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Document<br />

9<br />

Structural Studies of Aldose Reductase Inhibition<br />

David K. Wilson and Florante A. Quiocho<br />

Baylor College of Medicine, Houston, Texas<br />

J. Mark Petrash<br />

Washington University School of Medicine, St. Louis, Missouri<br />

I. Introduction<br />

Page 229<br />

Aldose reductase (ALR2; EC 1.1.1.21) is an ~36 kDa enzyme that catalyzes the reduction of a wide<br />

range of carbonyl-containing compounds to their corresponding alcohols. It is a member of an extensive<br />

aldo-keto oxidoreductase enzyme family, a collection of structurally similar proteins expressed in both<br />

animals and plants. Most members of the enzyme family possess similarities in molecular mass, pH<br />

optimum, coenzyme dependence, and demonstrate overlapping specificity for many substrates and<br />

inhibitors.<br />

While no essential physiological function has been established for ALR2, extensive experimental<br />

evidence suggests that it plays an important role in the development of diabetic complications affecting<br />

the visual, nervous, and renal systems [1]. The linkage between ALR2 and pathogenesis of diabetic<br />

complications lies in the polyol pathway of glucose metabolism (Figure 1). In hyperglycemic tissues<br />

such as in diabetes mellitus, the capacity of hexokinase to shunt glucose to glycolysis and other major<br />

pathways of glucose metabolism is exceeded. Consequently, enhanced flux of glucose through the<br />

polyol pathway occurs. The enzyme ALR2 catalyzes the first step in this pathway, producing sorbitol, an<br />

active osmolyte. The polyol pathway is completed <strong>by</strong> the NAD +-dependent oxidation of sorbitol to<br />

fructose, mediated <strong>by</strong> sorbitol dehydrogenase.<br />

Extensive evidence exists to suggest a linkage between the pathogenesis of diabetic complications and<br />

enhanced glucose metabolism via the polyol pathway. The polyol pathway functions in all tissues<br />

susceptible to clinically<br />

http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_229.html [4/5/2004 5:07:49 PM]

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