Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 391, Issue 1, Pages 187-192Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2009.11.029
Keywords
Acetyl-CoA carboxylase (ACC); Biotin carboxylase (BC); Fatty acid metabolism; AMP-activated protein kinase (AMPK); Phosphorylation; Short-term regulation; Soraphen A; Crystal structure
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Funding
- Korea Research Foundation Grant funded by the Korean Government (MOEHRD) [KRF-2007-313-C00621]
- BioGreen 21 Program, Rural Development Administration, South Korea [20070501034003]
- Korean Government [KRF-2008-313-C00745, KRF-2006-005-J04502]
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Acetyl-CoA carboxylases (ACCs) have been highlighted as therapeutic targets for obesity and diabetes. as they play Crucial roles in fatty acid metabolism. ACC activity is regulated through the short-term mechanism of inactivation by reversible phosphorylation. Here. we report the crystal structures of the biotin carboxylase (BC) domain of human ACC2 phosphorylated by AMP-activated protein kinase (AMPK) The phosphorylated Ser222 binds to the putative dimer interface of BC. disrupting polymerization and providing the molecular mechanism of inactivation by AMPK. We also determined the Structure of the human BC domain in complex with soraphen A, a macrocyclic polyketide natural product This Structure shows that the compound binds to the binding site of phosphorylated Ser222. implying that its inhibition mechanism is the same as that of phosphorylation by AMPK (c) 2009 Elsevier Inc. All rights reserved.
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