Selectivity determinants of the aldose and aldehyde reductase inhibitor-binding sites.
Aldose reductase and aldehyde reductase belong to the aldo-keto reductase superfamily of enzymes whose members are responsible for a wide variety of biological functions. Aldose reductase has been identified as the first enzyme involved in the polyol pathway of glucose metabolism which converts glucose into sorbitol. Glucose over-utilization through the polyol pathway has been linked to tissue-based pathologies associated with diabetes complications, which make the development of a potent aldose reductase inhibitor an obvious and attractive strategy to prevent or delay the onset and progression of the complications. Structural studies of aldose reductase and the homologous aldehyde reductase in complex with inhibitor were carried out to explain the difference in the potency of enzyme inhibition. The aim of this review is to provide a comprehensive summary of previous studies to aid the development of aldose reductase inhibitors that may have less toxicity problems than the currently available ones.
El-Kabbani
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Department of Medicinal Chemistry, Victorian College of Pharmacy, Monash University, (Parkville Campus), 381 Royal Parade, Parkville, Victoria, 3052 Australia. ossama.el-kabbani@vcp.monash.edu.au
Podjarny
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A
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics
D004791:Enzyme Inhibitors; D048289:Imidazolidines; D011994:Recombinant Proteins; C077139:fidarestat; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase; D005947:Glucose