NON-REDOX FUNCTIONS OF PYRIDINE COENZYMES

吡啶辅酶的非氧化还原功能

• 批准号: 8363589
• 负责人: NORMAN J OPPENHEIMER
• 金额: $ 1.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363589
• 关键词: ADP-ribosyl Cyclase; Adenosine Diphosphate Ribose; Apoptosis; Bacterial Toxins; Biological Process; Calcium; Cell Differentiation process; Cholera; Coenzymes; Computer Graphics; Cyclic ADP-Ribose; DNA Repair; Data; Diphtheria; Drosophila genus; Enzymes; Family; Funding; Glyceraldehyde-3-Phosphate Dehydrogenases; Grant; Histone Deacetylase; Hydrolysis; Imagery; Immune response; Informatics; Investigation; Laboratories; Longevity; Mutation; National Center for Research Resources; Niacinamide; Nuclear Protein; Oxidation-Reduction; Pertussis; Phosphotransferases; Play; Principal Investigator; Proteins; Regulation; Research; Research Infrastructure; Resources; Role; Second Messenger Systems; Source; Therapeutic Intervention; Transfer RNA; United States National Institutes of Health; Yeasts; biocomputing; cell growth regulation; cell transformation; cofactor; cost; design; extracellular; immunoregulation; inhibitor/antagonist; inorganic phosphate; pyridine; pyridine nucleotide; second messenger

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In addition to their functions as cellular redox cofactors, an ever-widening array of non-redox functions has been found for the pyridine nucleotide coenzymes in cellular regulation. First to be identified were bacterial toxins, including those responsible for the symptomology of cholera, diphtheria and pertussis. Evolutionarily related proteins include the multifunctional nuclear protein poly-ADPRibose synthase (PARP) involved in repair of DNA and apoptosis and ADPRibosyltransferases, both cytoplasmic and extracellular, that have been implicated in immunocompetency and immunoregulation. An evolutionarily distinct family of enzymes identified as CD38 correlates with cell transformation and cell differentiation and was found to be a dual functional enzyme. CD38 catalyzes the hydrolysis of NAD and cyclic-ADPribose (cADPR) as well as possesses ADP-Ribosyl cyclase activity. The product, cADPR, functions as a second messenger in calcium regulation while CD38 is critical for the innate immune response. A third distinct family of NAD -dependent enzymes is the histone deacetylase designated as SIR2. It catalyzes the cleavage of the nicotinamide-ribosyl bond with concomitant transfer of the acetyl group to generate a mixture of O2' and O3'-Acetyl-ADPRibose. Mutations in SIR2 in yeast and Drosophila have led to increases in life span of up to two fold. A fourth family of NAD -dependent enzymes is the tRNA phosphotransferase, TPT1, that is the final step in maturation of tRNA. TPT1 catalyses the cleavage of the nicotinamide-ribosyl bond and then transfers the terminal 2'-phosphate of tRNA to generate ADPRibose-1'-2'-cyclicphosphate. Our lab is collaborating in mechanistic studies of the enzymatic functions as well as exploring the design of inhibitors and alternative substrates that can be used to probe their biological functions as well as their potential for therapeutic intervention. There are structural data for all four families hence the facilities of the Computer Graphics Laboratory play a central role in these investigations. We have started a new project that will make extensive use of computer graphics involving the regulatory function of Glyceraldehyde-3-phosphate dehydrogenase.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 除了它们作为细胞氧化还原辅酶因子的功能外，人们还发现了吡啶核苷酸辅酶在细胞调节中的一系列不断扩大的非氧化还原功能。首先被确认的是细菌毒素，包括那些引起霍乱、白喉和百日咳症状的细菌毒素。与进化相关的蛋白质包括参与DNA修复和细胞凋亡的多功能核蛋白多腺苷核糖合成酶(PARP)和参与免疫功能和免疫调节的胞内和胞外的ADP核糖基转移酶。 一个进化上不同的酶家族被鉴定为CD38，它与细胞转化和细胞分化相关，被发现是一种双功能酶。CD38催化NAD和环-ADPribose(CADPR)的水解，并具有ADP-核糖环化酶活性。这种名为cADPR的产物在钙调节中发挥第二信使的作用，而CD38对先天性免疫反应至关重要。 第三个不同的NAD依赖酶家族是被指定为Sir2的组蛋白脱乙酰基酶。它催化烟酰胺-核糖键的断裂，伴随着乙酰基的转移，生成O2‘和O3’-乙酰基-ADPRibose的混合物。酵母和果蝇中Sir2基因的突变导致寿命增加了两倍。 第四个依赖NAD的酶家族是tRNA磷酸转移酶，TPT1，这是tRNA成熟的最后一步。TPT1催化烟酰胺-核糖键的断裂，然后转移tRNA末端的2‘-磷酸生成ADPRibose-1’-2‘-环磷酸。 我们的实验室正在合作进行酶功能的机制研究，并探索抑制剂和替代底物的设计，这些抑制剂和替代底物可用于探索它们的生物学功能以及它们用于治疗干预的潜力。所有四个家庭都有结构数据，因此计算机图形实验室的设施在这些调查中发挥着中心作用。 我们已经开始了一个新的项目，将广泛使用计算机图形技术，涉及甘油醛-3-磷酸脱氢酶的调节功能。