NON-REDOX FUNCTIONS OF PYRIDINE COENZYMES

吡啶辅酶的非氧化还原功能

• 批准号: 7723485
• 负责人: NORMAN J OPPENHEIMER
• 金额: $ 0.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723485
• 关键词: ADP-ribosyl Cyclase; Adenosine Diphosphate Ribose; Apoptosis; Bacterial Toxins; Biological Process; Calcium; Cell Differentiation process; Cholera; Coenzymes; Computer Graphics; Computer Retrieval of Information on Scientific Projects Database; Cyclic ADP-Ribose; DNA Repair; Data; Diphtheria; Drosophila genus; Enzymes; Family; Funding; Grant; Histone Deacetylase; Hydrolysis; Immune response; Institution; Investigation; Laboratories; Longevity; Mutation; Niacinamide; Nicotinamide adenine dinucleotide; Nuclear Protein; Nuclear Proteins; Object Attachment; Oxidation-Reduction; Pertussis; Phosphotransferases; Play; Proteins; Regulation; Research; Research Personnel; Resources; Role; Second Messenger Systems; Source; Therapeutic Intervention; Transfer RNA; United States National Institutes of Health; Yeasts; cell growth regulation; cell transformation; cofactor; 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. 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. 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.

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。 除了作为细胞氧化还原辅因子的功能外，吡啶核苷酸辅酶在细胞调节中还发现了一系列不断扩大的非氧化还原功能。首先被识别的是细菌毒素，包括导致霍乱、白喉和百日咳症状的细菌毒素。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聚 ADPR 核糖合酶 (PARP)，以及细胞质和细胞外的 ADP 核糖基转移酶，它们与免疫能力和免疫调节有关。 CD38 是一个进化上独特的酶家族，与细胞转化和细胞分化相关，并且被发现是一种双功能酶。 CD38 催化 NAD 和环 ADP 核糖 (cADPR) 的水解，并具有 ADP-核糖基环化酶活性。该产品 cADPR 在钙调节中充当第二信使，而 CD38 对于先天免疫反应至关重要。 第三个独特的 NAD 依赖性酶家族是组蛋白脱乙酰酶，称为 SIR2。它催化烟酰胺-核糖基键的断裂并伴随乙酰基的转移，生成 O2' 和 O3'-乙酰基-ADP 核糖的混合物。酵母和果蝇中 SIR2 的突变导致寿命延长了两倍。 第四个 NAD 依赖性酶家族是 tRNA 磷酸转移酶 TPT1，它是 tRNA 成熟的最后一步。 TPT1催化烟酰胺-核糖基键的裂解，然后转移tRNA的末端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，这些底物可用于探测其生物功能及其治疗干预的潜力。所有四个家族都有结构数据，因此计算机图形实验室的设施在这些调查中发挥着核心作用。