The surprising diversity of 6-desaturase substrates

A single gene encoding a 6-desaturase (FADS2) has been isolated and characterized in mammalian species. This 6-desaturase plays a major role in the biosynthesis of PUFAs (polyunsaturated fatty acids). It catalyses the rate-limiting desaturation of linoleic acid (C18:2 n− 6) and α-linolenic acid (C18:3 n− 3) required for the biosynthesis of long-chain PUFAs. Moreover, recent studies have provided strong evidence that this 6-desaturase also acts on 24-carbon PUFAs of both the n− 6 and n− 3 series. Another substrate of this 6-desaturase has been identified through complementary works from different investigators. This 6-desaturase acts on a saturated fatty acid, palmitic acid (C16:0), leading to the newly characterized biosynthesis of hexadecenoic acid (C16:1 n− 10) or sapienate. Introduction In mammals, at least three distinct desaturase enzymes introduce double bonds at the 9, 6 and 5 positions along the carbon fatty-acyl chains of some fatty acid substrates. 9-Desaturase, also named SCD (stearoyl-CoA desaturase), catalyses the rate-limiting step in the biosynthesis of monounsatured fatty acids. In mouse, four isoforms of SCD have been identified [1]. In human, a single SCD gene which is highly similar to mouse genes has been cloned and characterized [2]. 6and 5-desaturases govern rate-limiting steps in the biosynthesis of long-chain PUFAs (polyunsaturated fatty acids). The biosynthesis of long-chain PUFAs from C18:2 n− 6 and C18:3 n− 3 involves successive desaturation and elongation steps. The first step is the 6-desaturation of the 18-carbon precursors of the n− 6 and n− 3 series. The 6-desaturase cloned from human [3] and rodents [3,4], i.e. FADS2 [5], was shown to catalyse this initial reaction. The second 6-desaturation step from C24:4 n− 6 to C24:5 n− 6 and from C24:5 n− 3 to C24:6 n− 3, initially described by Sprecher and co-workers [6], had to be further explored. More recently, a palmitoyl-CoA 6-desaturase was reported for the first time to be present in mammals [7]. This finding has emerged from detailed study of the prepucial gland of mice with targeted disruption of SCD1, a major isoform of 9-desaturase. In this work, the impairment of C16:1 n− 7 biosynthesis in SCD1−/− mice correlated with an increased level of C16:1 n− 10. The palmitoyl-CoA 6desaturase responsible for this increased biosynthesis was not identified. We investigated the possibility that the rat 6-desaturase which acts on 18-carbon PUFA also acts on 24-carbon PUFA