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: 10651689
• 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/10651689
• 关键词: ATP Citrate (pro-S)-Lyase; Acetate-CoA Ligase; Acetyl Coenzyme A; Acetylation; Acetyltransferase; 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; Play; Positioning Attribute; Protein Acetylation; Protein Complex Subunit; Proteins; Proteome; RNA; Reaction; Regulation; Ribosomes; Role; Side; Stimulus; Substrate Specificity; Syndrome; Tertiary Protein Structure; amino group; base; cofactor; genetic regulatory protein; histone acetyltransferase; human disease; inhibitor; inhibitor therapy; isoprenoid; metabolome; pharmacologic; 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基转移反应是 对生命必不可少的进化保守的修改。后或共同翻译的乙酰化 蛋白质为生物体对外部和内部刺激做出反应提供了一种基本机制。例子 包括组蛋白的E-AMINO组的乙酰乙酸酯基团的赖氨酸侧链 N末端乙酰基转移酶（NAT），NATS，NATS，NATS），乙酰转移酶（帽子）或N端A氨基 分别; Nat10在胞苷碱基N4位置的乙酰化。乙酰基转化反应 产生细胞代谢产物，可以介导必需细胞构建基块的生物合成； 示例包括：由ATP-CITRATE裂解酶（ACLY）和乙酰-COA合成酶短 - 产生的乙酰辅酶A 连锁家庭成员2（ACSS2）;由脂肪酸合酶（FASN）产生的脂肪酸；和胆固醇和 通过许多酶的顺序反应形成的类异型。介导乙酰基的酶 转移反应通常在多个域蛋白或多亚基蛋白的背景下起作用 复合体，在相关底物识别和靶向的调节中起着重要作用 和/或催化保真度。各种蛋白质结构域和蛋白质辅助因子如何合作 各自的乙酰基转移反应仍然鲜为人知。与它们的生物学重要性相关， 乙酰基转移酶或其调节蛋白的异常活性与 包括癌症，罕见遗传疾病，心血管疾病以及代谢以及新陈代谢的几种疾病 神经退行性综合征，从而使这些酶有吸引力的治疗靶标。拍摄 在绝大多数人中，乙酰基转移反应起着重要的调节功能 蛋白质组，RNAOME和代谢组以及异常的乙酰基转移反应功能与 人类疾病。尽管乙酰基转移反应很重要，但有关机械信息 他们独特的监管方式对它们的理解很少，而针对它们的药理学剂是 无法使用。在此提案中，我们将解决乙酰基转移基础的以下广泛问题 反应：（a）蛋白质和RNA乙酰转移酶如何介导底物特异性？ （b）如何做 辅助蛋白和核糖体关联有助于NAT功能吗？ （c）乙酰辅酶A如何 代谢与染色质调节和脂肪酸合成？ （d）我们可以利用机械和 结构信息以开发乙酰基转移反应的有效和选择性抑制剂？一起， 这些研究将揭示如何通过其他蛋白质或结构域调节常见的乙酰基转移酶折叠 介导不同底物的乙酰化，如何通过调节调节N末端蛋白乙酰化 以及相关因素，剖析必需乙酰基转移酶的分子机制，并提供 探针更好地了解乙酰基转移酶的生物学，对治疗有明显的影响。

项目成果

Drugging the "Undruggable" MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers.

• DOI: 10.1158/0008-5472.can-20-3108
• 发表时间: 2021-04-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Wolpaw AJ;Bayliss R;Büchel G;Dang CV;Eilers M;Gustafson WC;Hansen GH;Jura N;Knapp S;Lemmon MA;Levens D;Maris JM;Marmorstein R;Metallo SJ;Park JR;Penn LZ;Rape M;Roussel MF;Shokat KM;Tansey WP;Verba KA;Vos SM;Weiss WA;Wolf E;Mossé YP
• 通讯作者: Mossé YP

Expanding the phenotypic spectrum of NAA10-related neurodevelopmental syndrome and NAA15-related neurodevelopmental syndrome.

• DOI: 10.1038/s41431-023-01368-y
• 发表时间: 2023-07
• 期刊: European journal of human genetics : EJHG

N-alpha-acetylation of Huntingtin protein increases its propensity to aggregate.

• DOI: 10.1016/j.jbc.2021.101363
• 发表时间: 2021-12
• 期刊: The Journal of biological chemistry
• 作者: Gottlieb L;Guo L;Shorter J;Marmorstein R
• 通讯作者: Marmorstein R

The GNU subunit of PNG kinase, the developmental regulator of mRNA translation, binds BIC-C to localize to RNP granules.

• DOI: 10.7554/elife.67294
• 发表时间: 2021-07-12
• 期刊: eLife
• 影响因子: 7.7
• 作者: Avilés-Pagán EE;Hara M;Orr-Weaver TL
• 通讯作者: Orr-Weaver TL