Isolation and characterization of cDNA clones encoding aldose reductase

Jm, Petrash; Ad, Favello

doi:10.3109/02713688908997394

Cited by 27 publications

(13 citation statements)

References 18 publications

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“…The cDNA for rat liver 3␣-HSD was found to share no sequence identity with other HSDs that had been cloned at that time, including 3␤-HSD/KSI (9 -11, 16), 11␤-HSD (79), and 17␤-HSD (45)(46)(47). Instead, a search of GenBank revealed that it shared high sequence identity with aldose-reductases from rat and bovine lens (112,113), human placental aldose reductase (114,115), prostaglandin F 2␣ synthase (116), and -crystallin from frog lens (117). These proteins all share in excess of 58% sequence identity and are known members of the AKR superfamily (see Section VII).…”

Section: B Cloning and Expression Of The 3␣-hsd Cdnasmentioning

confidence: 99%

Molecular Endocrinology of Hydroxysteroid Dehydrogenases*

1997

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Section: B Cloning and Expression Of The 3␣-hsd Cdnasmentioning

confidence: 99%

Molecular Endocrinology of Hydroxysteroid Dehydrogenases*

1997

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“…A total of 42 oxidoreductases have been identified as members of the AKR superfamily (Table 1), including seven HSDs [five of which are also dihydrodiol dehydrogenases (DDs ; EC 1.3.1.20)] [20,25,[27][28][29][30][31][32][33], seven ADRs [5,[34][35][36][37][38][39][40][41], six ALRs [5,[42][43][44][45][46][47], two 3-oxo-5β-steroid 4-dehydrogenases (∆%-3-ketosteroid 5β-reductases) (ED 1.3.99.6) [48,49], three plant chalcone reductases [12,50,51], two 2,5-diketo-gulonate reductases from Corynebacterium [52,53], Pseudomonas morphine dehydrogenase (EC 1.1.1.218) [54], a putative reductase from Leishmania [55], human liver bile acid binding protein [29,31], bovine lung prostaglandin F synthase [17], bovine DD3 [56], frog lens ρ-crystallin [57], a mouse vas deferens protein [58], apple sorbitol-6-phosphate reductase [59], two xylose reductases from yeast [60,61],…”

Section: The Akr Superfamilymentioning

confidence: 99%

Comparative anatomy of the aldo–keto reductase superfamily

Jez

Bennett

Schlegel

et al. 1997

Biochemical Journal

576

588

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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.

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“…The gene for ALR2 has been isolated from a number of tissues in man [25,[69][70][71][72]. The gene for SORD has also been cloned enabling the entire polyol pathway to be studied at a molecular level [73][74][75].…”

Section: Polymorphisms Of the Aldose Reductase (Alr2) Genementioning

confidence: 99%

Polymorphisms of the Aldose Reductase Gene and Susceptibility to Diabetic Microvascular Complications

Ag¹

2003

CMC

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Diabetes is a major cause of mortality and morbidity due to the long term microvascular complications of this disease. There is now convincing evidence to show that genetic factors together with elevated blood glucose play an important role in the susceptibility to diabetic nephropathy as well as retinopathy. The polyol pathway is thought to play an important role in the pathogenesis of diabetic microvascular complications. Aldose reductase is the first and rate-limiting enzyme of the polyol pathway. Polymorphisms in the promoter region as well as elsewhere in the gene have been associated with susceptibility to nephropathy, retinopathy as well as diabetic neuropathy. These associations have been replicated in patients with either type 1 or type 2 diabetes mellitus as well as across ethnic groups. These polymorphisms in the promoter region are also associated with expression of the gene. Although clinical trials using inhibitors of aldose reductase to treat diabetic microvascular complications have largely been unsuccessful, the identification of the susceptibility genes may help in the design of future drug regimens.

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Isolation and characterization of cDNA clones encoding aldose reductase

Cited by 27 publications

References 18 publications

Molecular Endocrinology of Hydroxysteroid Dehydrogenases*

Molecular Endocrinology of Hydroxysteroid Dehydrogenases*

Comparative anatomy of the aldo–keto reductase superfamily

Polymorphisms of the Aldose Reductase Gene and Susceptibility to Diabetic Microvascular Complications

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