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-COA）羧化酶（ACCS），丙酮酸羧化酶（PC），肉碱酰基转移酶以及AMP激活的蛋白激酶（AMPK）在脂肪酸酸和/或碳水化合物的代谢中起着至关重要的作用。 ACC催化乙酰辅酶A的生物素依赖性羧化产生丙二酰coA，并且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，体重和体重减少，这表明对ACC2的抑制剂可能有效地控制了体重和肥胖。 PC催化丙酮酸的羧化产生草乙酸。它对于从组织中去除丙酮酸至关重要，草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很重要。 PC缺乏症与人类的乳酸性酸中毒和智力低下有关。肉碱酰基转移酶会催化肉碱和COA之间的酰基交换。肉碱棕榈转移酶（CPTS）在线粒体中脂肪酸的氧化中具有至关重要的作用，而ACC2的丙二酰-COA产物是CPT-I酶的有效抑制剂。 CPT-I的缺陷与低血液血症，低血糖症和其他疾病有关。 AMPK是一种主要的代谢调节剂，并控制了单元格中的许多过程。其G亚基的突变与许多人类疾病有关，包括Wolff-Parkinson-White（WPW）综合征。肥胖流行的最新发作已经在这些重要的代谢酶中引起了重大的新利益。在上一个融资期间，我们对ACC和肉碱转移酶产生了大量的结构和生化数据，这些数据极大地增强了我们对这些酶的理解。但是，许多重要的问题仍未得到解决，目前在PC和AMPK上没有足够的结构信息。为了填补我们的知识，我们建议继续对ACC和Carnitine酰基转移酶进行生化，生物物理和结构研究，并在PC和AMPK上启动此类研究。拟议的研究应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提供基础。公共卫生相关性：最近的肥胖流行病已经对脂肪酸和碳水化合物代谢产生了重大的利益。我们提出的研究将对这些重要的代谢酶产生详细的结构和生化信息，为新型抑制剂/激动剂的设计和开发奠定了基础，这些抑制剂/激动剂在诊所中可能有效。

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）

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

DOI：
10.1073/pnas.0400891101
发表时间：
2004-04
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：
Hailong Zhang;B. Tweel;L. Tong

Crystal structure of DmdD, a crotonase superfamily enzyme that catalyzes the hydration and hydrolysis of methylthioacryloyl-CoA.