An Unlikely Sugar Substrate Site in the 1.65 Å Structure of the Human Aldose Reductase Holoenzyme Implicated in Diabetic Complications

• Published in: Science (American Association for the Advancement of Science) Vol. 257; no. 5066; pp. 81 - 84
• Main Authors: Wilson, David K., Bohren, Kurt M., Gabbay, Kenneth H., Quiocho, Florante A.
• Format: Journal Article
• Language: English
• Published: Washington, DC American Society for the Advancement of Science 03.07.1992; American Association for the Advancement of Science
• Subjects: Active sites; Aldehyde Reductase - chemistry; Aldehyde Reductase - metabolism; Amino Acid Sequence; Analytical, structural and metabolic biochemistry; Atoms; Binding Sites; Biological and medical sciences; Crystals; Diabetes; Diabetes Complications; Diabetes Mellitus - enzymology; Diphosphates; Electron density; Enzymes; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Hydrogen; Hydrogen bonds; Models, Molecular; Molecular Sequence Data; Oxidoreductases; Protein Conformation; X-Ray Diffraction - methods; Aldose reductase; Enzyme; Substrate specificity; Binding site; Review; Substrate enzyme complex; Structural analysis; Crystalline structure
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1621098

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 β8α8-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.