs catalyze the reduction of diverse carbonyl substrates, including sugars, steroids, and lipids, with specific roles in steroid double bond reduction (AKR1D) and ion channel regulation (AKR6).
- These enzymes share a conserved (α/β)8-barrel motif, a cofactor binding domain, and a catalytic tetrad, operating via an ordered bi bi kinetic mechanism.
Purpose of the Study:
- To review the structure, function, and significance of the aldo-keto reductase (AKR) superfamily.
- To highlight the involvement of specific human AKR enzymes (AKR1B1, AKR1C1-1C3, AKR1D1, AKR1B10) in various pathologies.
- To emphasize the potential of AKR inhibitors and the need for further genomic interrogation of AKR variants in human health and disease.
Main Methods:
- Literature review and analysis of existing data on AKR protein structure and function.
- Compilation of information on the roles of specific human AKR enzymes in disease.
- Discussion of inhibitor programs and future research directions using genomic and informatics approaches.
Main Results:
- AKRs are characterized by conserved structural motifs and a catalytic tetrad, with distinct substrate specificities governed by variable loops.
- Specific human AKRs are linked to diabetic complications, steroid hormone-related cancers, bile acid deficiency, and retinoic acid signaling defects.
- Inherited mutations in AKR1C and AKR1D1 are associated with developmental abnormalities and metabolic disorders, respectively.
Conclusions:
- The AKR superfamily is functionally diverse, with key roles in human health and disease.
- Targeted inhibition of specific AKRs offers therapeutic potential for various disorders.
- Further investigation into AKR variants using modern genomic and bioinformatics tools is crucial for understanding their impact on human health.
Keywords:
Hydroxysteroid dehydrogenasesPotassium channelsQuinone reductaseSteroid 5β-reductaseXenobioticsMore Related Videos
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