STRUCTURE FUNCTION STUDIES OF OXIDOREDUCTASES

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。醛糖还原酶（AR）是一种NADPH依赖的氧化还原酶，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通量是与高血糖状态（如糖尿病）相关的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，这些药物治疗糖尿病并发症的长期疗效仍有待证实。AR已与多种化合物结晶，这些化合物是多元醇途径（葡萄糖代谢的一部分）的成员，具有多种晶体形式。我们的研究表明，AR是一种有效的催化剂，可以还原4-羟基-反式-2-壬烯醛等化合物，这些化合物是脂质过氧化的产物（Dixit et al., (2000) J Bio Chem 275, 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，我们已经证明脂质化合物可以在多个方向上结合AR的活性位点（Ramana et al. (2000) Biochemistry 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结合方向。

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.