An alternate pathway to long-chain polyunsaturates: the FADS2 gene product Δ8-desaturates 20:2n-6 and 20:3n-3

The mammalian Δ6-desaturase coded by fatty acid desaturase 2 (FADS2; HSA11q12-q13.1) catalyzes the first and rate-limiting step for the biosynthesis of long-chain polyunsaturated fatty acids. FADS2 is known to act on at least five substrates, and we hypothesized that the FADS2 gene product would have Δ8-desaturase activity. Saccharomyces cerevisiae transformed with a FADS2 construct from baboon neonate liver cDNA gained the function to desaturate 11,14-eicosadienoic acid (20:2n-6) and 11,14,17-eicosatrienoic acid (20:3n-3) to yield 20:3n-6 and 20:4n-3, respectively. Competition experiments indicate that Δ8-desaturation favors activity toward 20:3n-3 over 20:2n-6 by 3-fold. Similar experiments show that Δ6-desaturase activity is favored over Δ8-desaturase activity by 7-fold and 23-fold for n-6 (18:2n-6 vs 20:2n-6) and n-3 (18:3n-3 vs 20:3n-3), respectively. In mammals, 20:3n-6 is the immediate precursor of prostaglandin E1 and thromboxane B1. 20:3n-6 and 20:4n-3 are also immediate precursors of long-chain polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid, respectively. These findings provide unequivocal molecular evidence for a novel alternative biosynthetic route to long-chain polyunsaturated fatty acids in mammals from substrates previously considered to be dead-end products. The mammalian Δ6-desaturase coded by fatty acid desaturase 2 (FADS2; HSA11q12-q13.1) catalyzes the first and rate-limiting step for the biosynthesis of long-chain polyunsaturated fatty acids. FADS2 is known to act on at least five substrates, and we hypothesized that the FADS2 gene product would have Δ8-desaturase activity. Saccharomyces cerevisiae transformed with a FADS2 construct from baboon neonate liver cDNA gained the function to desaturate 11,14-eicosadienoic acid (20:2n-6) and 11,14,17-eicosatrienoic acid (20:3n-3) to yield 20:3n-6 and 20:4n-3, respectively. Competition experiments indicate that Δ8-desaturation favors activity toward 20:3n-3 over 20:2n-6 by 3-fold. Similar experiments show that Δ6-desaturase activity is favored over Δ8-desaturase activity by 7-fold and 23-fold for n-6 (18:2n-6 vs 20:2n-6) and n-3 (18:3n-3 vs 20:3n-3), respectively. In mammals, 20:3n-6 is the immediate precursor of prostaglandin E1 and thromboxane B1. 20:3n-6 and 20:4n-3 are also immediate precursors of long-chain polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid, respectively. These findings provide unequivocal molecular evidence for a novel alternative biosynthetic route to long-chain polyunsaturated fatty acids in mammals from substrates previously considered to be dead-end products. Long-chain polyunsaturated fatty acids (LCPUFAs) are ubiquitous in mammalian tissue, achieving highest concentrations in the membranes of neural and other excitable tissue (1Brenna J.T. Diau G.Y. The influence of dietary docosahexaenoic acid and arachidonic acid on central nervous system polyunsaturated fatty acid composition.Prostaglandins Leukot. Essent. Fatty Acids. 2007; 77: 247-250Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). LCPUFA of the n-3 and n-6 families, especially eicosapentaenoic acid (EPA; 20:5n-3), docosahexaenoic acid (22:6n-3), and arachidonic acid (20:4n-6), are bioactive components of membrane phospholipids and serve as substrates for signaling molecules (2Kinsella J.E. Lokesh B. Broughton S. Whelan J. Dietary polyunsaturated fatty acids and eicosanoids: potential effects on the modulation of inflammatory and immune cells: an overview.Nutrition. 1990; 6 (discussion 59–62).: 24-44PubMed Google Scholar). 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Chem. 1999; 274: 37335-37339Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar), as well as a third putative desaturase gene (FADS3) (16Marquardt A. Stohr H. White K. Weber B.H. cDNA cloning, genomic structure, and chromosomal localization of three members of the human fatty acid desaturase family.Genomics. 