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Science 3 July 1992:
Vol. 257. no. 5066, pp. 81 - 84
DOI: 10.1126/science.1621098
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Articles

Science, Vol 257, Issue 5066, 81-84
Copyright © 1992 by American Association for the Advancement of Science

articles

An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications

DK Wilson, KM Bohren, KH Gabbay, and FA Quiocho

Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030.

Aldose reductase, which catalyzes the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of a wide variety of aromatic and aliphatic carbonyl compounds, is implicated in the development of diabetic and galactosemic complications involving the lens, retina, nerves, and kidney. A 1.65 angstrom refined structure of a recombinant human placenta aldose reductase reveals that the enzyme contains a parallel beta 8/alpha 8-barrel motif and establishes a new motif for NADP-binding oxidoreductases. The substrate-binding site is located in a large, deep elliptical pocket at the COOH-terminal end of the beta barrel with a bound NADPH in an extended conformation. The highly hydrophobic nature of the active site pocket greatly favors aromatic and apolar substrates over highly polar monosaccharides. The structure should allow for the rational design of specific inhibitors that might provide molecular understanding of the catalytic mechanism, as well as possible therapeutic agents.


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Science. ISSN 0036-8075 (print), 1095-9203 (online)