ALDOSE REDUCTASE: KINETICS, MECHANISM & DIABETES

醛糖还原酶的作用（EC 1.1.1.21；“低Km”醛还原酶； ALR2）与糖尿病眼部并发症的病因有关， 肾脏、心脏和神经。 特异性醛糖还原酶的能力 抑制剂（ARIs）以防止并发症的发生（地下室 膜增厚、肾肥大、轴突运输缺陷和 神经传导速度）在各种组织中已证实中枢 ALR2 在正常和糖尿病代谢中的作用。 这个结论是 得到系统发育保护的免疫学证据的支持 哺乳动物 ALR2 基因产物。 同质牛肾 ALR2 (BKALR2) 与牛肾 ALR2 几乎相同 晶状体 ALR2，但只有在 BKALR2 经历了缓慢的、硫醇依赖性的 活化至稳定形式。 激活过程，导致 动力学行为的改变（抑制的敏感性降低 索宾尼尔，硫酸盐刺激减少，非线性出现 甘油醛的双倒数图），与 人体组织中观察到的激活和可变的 ARI 敏感性。 进一步 使用同质 BKALR2 的机制研究将侧重于表征 使用动力学和免疫学技术的激活过程， 通过结构-活性鉴定生理底物 研究并确定 ARI 抑制模式。 的延伸 这些对人肾ALR2和“高Km”醛还原酶的研究将 利用单特异性兔抗 BKALR2 进行分离和 HKALR2 的表征。 关键实验，基于结果 牛系统，将评估 ARI 抑制的模式和敏感性， 以及激活（如 BKALR2 的记录）在人体系统中的作用。

The Action of aldose reductase (EC 1.1.1.21; "low-Km" aldehyde reductase; ALR2) is implicated in the etiology of diabetic complications of the eye, kidney, heart, and nerve. The ability of specific aldose reductase inhibitors (ARIs) to prevent the development of complications (basement membrane thickening, renal hypertrophy, defective axonal transport and nerve conduction velocity) in various tissues has confirmed the central role of ALR2 in normal and diabetic metabolism. This conclusion is supported by immunologic evidence for phylogenetic conservation of the mammalian ALR2 gene product. Homogeneous bovine kidney ALR2 (BKALR2) is virtually identical to bovine lens ALR2, but only after the BKALR2 has undergone a slow, thiol-dependent activation to a stable form. The activation process, which results in alteration of the kinetic behavior (decreased sensitivity to inhibition by Sorbinil, decreased stimulation by sulfate, appearance of non-linearity in the double-reciprocal plot for glyceraldehyde), is relevant to the activation and variable ARI sensitivity seen in human tissues. Further mechanistic studies using homogeneous BKALR2 will focus on characterization of the activation process using kinetic and immunologic techniques, identification of the physiological substrate by structure-activity studies, and determination of the mode of ARI inhibition. The extension of these studies to human kidney ALR2 and "high-Km" aldehyde reductase will utilize mon-specific rabbit anti-BKALR2 for the isolation and characterization of HKALR2. Key experiments, based on the results from the bovine system, will evaluate the mode and sensitivity to ARI inhibition, and the role of activation (as documented for BKALR2) in the human system.