Acetyl coenzyme A (acetyl-CoA) carboxylases (ACCs) and carnitine acyltransferases have crucial roles in the biosynthesis and the metabolism of fatty acids. In humans and other mammals, the ACC 1 isoform catalyzes the ATP-dependent carboxylation of acetyl-CoA to produce malonyl-CoA, the first and the committed step in the biosynthesis of long-chain fatty acids. At the same time, the malonyl-CoA product from the ACC2 isoform is a crucial regulator of fatty acid oxidation by potently inhibiting the carnitine palmitoyltransferase enzyme (CPT-I). CPT-I and CPT-II enable the transport of long-chain fatty acyl-CoAs from the cytosol into the mitochondria for oxidation. Mice that are deficient for ACC2 have reduced body fat content and body weight despite consuming more food, due to elevated fatty acid oxidation. A covalent inhibitor of CPT-I has proven to be effective in treating diabetes in humans and animals, although the clinical use of this compound is severely limited by its toxicity. An agonist of CPT-I can increase fatty acid oxidation and lower body weight. These results demonstrate that ACCs and CPTs are important targets for the development of therapeutic agents against obesity, diabetes, as well as bacterial infections. In addition, inhibitors of the carboxyltransferase domain of plant ACCs are used commercially as herbicides, confirming the therapeutic relevance of ACC as a drug discovery target. ? ? We have recently determined the crystal structures of mouse carnitine acetyltransferase (CRAT) and the carboxyltransferase domain of yeast ACC. These represent the first structural information on any of these enzymes. The initial results set the stage for detailed structural, biochemical, and biological studies of these crucial enzymes, which will be the focus of this proposed research project. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK067238-01
Application #
6759846
Study Section
Physical Biochemistry Study Section (PB)
Program Officer
Sechi, Salvatore
Project Start
2004-06-01
Project End
2008-03-31
Budget Start
2004-06-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$324,553
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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