Kinetic Alteration of Human Aldose Reductase by Mutagenesis of Cysteine Residues
Aldose reductase (ALR21: alditol:NADPH oxidoreductase: E.C. 22.214.171.124) catalyzes the NADPH-linked reduction of aldoses to their corresponding alcohols or polyols, the first step of the polyol pathway. Enhanced flux of glucose through the polyol pathway and consequent biochemical imbalances are thought to be crucial to the onset and progression of many complications of diabetes mellitus including cataract, retinopathy, neuropathy and nephropathy (Kinoshita and Nishimura, 1988). In light of its rate-limiting position in the polyol pathway as well as its apparent metabolic dispensability (Yancey et al., 1990), strategies to control or prevent the onset of diabetic complications through inhibition of aldose reductase are being aggressively pursued. While a structurally-diverse array of aldose reductase inhibitors (ARI) have yielded impressive results in animal studies, their effectiveness in arresting or preventing diabetic neuropathy (Boulton et al., 1990) and retinopathy (Sorbinil Retinopathy Trial Research Group, 1990) in human trials has been less encouraging (Frank, 1990).
KeywordsCysteine Residue Aldose Reductase Polyol Pathway Aldose Reductase Inhibitor Aldose Reductase Activity
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