Chemical Approaches for Studying the Biology of NAD-consuming Enzymes

研究 NAD 消耗酶生物学的化学方法

• 批准号: 8631881
• 负责人: Hening Lin
• 金额: $ 26.92万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631881
• 关键词: Address; Adenosine Diphosphate Ribose; Aging; Antineoplastic Agents; Biological Process; Biology; Boxing; Catalytic Domain; Cell membrane; Cell surface; Cells; Chemicals; Cyclic ADP-Ribose; DNA Repair; Data; Deacetylase; Development; Diabetes Mellitus; Differentiation Antigens; Disease; Enzymes; Genetic Transcription; Genome Stability; Glycoside Hydrolases; Goals; Hematopoietic; Human; Hydrolysis; Immune; In Vitro; Label; Lead; Longevity; Lymphoma; Lysine; Malignant Neoplasms; Membrane Proteins; Metabolism; Mitosis; Modification; Molecular; Multiple Myeloma; Nerve Degeneration; Nicotinamide adenine dinucleotide; Nuclear Envelope; Orphan; Osteoporosis; Oxidation-Reduction; Parkinson Disease; Peptides; Pharmacologic Substance; Physiological; Poly(ADP-ribose) Polymerases; Polymers; Post-Translational Protein Processing; Process; Proteins; Regulation; Reporting; Second Messenger Systems; Sirtuins; Site; Therapeutic; Transcriptional Regulation; United States National Institutes of Health; acyl group; amidase; analog; biological adaptation to stress; cofactor; human disease; inhibitor/antagonist; insight; leukemia; metaplastic cell transformation; novel; public health relevance; screening; second messenger; small molecule

This is a competitive renewal of R01 GM086703. Nicotinamide adenine dinucleotide (NAD), commonly known as an important redox cofactor in biology, are also used as a co-substrate by many NAD-consuming enzymes. These enzymes include CD38 (an NAD glycohydrolase and cyclase), poly(ADP-ribose) polymerases (PARPs), and sirtuins (NAD-dependent protein lysine deacylases). All these NAD-consuming enzymes have important biological functions and deregulation of them is associated with various human diseases, including cancer, diabetes, and neurodegeneration. However, many fundamental questions about the functions of NAD-consuming enzymes are poorly understood. The goal of this proposal is to develop and use chemical probes to help understand the function of these NAD consuming enzymes. In the last four years with NIH support, we have developed several NAD analogs to study these NAD- consuming enzymes and have made a number of important progresses. These include the development of covalent cell permeable probes for CD38, the development of a clickable NAD analog for labeling the substrate proteins of PARPs, and the discovery of Sirt5 as an NAD-dependent desuccinylase/demalonylase and Sirt6 as an NAD-dependent defatty-acylase. Building on these progresses, in this proposal, we will use the probes we already developed to understand the function of CD38 and PARPs, and to develop new probes for the study of PARPs and sirtuins. We believe our proposed studies will provide important insights to understand the biological functions of NAD-consuming enzymes, lead to the discovery of novel protein posttranslational modifications, and ultimately lead to the development of better therapeutics for treating human diseases involving NAD-consuming enzymes.

这是 R01 GM086703 的竞争性更新。烟酰胺腺嘌呤二核苷酸（NAD），通常 被称为生物学中重要的氧化还原辅助因子，也被许多 NAD 消耗者用作辅助底物 酶。这些酶包括 CD38（一种 NAD 糖水解酶和环化酶）、聚（ADP-核糖） 聚合酶 (PARP) 和 Sirtuins（NAD 依赖性蛋白赖氨酸脱酰酶）。所有这些都消耗NAD 酶具有重要的生物学功能，其失调与人类的多种疾病有关。 疾病，包括癌症、糖尿病和神经退行性疾病。然而，许多基本问题 NAD 消耗酶的功能知之甚少。该提案的目标是开发 并使用化学探针来帮助了解这些 NAD 消耗酶的功能。 在过去四年中，在 NIH 的支持下，我们开发了几种 NAD 类似物来研究这些 NAD- 消耗酶并取得了许多重要进展。这些包括开发 CD38 的共价细胞渗透性探针，开发用于标记 CD38 的可点击 NAD 类似物 PARP 的底物蛋白，以及 Sirt5 作为 NAD 依赖性脱琥珀酰酶/脱丙二酰酶的发现 Sirt6 是一种 NAD 依赖性脱脂酰基转移酶。在这些进展的基础上，在本提案中，我们将使用 我们已经开发的探针用于了解 CD38 和 PARP 的功能，并开发新的 用于研究 PARP 和 Sirtuins 的探针。我们相信我们提出的研究将提供重要的见解 了解 NAD 消耗酶的生物学功能，从而发现新的蛋白质 翻译后修饰，并最终导致更好的治疗方法的开发 涉及 NAD 消耗酶的人类疾病。