Structural biology of enzymes in fatty acid metabolism

脂肪酸代谢酶的结构生物学

基本信息

批准号：
8266394
负责人：
LIANG TONG
金额：
$ 33.49万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-06-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8266394
关键词：
5&apos -AMP-activated protein kinase Acetyl Coenzyme A Acetyl-CoA Carboxylase Active Sites Agonist Amino Acids Anabolism Bicarbonates Binding Biochemical Biological Biological Models Biotin Biotin carboxylase Body Weight Body fat Carbohydrates Carbon Carnitine Carnitine Acyltransferases Carnitine O-Palmitoyltransferase Carnitine Palmitoyltransferase I Carnitine Palmitoyltransferase II Catalysis Cell physiology Cells Cholesterol Clinic Coenzyme A Communication Complex Cryoelectron Microscopy Data Development Disease Drug Design Enzyme Inhibition Enzymes Epidemic Fat Body Fatty Acids Foundations Funding Gluconeogenesis Glucose Goals Health Human Hypoglycemia In Vitro Kinetics Knowledge Lactic Acidosis Link Malonyl Coenzyme A Mental Retardation Metabolic Mitochondria Molecular Mus Mutagenesis Mutation Obesity Oxaloacetates Play Principal Investigator Process Protein Kinase Pyruvate Pyruvate Carboxylase Regulation Research Role Staphylococcus aureus Structure Tissues Wolff-Parkinson-White Syndrome X-Ray Crystallography Yeasts acyl group analog base biotin carboxyl carrier protein carbohydrate metabolism carboxylation design dimer disease-causing mutation fatty acid biosynthesis fatty acid metabolism fatty acid oxidation human disease inhibitor/antagonist insight insulin secretion interest ketotic hyperglycinemia long chain fatty acid methylmalonyl-CoA decarboxylase novel oxidation research study structural biology

项目摘要

DESCRIPTION (provided by applicant): Acetyl-coenzyme A (acetyl-CoA) carboxylases (ACCs), pyruvate carboxylase (PC), carnitine acyltransferases, and AMP-activated protein kinase (AMPK) play crucial roles in the metabolism of fatty acids and/or carbohydrates, as well as other important cellular processes. ACCs catalyze the biotin-dependent carboxylation of acetyl-CoA to produce malonyl-CoA, and are crucial for the biosynthesis and oxidation of long-chain fatty acids. ACC2-/- mice have elevated fatty acid oxidation and reduced body fat and body weight, suggesting that an inhibitor against ACC2 may be efficacious in the control of body weight and obesity. PC catalyzes the carboxylation of pyruvate to produce oxaloacetate. It is crucial for removing pyruvate from tissues, and the oxaloacetate product is important for gluconeogenesis, fatty acid biosynthesis, and glucose-induced insulin secretion. PC deficiency is linked to lactic acidosis and mental retardation in humans. Carnitine acyltransferases catalyze the exchange of acyl groups between carnitine and CoA. The carnitine palmitoyltransferases (CPTs) have crucial roles in the ?-oxidation of fatty acids in the mitochondria, and the malonyl-CoA product of ACC2 is a potent inhibitor of the CPT-I enzymes. Deficiencies in CPT-Is are linked to hypoketonemia, hypoglycemia and other diseases. AMPK is a master metabolic regulator and controls many processes in the cell. Mutations in its g subunit have been linked to many human diseases including Wolff-Parkinson-White (WPW) syndrome. The recent onset of the obesity epidemic has generated significant renewed interests in these important metabolic enzymes. During the previous funding period, we produced a large amount of structural and biochemical data on ACC and the carnitine acyltransferases that have greatly enhanced our understanding of these enzymes. However, many significant questions remain unanswered, and currently there is insufficient structural information on PC and AMPK. To fill these gaps in our knowledge, we propose to continue the biochemical, biophysical and structural studies on ACC and carnitine acyltransferases, as well as initiate such studies on PC and AMPK. The proposed research should provide significant new insights into the mechanism and regulation of these enzymes, and provide a foundation for the design and development of their inhibitors or agonists. PUBLIC HEALTH RELEVANCE: The recent onset of the obesity epidemic has generated significant renewed interests in fatty acid and carbohydrate metabolism. Our proposed research will produce detailed structural and biochemical information on these important metabolic enzymes, laying the foundation for the design and development of novel inhibitors/agonists that could be efficacious in the clinic.

