Metabolic regulation and inhibition of ATP-citrate lyase
ATP-柠檬酸裂解酶的代谢调节和抑制
基本信息
- 批准号:10588229
- 负责人:
- 金额:$ 62.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2027-03-31
- 项目状态:未结题
- 来源:
- 关键词:ATP Citrate (pro-S)-LyaseAcetyl Coenzyme AAcetylationAcetyltransferaseAcidsBindingBinding SitesBiochemicalBiological ModelsCancer ModelCarcinogensCardiovascular DiseasesCatalysisCell ProliferationCell modelCellsCholesterolCitratesCoenzyme ACryoelectron MicroscopyDataDeacetylaseDependenceDevelopmentDietDiseaseEnzymesExclusionExonsFDA approvedFatty AcidsFeedbackGlucoseGoalsHandHepatocarcinogenesisHepatocyteHistone AcetylationHumanIn VitroIndividualKnockout MiceKnowledgeLeadMalignant NeoplasmsMalignant neoplasm of liverMediatingMetabolicMetabolic DiseasesMitochondriaModificationMolecularMolecular ConformationMusMutagenesisNormal CellOxaloacetatesPCAF genePharmaceutical PreparationsPhenotypePhosphorylationPhosphorylation SitePositioning AttributePost-Translational Protein ProcessingPrimary carcinoma of the liver cellsProductionProgram DevelopmentProtein AcetylationProtein IsoformsProtein SubunitsRNA SplicingReactionRegulationReportingRiskRoleSiteSourceStructureTestingTherapeutic UsesValidationWorkadductbiophysical analysiscancer cellcancer therapydrug developmentexperimental studygenetic regulatory proteinin vivoinhibitorinhibitor therapyisoprenoidlipid biosynthesismouse modelmutantnovelposttranscriptionaltumortumor metabolism
项目摘要
The overall goal of this proposal is to dissect the molecular mechanisms of metabolic regulation of ATP-citrate
lyase (ACLY) and to characterize ACLY inhibitors for cancer therapy. ACLY is the predominant source of
nucleocytosolic acetyl-CoA, an essential building block for the production of fatty acids, cholesterol,
isoprenoids and protein acetylation. Elevated ACLY activity is found in metabolic disorders, cardiovascular
diseases and many cancers, prompting the development of several ACLY inhibitors. While many ACLY
inhibitors have been developed, only bempedoic acid, which forms an active bempedoyl-CoA adduct in
hepatocytes, has been approved by the FDA for therapeutic use. Risk of hepatocellular carcinoma is elevated
in individuals with metabolic disorders, many of whom may be candidates for treatment with bempedoic acid;
yet metabolic regulation of ACLY activity and its functional role in hepatocellular carcinoma remain poorly
understood. Elevated levels of ACLY acetylation at K540, K546 and K554 and phosphorylation at S455 and
S481, and retention of exon 14 encoding a region with S481, have also been correlated with cancer, thus also
suggesting roles for ACLY posttranslational and posttranscriptional modification in cancer metabolism. ACLY
is an ~500 kD multidomain homotetrameric enzyme that uses citrate, CoA and ATP cosubstrates to produce
oxaloacetate (OAA) and acetyl-CoA. Until recently, the lack of structural information on intact human ACLY has
hampered understanding of its molecular mechanism of catalysis and the structure-based development of
inhibitors. The Wellen lab recently reported on various disease-associated phenotypes associated with
dysregulated ACLY function; and the Marmorstein lab reported on the cryo-EM structures of ACLY in different
reaction states, along with associated biochemical and biophysical studies, to elucidate the molecular basis for
acetyl-CoA production by ACLY. The latter findings lead to several unresolved questions underlying the
metabolic regulation of ACLY and set the stage for the structure-based development of more potent and
selective ACLY inhibitors for therapeutic applications. These recent studies now position the Wellen and
Marmorstein labs to work together to resolve important gaps in knowledge in metabolic regulation and
inhibition of ACLY, through the following specific aims: (1) Evaluate the role of metabolic binders in ACLY
activity, (2) Determine the molecular mechanism of how posttranslational modifications and exon 14 retention
impact ACLY regulation, and (3) Evaluate the molecular mode of action of ACLY inhibitors. Together, these
studies will reveal the molecular mechanisms for how ACLY activity and regulation is mediated by the binding
of metabolites, and posttranscriptional and posttranslational modification and will lead to the rational
development of ACLY drugs to treat cancer.
该提案的总体目标是剖析ATP-柠檬酸盐代谢调节的分子机制
裂解酶(ACLY)的活性,并表征用于癌症治疗的ACLY抑制剂。ACLY是主要来源,
核胞质乙酰辅酶A,是生产脂肪酸,胆固醇,
类异戊二烯和蛋白质乙酰化。ACLY活性升高见于代谢性疾病、心血管疾病、
许多疾病和癌症,促进了几种ACLY抑制剂的开发。虽然许多ACLY
已经开发了抑制剂,只有bempedoic酸,其在体内形成活性bempedoyl-CoA加合物。
肝细胞,已经被FDA批准用于治疗用途。肝细胞癌的风险增加
在患有代谢紊乱的个体中,其中许多人可能是用bempedoic酸治疗的候选人;
然而,ACLY活性的代谢调节及其在肝细胞癌中的功能作用仍然很差
明白K540、K546和K554处的ACLY乙酰化水平升高以及S455处的磷酸化水平升高,
S481和编码具有S481的区域的外显子14的保留也与癌症相关,因此也
提示ACLY翻译后和转录后修饰在癌症代谢中的作用。ACLY
是一种约500 kD的多结构域同源四聚体酶,使用柠檬酸盐、CoA和ATP共底物产生
草酰乙酸(OAA)和乙酰辅酶A。直到最近,由于缺乏完整的人类ACLY的结构信息,
阻碍了对其催化作用的分子机制的理解,
抑制剂的韦伦实验室最近报告了与以下疾病相关的各种疾病相关表型
ACLY功能失调; Marmorstein实验室报告了不同组织中ACLY的冷冻EM结构
反应状态,沿着相关的生物化学和生物物理学研究,以阐明
通过ACLY生产乙酰辅酶A。后一项发现引出了几个未解决的问题,
ACLY的代谢调节,并为基于结构的更有效和
用于治疗应用的选择性ACLY抑制剂。这些最近的研究现在将韦伦和
Marmorstein实验室共同努力,解决代谢调节知识的重要差距,
通过以下具体目标抑制ACLY:(1)评估代谢结合剂在ACLY中的作用
(2)确定翻译后修饰和外显子14保留的分子机制
影响ACLY调节,和(3)评估ACLY抑制剂的分子作用模式。所有这些
研究将揭示ACLY活性和调节如何通过结合介导的分子机制,
以及转录后和翻译后修饰,并将导致合理的
开发ACLY药物治疗癌症。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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George Burslem其他文献
George Burslem的其他文献
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{{ truncateString('George Burslem', 18)}}的其他基金
Metabolic regulation and inhibition of ATP-citrate lyase
ATP-柠檬酸裂解酶的代谢调节和抑制
- 批准号:
10444160 - 财政年份:2022
- 资助金额:
$ 62.2万 - 项目类别:
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