Molecular Mechanisms, Pathways and Inhibition of Acetyl-Transfer Reactions

乙酰基转移反应的分子机制、途径和抑制

• 批准号: 10163349
• 负责人: Ronen Marmorstein
• 金额: $ 57.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10163349
• 关键词: ATP Citrate (pro-S)-Lyase; Acetate-CoA Ligase; Acetyl Coenzyme A; Acetylation; Acetyltransferase; Address; Anabolism; Biological; Biology; Cardiovascular Diseases; Cholesterol; Chromatin; Cytidine; Enzymes; Family member; Fatty Acids; Fatty-acid synthase; Histones; Human; Life; Link; Lysine; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Modification; Molecular; N-terminal; Nerve Degeneration; Organism; Pathway interactions; Pharmacology; Play; Positioning Attribute; Protein Acetylation; Proteins; Proteome; RNA; Reaction; Regulation; Ribosomes; Role; Side; Stimulus; Structure; Substrate Specificity; Syndrome; Tertiary Protein Structure; amino group; base; cofactor; genetic regulatory protein; histone acetyltransferase; human disease; inhibitor/antagonist; isoprenoid; metabolome; protein complex; rare genetic disorder; targeted agent; targeted treatment

The acetylation of proteins and RNA, and acetyl-transfer reactions that produce cellular metabolites, are evolutionarily conserved modifications that are essential for life. The post- or co-translational acetylation of proteins provides an essential mechanism for organisms to react to external and internal stimuli; examples include acetylation of the e-amino group of lysine side chains of histone proteins by histone acetyltransferases (HATs) or the N-terminal a-amino group by N-terminal acetyltransferases (NATs), respectively; and the acetylation at the N4 position of cytidine bases by Nat10. Acetyl-transfer reactions produce cellular metabolites that can mediate the biosynthesis of essential cellular building blocks; examples include: acetyl-CoA produced by ATP-citrate lyase (ACLY) and acetyl-CoA synthetase short- chain family member 2 (ACSS2); fatty acids produced by Fatty Acid Synthase (FASN); and cholesterol and isoprenoids formed through the sequential reactions of many enzymes. The enzymes that mediate acetyl- transfer reactions often function in the context of multiple domain proteins or multisubunit protein complexes, which play essential roles in the regulation of cognate substrate recognition and targeting and/or catalytic fidelity. How the various protein domains and protein cofactors cooperate for their respective acetyl-transfer reactions remains poorly understood. Correlating with their biological importance, the aberrant activities of acetyl-transfer enzymes or their regulatory proteins have been associated with several maladies including cancers, rare genetic disorders, cardiovascular diseases and metabolic and neurodegenerative syndromes, thus making these enzymes attractive drug targets for therapy. Taken together, acetyl-transfer reactions play an important regulatory function in the vast majority of the human proteome, RNAome and metabolome, and aberrant acetyl-transfer reaction function is correlated with human disease. Despite the importance of acetyl-transfer reactions, mechanistic information regarding their distinct modes of regulation are poorly understood and pharmacological agents that target them are not available. In this proposal, we will address the following broad questions underlying acetyl-transfer reactions: (A) How do protein and RNA acetyltransferases mediate substrate specificity? (B) How do auxiliary proteins and ribosome association contribute to NAT function? (C) How does acetyl-CoA metabolism link to chromatin regulation and fatty acid synthesis? (D) Can we leverage mechanistic and structural information to develop potent and selective inhibitors for acetyl-transfer reactions? Together, these studies will reveal how a common acetyltransferase fold is modulated by other proteins or domains to mediate the acetylation of distinct substrates, how N-terminal protein acetylation is modulated by regulatory and associated factors, dissect the molecular mechanism of essential acetyl-transfer enzymes, and provide probes to better understand the biology of acetyl-transfer enzymes with clear implications for therapy.

蛋白质和 RNA 的乙酰化以及产生细胞代谢物的乙酰转移反应是 进化上保守的修饰对生命至关重要。翻译后或共翻译乙酰化 蛋白质为生物体提供了对外部和内部刺激做出反应的重要机制；例子 包括组蛋白赖氨酸侧链的 e-氨基被组蛋白乙酰化 乙酰转移酶 (HAT) 或 N 末端乙酰转移酶 (NAT) 的 N 末端 a-氨基， 分别;以及胞苷碱基的 N4 位被 Nat10 乙酰化。乙酰基转移反应 产生可以介导必需细胞构件生物合成的细胞代谢物； 例子包括：由 ATP-柠檬酸裂解酶 (ACLY) 和乙酰辅酶 A 合成酶短链产生的乙酰辅酶 A 链家族成员2 (ACSS2)；由脂肪酸合酶（FASN）产生的脂肪酸；和胆固醇和 类异戊二烯是通过许多酶的连续反应形成的。介导乙酰基的酶 转移反应通常在多结构域蛋白或多亚基蛋白的背景下起作用 复合物，在同源底物识别和靶向的调节中发挥重要作用 和/或催化保真度。各种蛋白质结构域和蛋白质辅因子如何合作以发挥其作用 各自的乙酰基转移反应仍然知之甚少。与其生物学重要性相关， 乙酰转移酶或其调节蛋白的异常活性与 多种疾病，包括癌症、罕见遗传性疾病、心血管疾病以及代谢和疾病 神经退行性综合征，从而使这些酶成为有吸引力的治疗药物靶点。采取 总之，乙酰转移反应在绝大多数人类中发挥着重要的调节功能。 蛋白质组、RNA组和代谢组，以及异常的乙酰转移反应功能与 人类疾病。尽管乙酰转移反应很重要，但有关的机制信息 人们对它们独特的调节模式知之甚少，针对它们的药物制剂也不清楚 无法使用。在本提案中，我们将解决乙酰基转移的以下广泛问题 反应： (A) 蛋白质和 RNA 乙酰转移酶如何介导底物特异性？ （二）如何做 辅助蛋白和核糖体关联有助于 NAT 功能？ (C) 乙酰辅酶A如何 新陈代谢与染色质调节和脂肪酸合成有何联系？ (D) 我们能否利用机械和 结构信息来开发乙酰转移反应的有效和选择性抑制剂？一起， 这些研究将揭示常见的乙酰转移酶折叠如何被其他蛋白质或结构域调节以 介导不同底物的乙酰化，N-末端蛋白质乙酰化如何通过调节来调节 和相关因素，剖析必需乙酰转移酶的分子机制，并提供 探针可以更好地了解乙酰转移酶的生物学，对治疗具有明确的意义。