An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications.
An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications.
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DOI：
10.1126/science.1621098
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发表时间：
1992-07
期刊：
影响因子：
56.9
通讯作者：
David K Wilson;K. Bohren;K. Gabbay;F. Quiocho
中科院分区：
文献类型：
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作者：
David K Wilson;K. Bohren;K. Gabbay;F. Quiocho
醛糖还原酶催化多种芳香族和脂肪族羰基化合物的还原形式的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）依赖性还原，与涉及透镜、视网膜、神经和肾脏的糖尿病和半乳糖血症并发症的发生有关。重组人胎盘醛糖还原酶的1.65埃精细结构揭示了该酶含有平行的β 8/α 8桶基序，并为NADP结合氧化还原酶建立了新的基序。底物结合位点位于β桶COOH末端的一个大而深的椭圆形口袋中，结合的NADPH处于延伸构象。活性位点口袋的高度疏水性质极大地有利于芳香族和非极性底物而不是高极性单糖。该结构应允许合理设计的具体抑制剂，可能提供的催化机制的分子理解，以及可能的治疗剂。
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.