Document Detail


Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-gamma-linolenic acid.
MedLine Citation:
PMID:  21908709     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Human fatty acid synthase (hFAS) is a homodimeric multidomain enzyme that catalyzes a series of reactions leading to the de novo biosynthesis of long-chain fatty acids, mainly palmitate. The carboxy-terminal thioesterase (TE) domain determines the length of the fatty acyl chain and its ultimate release by hydrolysis. Because of the upregulation of hFAS in a variety of cancers, it is a target for antiproliferative agent development. Dietary long-chain polyunsaturated fatty acids (PUFAs) have been known to confer beneficial effects on many diseases and health conditions, including cancers, inflammations, diabetes, and heart diseases, but the precise molecular mechanisms involved have not been elucidated. We report the 1.48 Å crystal structure of the hFAS TE domain covalently modified and inactivated by methyl γ-linolenylfluorophosphonate. Whereas the structure confirmed the phosphorylation by the phosphonate head group of the active site serine, it also unexpectedly revealed the binding of the 18-carbon polyunsaturated γ-linolenyl tail in a long groove-tunnel site, which itself is formed mainly by the emergence of an α helix (the "helix flap"). We then found inhibition of the TE domain activity by the PUFA dihomo-γ-linolenic acid; γ- and α-linolenic acids, two popular dietary PUFAs, were less effective. Dihomo-γ-linolenic acid also inhibited fatty acid biosynthesis in 3T3-L1 preadipocytes and selective human breast cancer cell lines, including SKBR3 and MDAMB231. In addition to revealing a novel mechanism for the molecular recognition of a polyunsaturated fatty acyl chain, our results offer a new framework for developing potent FAS inhibitors as therapeutics against cancers and other diseases.
Authors:
Wei Zhang; Bornali Chakravarty; Fei Zheng; Ziwei Gu; Hongmei Wu; Jianqiang Mao; Salih J Wakil; Florante A Quiocho
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-09
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  108     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-09-21     Completed Date:  2011-12-12     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15757-62     Citation Subset:  IM    
Affiliation:
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Data Bank Information
Bank Name/Acc. No.:
PDB/3TJM
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MeSH Terms
Descriptor/Qualifier:
3T3-L1 Cells
8,11,14-Eicosatrienoic Acid / pharmacology*
Adipocytes / drug effects,  metabolism
Animals
Biocatalysis / drug effects
Catalytic Domain
Cell Line, Tumor
Crystallization
Crystallography, X-Ray
Fatty Acid Synthetase Complex / chemistry*,  metabolism
Fatty Acids / biosynthesis
Fatty Acids, Unsaturated / chemistry*,  metabolism
Humans
Mice
Models, Molecular
Molecular Structure
Protein Binding / drug effects
Protein Structure, Tertiary*
Thiolester Hydrolases / chemistry,  metabolism
alpha-Linolenic Acid / pharmacology
Grant Support
ID/Acronym/Agency:
R01GM0063115/GM/NIGMS NIH HHS; R01GM088803/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/Fatty Acids, Unsaturated; 463-40-1/alpha-Linolenic Acid; 7324-41-6/8,11,14-Eicosatrienoic Acid; EC 3.1.2.-/Thiolester Hydrolases; EC 6.-/Fatty Acid Synthetase Complex
Comments/Corrections

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