STRUCTURE FUNCTION STUDIES OF OXIDOREDUCTASES AND NUCLEIC ACID BINDING PROTEINS

氧化还原酶和核酸结合蛋白的结构功能研究

• 批准号: 7721922
• 负责人: GANESARATNAM K BALENDIRAN
• 金额: $ 0.17万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7721922
• 关键词: Aldehyde Reductase; Aldehydes; Amino Acids; Bacteria; Biological; Citrate; Citrates; Class; Clinical Data; Clinical Trials; Complex; Complications of Diabetes Mellitus; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Restriction-Modification Enzymes; Data; Diabetes Mellitus; Dimethylarsinate; Escherichia coli; Functional disorder; Funding; Genes; Glucose; Glucose-6-Phosphate; Grant; Hexoses; Hyperglycemia; IDD384; Injury; Institution; Knowledge; Lipids; NADP; Names; Oxidoreductase; Pathway interactions; Property; Proteins; Regulation; Relative (related person); Research; Research Personnel; Resources; Role; Sorbitol; Source; Structure; System; Tissues; United States National Institutes of Health; Virus Diseases; base; citrate carrier; design; drug efficacy; fidarestat; inhibitor/antagonist; mutant; novel; nucleic acid binding protein; sorbinil; tolrestat; zopolrestat

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. Project 1: Oxidoreductase: 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 sorbitol, fidarestat, zopolrestat, tolrestat, sorbinil, citrate, cacodylate, glucose 6-phosphate, oxazolecarbamate, WF-3681 and IDD384 in more than one crystal form. Employing structure-based inhibitor design approach we have demonstrated a novel class of compounds as AR inhibitors. Our current aim is to collect x-ray diffraction data at SSRL to determine the complex structures of these lipid based compounds with wild-type and mutant forms of AR. Crystal structures of AR with the lipid based compounds will provide the specific interactions between the amino acid residues of AR and these compounds. The knowledge of the interactions will help to us distinguish the unique contacts responsible for varied inhibition properties in combination with biological and clinical data. Project 2: Nucleic acid binding protein: Protection from DNA invasion is afforded by restriction-modification systems in many bacteria. The efficiency of protection depends crucially on the relative expression levels of restriction versus methytransferase genes. This regulation is provided by a controller protein, named C protein. Studies of the BclI system in E. coli suggests that C.Bcll functions as a negative regulator for M.BclI expression, implying a role in defense of foreign DNA during virus infection.

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。 项目1：氧化还原酶：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与几种化合物山梨醇、fidarestat、佐波利司他、托瑞司他、山梨醇、柠檬酸盐、氨基甲酸酯、6-磷酸葡萄糖、恶唑氨基甲酸酯、WF-3681和IDD384以一种以上的晶型结晶。利用基于结构的抑制剂设计方法，我们展示了一类新的化合物作为AR抑制剂。我们目前的目标是在SSRL收集X射线衍射数据，以确定这些含有野生型和突变型AR的脂类化合物的复杂结构。AR与脂基化合物的晶体结构将提供AR的氨基酸残基与这些化合物之间的特异性相互作用。对相互作用的了解将有助于我们结合生物学和临床数据区分导致不同抑制特性的独特接触。项目2：核酸结合蛋白：在许多细菌中，限制修饰系统提供了免受DNA入侵的保护。保护的效率关键取决于限制基因相对于甲基转移酶基因的相对表达水平。这种调节是由一种名为C蛋白的控制蛋白提供的。对大肠杆菌中BclI系统的研究表明，C.Bcl1对M.BclI的表达具有负调控作用，这意味着在病毒感染过程中对外源DNA的防御作用。