STRUCTURE FUNCTION STUDIES OF OXIDOREDUCTASES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 醛糖还原酶(AR)是一种依赖于NADPH的氧化还原酶，可催化包括葡萄糖在内的多种醛的还原。研究表明，通过AR催化途径增加的己糖流量是糖尿病等高血糖状态下组织损伤和功能障碍的潜在原因之一。AR抑制剂的临床试验结果不确定，这些药物在治疗糖尿病并发症方面的长期疗效仍有待证实。Ar已经与几种化合物结晶，这些化合物是多元醇途径(葡萄糖代谢的一部分)的成员，以不止一种晶体形式存在。我们的研究表明，AR是一种有效的催化剂，用于还原4-羟基-反式-2-壬醛等化合物，这些化合物是脂质过氧化的产物(Dixit等人，(2000年)J Bio Chem275,21587)。此外，4-羟基-反式-2-壬烯醛是一种比所有已知的糖代谢相关化合物更好的底物。进一步利用结构功能研究，我们已经证明了基于脂类的化合物可以以不止一个方向结合在AR的活性部位(Ramana等人)。(2000年)生物化学39,12172)。AR与脂基化合物的晶体结构将提供AR残基与这些化合物之间的特定相互作用。这将有助于区分不同的绑定方向。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Aldose reductase (AR) is an NADPH dependent oxidoreductase that catalyzes the reduction of a wide variety of aldehydes including glucose. It has been shown that increased flux of hexoses via the AR catalyzed pathway is one of the underlying causes of tissue injury and dysfunction associated with hyperglycemic states such as diabetes mellitus. Clinical trials with AR inhibitors have yielded uncertain results and the long-term efficacy of these drugs in treating diabetic complications remains to be demonstrated. AR has been crystallized with several compounds which, are members of polyol pathway (part of glucose metabolism) in more than one crystal form. Our studies show that AR is an efficient catalyst for the reduction of compounds like 4-hydroxy-trans-2-nonenal, which, are products of lipid peroxidation (Dixit et al., (2000) J Bio Chem 275, 21587). In addition 4-hydroxy-trans-2-nonenal is a better substrate than all the known glucose metabolism related compounds. Further exploiting structure function studies we have demonstrated that the lipid based compounds could bind in the active site of AR in more than one orientation (Ramana et al. (2000) Biochemistry 39, 12172). Crystal structures of AR with the lipid based compounds will provide the specific interactions between AR residues and these compounds. This will help to distinguish between different orientations of binding.