Shen C, Sigman D S
Department of Biological Chemistry School of Medicine, University of California, Los Angeles 90024.
Arch Biochem Biophys. 1991 May 1;286(2):596-603. doi: 10.1016/0003-9861(91)90086-x.
Aldose reductase is an NADPH-dependent enzyme which catalyzes the reduction of glucose to sorbitol. Specific potent inhibitors of aldose reductase are of potential pharmacological use because elevated levels of sorbitol produced by this enzyme in lens, peripheral nerve, retina, and renal glomeruli may be responsible for the pathogenesis associated with chronic diabetes. These inhibitors could also serve as probes of the mechanism of action of aldose reductase. anti-Oximes of aromatic aldehydes (e.g., benzaldoxime and 4-fluorobenzaldoxime) have proved to be effective inhibitors of aldose reductase rivaling pharmacological agents currently used to inhibit this enzyme in vivo. The kinetic patterns of inhibition in which benzyl alcohol is used as the oxidizable substrate suggest that the inhibition is due to the formation of a stable ternary complex composed of aldose reductase, NADP+, and the anti-oxime. Analogus ternary complexes are formed at the active site of horse liver alcohol dehydrogenase which is also inhibited by anti-oximes of efficient substrates.
醛糖还原酶是一种依赖烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的酶，它催化葡萄糖还原为山梨醇。醛糖还原酶的特异性强效抑制剂具有潜在的药理学用途，因为该酶在晶状体、外周神经、视网膜和肾小球中产生的山梨醇水平升高，可能与慢性糖尿病相关的发病机制有关。这些抑制剂还可作为醛糖还原酶作用机制的探针。芳香醛的抗肟（如苯甲醛肟和4-氟苯甲醛肟）已被证明是醛糖还原酶的有效抑制剂，可与目前用于体内抑制该酶的药物相媲美。以苯甲醇作为可氧化底物的抑制动力学模式表明，这种抑制是由于形成了由醛糖还原酶、NADP⁺和抗肟组成的稳定三元复合物。类似的三元复合物在马肝醇脱氢酶的活性位点形成，该酶也受到有效底物抗肟的抑制。
