STRUCTURE FUNCTION STUDIES OF OXIDOREDUCTASES

氧化还原酶的结构功能研究

• 批准号: 7597900
• 负责人: GANESARATNAM K BALENDIRAN
• 金额: $ 0.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7597900
• 关键词: Active Sites; Aldehyde Reductase; Aldehydes; Binding; Clinical Trials; Complications of Diabetes Mellitus; Computer Retrieval of Information on Scientific Projects Database; Diabetes Mellitus; Functional disorder; Funding; Glucose; Grant; Hexoses; Hyperglycemia; Injury; Institution; Lipid Peroxidation; Lipids; NADP; Oxidoreductase; Pathway interactions; Research; Research Personnel; Resources; Source; Structure; Tissues; United States National Institutes of Health; base; catalyst; drug efficacy; glucose metabolism; inhibitor/antagonist; member; polyol

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 醛糖还原酶 (AR) 是一种 NADPH 依赖性氧化还原酶，可催化包括葡萄糖在内的多种醛的还原。 已经表明，通过 AR 催化途径增加的己糖通量是与高血糖状态（例如糖尿病）相关的组织损伤和功能障碍的根本原因之一。 AR抑制剂的临床试验产生了不确定的结果，这些药物治疗糖尿病并发症的长期疗效仍有待证明。 AR 已与多种化合物一起结晶，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 是还原 4-羟基-反式-2-壬烯醛等化合物的有效催化剂，这些化合物是脂质过氧化的产物（Dixit 等人，(2000) J Bio Chem 275, 21587）。 此外，4-羟基-反式-2-壬烯醛是比所有已知的葡萄糖代谢相关化合物更好的底物。 进一步利用结构功能研究，我们已经证明基于脂质的化合物可以以多个方向结合在AR的活性位点上（Ramana等人（2000）Biochemistry 39, 12172）。 AR 与基于脂质的化合物的晶体结构将提供 AR 残基和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。