NON-REDOX FUNCTIONS OF PYRIDINE COENZYMES

吡啶辅酶的非氧化还原功能

• 批准号: 7955475
• 负责人: NORMAN J OPPENHEIMER
• 金额: $ 0.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955475
• 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; Imagery; Immune response; Informatics; Institution; Investigation; Laboratories; Longevity; Mutation; Niacinamide; Nuclear Protein; Nuclear Proteins; 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; biocomputing; 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 除了作为细胞氧化还原辅因子的功能外，还发现吡啶核苷酸辅酶在细胞调节中具有越来越广泛的非氧化还原功能。首先确定的是细菌毒素，包括那些导致霍乱、白喉和百日咳的细菌毒素。进化上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ADP核糖合酶（PARP），以及细胞质和细胞外的ADP核糖基转移酶，其已经涉及免疫能力和免疫调节。 被鉴定为CD 38的进化上不同的酶家族与细胞转化和细胞分化相关，并且被发现是双功能酶。 CD 38催化NAD和环状ADP核糖（cADPR）的水解，并具有ADP-核糖环化酶活性。该产物cADPR在钙调节中作为第二信使发挥作用，而CD 38对先天免疫应答至关重要。 NAD依赖性酶的第三个不同家族是命名为SIR 2的组蛋白脱乙酰酶。催化烟酰胺-核糖键的断裂，同时乙酰基转移，生成O2'和O3'-乙酰基-ADP核糖的混合物。酵母和果蝇中SIR 2的突变导致寿命增加了两倍。 NAD依赖性酶的第四个家族是tRNA磷酸转移酶TPT 1，其是tRNA成熟的最后一步。TPT 1催化烟酰胺-核糖键的断裂，然后转移tRNA的末端2 '-磷酸，生成ADP核糖-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测其生物学功能以及其治疗干预的潜力。有所有四个家庭的结构数据，因此计算机图形实验室的设施在这些调查中发挥了核心作用。