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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067238-07
Application #
8064666
Study Section
Macromolecular Structure and Function E Study Section (MSFE)
Program Officer
Sechi, Salvatore
Project Start
2004-06-01
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
7
Fiscal Year
2011
Total Cost
$334,888
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Maderbocus, Riyaz; Fields, Blanche L; Hamilton, Keith et al. (2017) Crystal structure of a Pseudomonas malonate decarboxylase holoenzyme hetero-tetramer. Nat Commun 8:160
Harriman, Geraldine; Greenwood, Jeremy; Bhat, Sathesh et al. (2016) Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc Natl Acad Sci U S A 113:E1796-805
Wei, Jia; Zhang, Yixiao; Yu, Tai-Yuan et al. (2016) A unified molecular mechanism for the regulation of acetyl-CoA carboxylase by phosphorylation. Cell Discov 2:16044
Choi, Philip H; Jo, Jeanyoung; Lin, Yu-Cheng et al. (2016) A distinct holoenzyme organization for two-subunit pyruvate carboxylase. Nat Commun 7:12713
Choi, Philip H; Sureka, Kamakshi; Woodward, Joshua J et al. (2015) Molecular basis for the recognition of cyclic-di-AMP by PstA, a PII-like signal transduction protein. Microbiologyopen 4:361-74
Jurado, Ashley R; Huang, Christine S; Zhang, Xing et al. (2015) Structure and substrate selectivity of the 750-kDa ?6?6 holoenzyme of geranyl-CoA carboxylase. Nat Commun 6:8986
Huynh, TuAnh Ngoc; Luo, Shukun; Pensinger, Daniel et al. (2015) An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence. Proc Natl Acad Sci U S A 112:E747-56
Wei, Jia; Tong, Liang (2015) Crystal structure of the 500-kDa yeast acetyl-CoA carboxylase holoenzyme dimer. Nature 526:723-7
Tran, Timothy H; Hsiao, Yu-Shan; Jo, Jeanyoung et al. (2015) Structure and function of a single-chain, multi-domain long-chain acyl-CoA carboxylase. Nature 518:120-4
Sureka, Kamakshi; Choi, Philip H; Precit, Mimi et al. (2014) The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function. Cell 158:1389-1401

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