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: 8169988
• 负责人: GANESARATNAM K BALENDIRAN
• 金额: $ 0.34万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169988
• 关键词: Aldehyde Reductase; Aldehydes; Amino Acids; Bacteria; Biological; Citrates; 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; 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 项目1：氧化还原酶：醛糖还原酶（AR）是NADPH依赖性氧化还原酶，可催化包括葡萄糖在内的各种醛的还原。已经表明，通过AR催化途径增加的己糖的通量是组织损伤和与高血糖状态（如糖尿病）相关的功能障碍的根本原因之一。用AR抑制剂进行的临床试验产生了不确定的结果，这些药物在治疗糖尿病并发症方面的长期疗效仍有待证明。 AR已用几种化合物山梨糖醇，Fidarestat，Zopolrestat，tolrestat，sorbinil，柠檬酸盐，cacodylate，6-磷酸盐，氧化甲酸酯，WF-3681和IDD384以多于一种晶体形式以多种水晶形式而结晶。采用基于结构的抑制剂设计方法，我们证明了一类新型化合物作为AR抑制剂。我们目前的目的是在SSRL上收集X射线衍射数据，以确定这些基于脂质和突变体AR的基于脂质的化合物的复杂结构。 AR与脂质基化合物的晶体结构将提供AR和这些化合物的氨基酸残基之间的特定相互作用。相互作用的知识将有助于我们区分负责各种抑制特性的独特接触，并结合生物学和临床数据。 项目2：核酸结合蛋白：许多细菌中的限制性修饰系统提供了防止DNA侵袭的保护。保护效率取决于限制与甲基转移酶基因的相对表达水平。该调节由称为C蛋白的控制器蛋白提供。大肠杆菌中BCLI系统的研究表明，C.BCLL是M.BCLI表达的负调节剂，这意味着在病毒感染过程中捍卫异物DNA中的作用。