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

David K. Wilson, Kurt M. Bohren, Kenneth H. Gabbay, Florante A. Quiocho

Research output: Contribution to journalArticle

368 Citations (Scopus)

Abstract

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. A1.65 angstrom refined structure of a recombinant human placenta aldose reductase reveals that the enzyme contains a parallel β8/α8-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 β 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.

Original languageEnglish (US)
Pages (from-to)81-84
Number of pages4
JournalScience
Volume257
Issue number5066
StatePublished - 1992
Externally publishedYes

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Aldehyde Reductase
Holoenzymes
Diabetes Complications
NADP
Monosaccharides
Placenta
Lenses
Retina
Catalytic Domain
Oxidoreductases
Binding Sites
Kidney
Enzymes
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

An unlikely sugar substrate site in the 1.65 Å structure of the human aldose reductase holoenzyme implicated in diabetic complications. / Wilson, David K.; Bohren, Kurt M.; Gabbay, Kenneth H.; Quiocho, Florante A.

In: Science, Vol. 257, No. 5066, 1992, p. 81-84.

Research output: Contribution to journalArticle

Wilson, David K. ; Bohren, Kurt M. ; Gabbay, Kenneth H. ; Quiocho, Florante A. / An unlikely sugar substrate site in the 1.65 Å structure of the human aldose reductase holoenzyme implicated in diabetic complications. In: Science. 1992 ; Vol. 257, No. 5066. pp. 81-84.
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