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Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-gamma-linolenic acid.

ABSTRACT: 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 ?-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 ?-linolenyl tail in a long groove-tunnel site, which itself is formed mainly by the emergence of an ? helix (the "helix flap"). We then found inhibition of the TE domain activity by the PUFA dihomo-?-linolenic acid; ?- and ?-linolenic acids, two popular dietary PUFAs, were less effective. Dihomo-?-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.

SUBMITTER: Zhang W

PROVIDER: S-EPMC3179057 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-gamma-linolenic acid.

Zhang Wei W Chakravarty Bornali B Zheng Fei F Gu Ziwei Z Wu Hongmei H Mao Jianqiang J Wakil Salih J SJ Quiocho Florante A FA

Proceedings of the National Academy of Sciences of the United States of America 20110909 38

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 ...[more]

PMID: 21908709

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Project description:Background: The impact of abdominal obesity (AO) on plasma fatty acid changes and cardiometabolic risk in children who are obese and overweight has rarely been investigated. This study determined whether plasma fatty acid composition differed between children with AO and those without AO and its relationship with metabolic risk, particularly in the obese and overweight groups. Methods: A total of 181 schoolchildren (aged 7-18 years) were included. Anthropometric and biochemical data and plasma fatty acid profiles were analyzed, and the indices of desaturase activity were estimated. Children were categorized based on their body weight and AO status. A continuous metabolic risk score was calculated using the sum of the z-scores of metabolic variables. A one-way analysis of variance test was used to compare the composition ratio of fatty acids between children with and without AO in the obese and overweight groups and normal-weight controls. Pearson analysis was also used to explore significant fatty acid and desaturase indicators associated with metabolic abnormalities. Results: Children who were obese and overweight (N = 126) displayed higher dihomo-γ-linolenic acid (20:3n-6) and γ-linolenic acid (18:3n-6) proportions than normal-weight controls (N = 55), but lower heptadecanoic acid (17:0) proportion, regardless of the AO status of each individual. Obese and overweight children with AO (N = 89), but not their non-AO counterparts (N = 37), exhibited a significantly higher proportion of palmitoleic acid (16:1n-7) than the remaining study groups. Pearson analysis showed that high proportions of palmitoleic acid and dihomo-γ-linolenic acid, as well as increased stearoyl-coenzyme A desaturase-1(16) and delta-6 desaturase and decreased delta-5 desaturase activities, are strongly correlated with weight-height ratio, homeostasis model of assessment values for insulin resistance, hypertriglyceridemia, and continuous metabolic risk scores. Conclusion: Higher palmitoleic acid and dihomo-γ-linolenic acid proportions, as well as increased stearoyl-coenzyme A desaturase-1(16) and delta-6 desaturase and decreased delta-5 desaturase activities are associated with AO and increased metabolic risk in children who are obese and overweight.

Dataset Information

Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-gamma-linolenic acid.

Publications

Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-gamma-linolenic acid.

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