描述（由申请人提供）：乙酰辅酶 A（乙酰辅酶 A）羧化酶（ACC）、丙酮酸羧化酶（PC）、肉碱酰基转移酶和 AMP 激活蛋白激酶（AMPK）在脂肪酸和/或脂肪酸的代谢中发挥着至关重要的作用。或碳水化合物，以及其他重要的细胞过程。 ACC 催化乙酰辅酶 A 的生物素依赖性羧化以产生丙二酰辅酶 A，对于长链脂肪酸的生物合成和氧化至关重要。 ACC2-/-小鼠的脂肪酸氧化升高，体脂和体重减少，表明ACC2抑制剂可能有效控制体重和肥胖。 PC催化丙酮酸羧化生成草酰乙酸。它对于从组织中去除丙酮酸至关重要，草酰乙酸产物对于糖异生、脂肪酸生物合成和葡萄糖诱导的胰岛素分泌也很重要。 PC 缺乏与人类乳酸性酸中毒和智力低下有关。肉碱酰基转移酶催化肉碱和CoA之间的酰基交换。肉碱棕榈酰转移酶 (CPT) 在线粒体中脂肪酸的 β-氧化中具有至关重要的作用，ACC2 的丙二酰辅酶 A 产物是 CPT-I 酶的有效抑制剂。 CPT-Is 缺乏与低酮血症、低血糖和其他疾病有关。 AMPK 是主要的代谢调节剂，控制细胞中的许多过程。其 g 亚基突变与许多人类疾病有关，包括沃尔夫-帕金森-怀特 (WPW) 综合征。最近肥胖流行的爆发引起了人们对这些重要代谢酶的极大兴趣。在上一个资助期间，我们产生了大量关于 ACC 和肉碱酰基转移酶的结构和生化数据，这极大地增强了我们对这些酶的理解。然而，许多重要问题仍未得到解答，目前有关 PC 和 AMPK 的结构信息不足。为了填补这些知识空白，我们建议继续对 ACC 和肉碱酰基转移酶进行生化、生物物理和结构研究，并启动对 PC 和 AMPK 的此类研究。拟议的研究应该为这些酶的机制和调节提供重要的新见解，并为其抑制剂或激动剂的设计和开发奠定基础。公共卫生相关性：最近肥胖流行的爆发引起了人们对脂肪酸和碳水化合物代谢的极大兴趣。我们提出的研究将产生这些重要代谢酶的详细结构和生化信息，为设计和开发在临床上有效的新型抑制剂/激动剂奠定基础。

项目成果

期刊论文数量（27）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A different mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by tepraloxydim.

tepraloxydim 抑制乙酰辅酶 A 羧化酶羧基转移酶结构域的不同机制。

DOI：
发表时间：
2009-12-08
期刊：
影响因子：
11.1
作者：
Xiang, Song;Callaghan, Matthew M;Watson, Keith G;Tong, Liang
通讯作者：
Tong, Liang

Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1.

人类 BRCA1 的 BRCT 结构域与人类 ACC1 的磷酸肽之间直接相互作用的结构证据。

DOI：
10.1021/bi800314m
发表时间：
2008-05-02
期刊：
Biochemistry
影响因子：
2.9
作者：
Yang Shen;L. Tong
通讯作者：
L. Tong

Crystal structure of mouse carnitine octanoyltransferase and molecular determinants of substrate selectivity.

小鼠肉毒碱辛酰基转移酶的晶体结构和底物选择性的分子决定因素。

DOI：
发表时间：
2005-01-07
期刊：
影响因子：
0
作者：
Jogl, Gerwald;Hsiao, Yu;Tong, Liang
通讯作者：
Tong, Liang

Crystal structures of malonyl-coenzyme A decarboxylase provide insights into its catalytic mechanism and disease-causing mutations.

丙二酰辅酶 A 脱羧酶的晶体结构提供了对其催化机制和致病突变的深入了解。

DOI：
发表时间：
2013-07-02
期刊：
影响因子：
0
作者：
Froese, D Sean;Forouhar, Farhad;Tran, Timothy H;Vollmar, Melanie;Kim, Yi Seul;Lew, Scott;Neely, Helen;Seetharaman, Jayaraman;Shen, Yang;Xiao, Rong;Acton, Thomas B;Everett, John K;Cannone, Giuseppe;Puranik, Sriharsha;Savitsky, Pavel;Krojer
通讯作者：
Krojer

Molecular basis for the inhibition of the carboxyltransferase domain of acetyl-coenzyme-A carboxylase by haloxyfop and diclofop.

氟草灵和敌草灵抑制乙酰辅酶 A 羧化酶羧基转移酶结构域的分子基础。

DOI：
10.1073/pnas.0400891101
发表时间：
2004-04-20
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Hailong Zhang;B. Tweel;L. Tong
通讯作者：
L. Tong