Dihomo-gamma-linolenic acid (DGLA) is a precursor of physiologically active eicosanoids, including group 1 prostaglandins and thromboxanes. DGLA is used in combination with interferons for the enhancement of the anti-virus, anti-cancer, or anti-inflammatory effects, and in combination with prostaglandin E1 for the treatment of atopy of the skin and mucosa. For nutritional supplementation, also for treating dietary shortage or imbalance. The role of FASN inhibition is unknown. Dihomo-gamma-linolenic acid is a 20-carbon-chain fatty acid, unsaturated at positions 8, 11, and 14. It differs from arachidonic acid, 5,8,11,14-eicosatetraenoic acid, only at position 5.
Title: Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-gamma-linolenic acid Zhang W, Chakravarty B, Zheng F, Gu Z, Wu H, Mao J, Wakil SJ, Quiocho FA Ref: Proc Natl Acad Sci U S A, 108:15757, 2011 : PubMed
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 A crystal structure of the hFAS TE domain covalently modified and inactivated by methyl gamma-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 gamma-linolenyl tail in a long groove-tunnel site, which itself is formed mainly by the emergence of an alpha helix (the "helix flap"). We then found inhibition of the TE domain activity by the PUFA dihomo-gamma-linolenic acid; gamma- and alpha-linolenic acids, two popular dietary PUFAs, were less effective. Dihomo-gamma-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.