ALDOSE REDUCTASE: KINETICS, MECHANISM, AND DIABETES

点击翻译按钮获取中文摘要

The action of aldose reductase (EC 1.1.1.21) is implicated in the etiology of diabetic complications of the lens, peripheral nerve, and kidney. These manifestations of the disease are thought to be a direct consequence of the osmotic effects generated by a large intracellular accumulation of the sugar alcohol, D-sorbitol. While the involvement of aldose reductase in diabetic cataract formation is well-established, participation of the enzyme in the interstitial nephritis and papillary atrophy seen in uncontrolled diabetics and animal models has not been evaluated. There is also evidence that the enzyme may differ in each of these systems, as shown by its varying susceptibility to inhibition by compounds (e.g., Sorbanil) of potential interest as therapeutic agents. Further, the question of precisely how these compounds inhibit aldose reductase has not been adequately addressed. Previous studies are hindered by the lack of a mechanistic basis, both chemical and kinetic, for distinguishing and "aldose reductase" from other NADP-linked aldehyde reductases with similar properties. The in vivo metabolic role of aldose reductase is not known. Preparation of a large quantity of homogeneous aldose reductase from bovine kidney will facilitate a detailed investigation of the structural requirements for substrate activity, the mode of inhibition by various compounds of potential therapeutic interest, and the normal role of the enzyme in vivo. Determination of the chemical and kinetic mechanisms for the enzymic reaction will establish a firm basis for classification of this type of NADP-linked aldehyde reductase. Once this system is completely characterized, the information can be used in the design of, and the homogeneous enzyme used to screen for, potential drugs. In addition, this study will establish the sensitivity to inhibition of the kidney enzyme relative to the enzyme from other tissues (e.g., lens and brain), and may also reveal any toxic side-effects that may arise as a consequence of systemic therapy with aldose reductase inhibitors. It is planned to extend these studies to human tissues.