NON-REDOX FUNCTIONS OF PYRIDINE COENZYMES

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。 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。

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.