2000; 66: 175-183Crossref PubMed Scopus (225) Google Scholar), which thus far has no known substrate despite high homology to FADS1 and FADS2. Figure 1shows the common n-3 and n-6 LCPUFA pathways mediated by Δ6 and Δ5 desaturases. The Δ6-desaturase (FADS2) is known to operate on both 18:3n-3 and 18:2n-6, resulting in the synthesis of 6,9,12,15-18:4 and 6,9,12-18:3 (γ-linolenic acid), respectively. This step is rate limiting and is followed by elongation to 8,11,14,17-20:4 and 8,11,14-20:3 (dihomo-γ-linolenic acid). A rapid Δ5-desaturation (FADS1) on these PUFA produces EPA and arachidonic acid. EPA can be further elongated and desaturated to yield docosahexaenoic acid by the pathway shown, which is accepted as mammalian pathway, or via a Δ4-desaturase as demonstrated in Thraustochytrium (17Qiu X. Hong H. MacKenzie S.L. Identification of a Delta 4 fatty acid desaturase from Thraustochytrium sp. involved in the biosynthesis of docosahexanoic acid by heterologous expression in Saccharomyces cerevisiae and Brassica juncea.J. Biol. Chem. 2001; 276: 31561-31566Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). The operation of an alternative pathway via C20 fatty acids using a Δ8-desaturase reported in unicellular organisms (18Korn E.D. The polyunsaturated 20-carbon and 22-carbon fatty acids of Euglena.Biochem. Biophys. Res. Commun. 1964; 14: 1-6Crossref PubMed Scopus (7) Google Scholar, 19Korn E.D. Biosynthesis of unsaturated fatty acids in Acanthamoeba Sp.J. Biol. Chem. 1964; 239: 396-400Abstract Full Text PDF PubMed Google Scholar, 20Lees A.M. Korn E.D. 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S. cerevisiae and S. cerevisiae respectively. S. cerevisiae and S. cerevisiae with have no activity toward 20:3n-6 and 20:4n-3, as a product with is the at and to the and of a is the of at and to the and for 20:3n-6 and of and and and in FADS2 action on are to in 2 and synthesis of Figure alternative to Δ8-desaturation of 20:2n-6 is followed by into the pathway The S. cerevisiae contain and and thus have pathway is Figure the product with as a is for the or the cells transformed with FADS2 and of product is further elongated to 20:3n-6 (18:2n-6 There is also elongation of to The putative of a alternative pathway, in of two with 20:2n-6 as a product with 20:2n-6 for that There is to in all of product to is in the FADS2 cells and is of the The Δ8-desaturation is in putative in the alternative the of the conversion of 20:3n-6 can for a of the that Δ8-desaturation by the FADS2 product conversion of 20:2n-6 to that S. cerevisiae gained the to 20-carbon the activity in Δ8-desaturase activity toward n-3 and n-6 fatty acids by with a of 20:2n-6 and 20:3n-3 as and by of by and 1shows that 20:2n-6 20:3n-6 and 20:3n-3 20:4n-3 over a a conversion of the n-3 n-6 and n-3 fatty of 20:2n-6 20:3n-3 in a In a of or to to the Δ6-desaturase and Δ8-desaturase that and n-6 20:3n-6 and a activity of The 18:3n-3 and 20:3n-3 20:4n-3 and the conversion of and of 20:2n-6 18:3n-3 20:3n-3 in a of fatty a Scholar) that the n-6 PUFA in growth of on a diet with as their of The of activity with activity of for all other fatty acids two the pathway from to by as the route of The has been of over the of the of in mammalian tissue, as has a third is to by the action of activity in mammalian tissue or cells that or of a Δ8-desaturase are to of the of the that molecular of a activity are Sprecher H. 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P. of acid to acid by rat Delta Lipid Res. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). are no reports of FADS2 gene product activity toward The alternative synthetic pathways to arachidonic acid from 20:2n-6 are by action of a Δ8-desaturase and a Δ5-desaturase or Δ8-desaturation the precursor Δ5-desaturase activity There are reports that is to Sprecher H. The of a desaturase in the biosynthesis of polyunsaturated fatty 2000; PubMed Scopus (17) Google Scholar, H. The of an in rat a of pathways for the metabolism of and Biophys. Acta. PubMed Scopus Google Scholar, T. The of acid to arachidonic Chem. Google Scholar, Sprecher H. in vitro and in of the conversion of eicosa-11,14-dienoic acid to acid and of the conversion of acid to acid in the Biophys. Acta. PubMed Scopus Google J. M.J. I. P. A. route for the biosynthesis of polyunsaturated fatty acids in J. PubMed Scopus Google Scholar). no evidence for the conversion of to has been Sprecher H. 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These are also are with in vitro that the biosynthesis of n-6 PUFA is by of of as is to n-3 PUFA biosynthesis The of the of fatty acids in human Nutr. 1998; PubMed Google Scholar), that the of the biosynthetic favors n-3 experiments also that the FADS2 gene product both Δ6-desaturase and Δ8-desaturase both substrates are the FADS2 gene product higher Δ6-desaturase activity by on the substrate to 7-fold product for the The action activity toward the n-3 at that the pathway would be favored both substrates are In baboon FADS2 gene into S. cerevisiae of Δ8-desaturase in to for Δ6-desaturase activity. activity on 20:2n-6 to the immediate precursor of and of evidence that Δ8-desaturation is a pathway, but further show that is high for as in or in in which 20:3n-6 as a precursor to E1 and acids, or thromboxane B1. This alternative pathway to the precursors that 20:2n-6 are to human