A fatty-acid synthesis mechanism specialized for parasitism

Key Points Trypanosoma brucei , T. cruzi and Leishmania spp. parasites are early branching eukaryotes that cause disease mainly in tropical countries. T. brucei synthesizes fatty acids (FAs) de novo . While bloodstream forms make myristate (C14) for glycosylphosphatidylinositol (GPI) anchors of their variant surface glycoprotein (which mediate antigenic variation), procyclic forms make mainly stearate (C18). Rather than a conventional type I or II FA synthase, T. brucei uses a coenzyme A (CoA)-dependent microsomal FA elongase (ELO) pathway for most of its de novo synthesis. In other eukaryotes, the ELO pathway simply lengthens already long fatty acyl-CoAs. The T. brucei mitochondrial type II synthase is more specialized and makes octanoate (C8), a lipoic-acid precursor, as well as longer FAs up to C16. While TbELO1–3 elongate C4 primer to C18, TbELO4 functions as a polyunsaturated FA ELO that lengthens arachidonate (C20:4) salvaged from the host. In addition to TbELO1–4 orthologues, L. major has desaturases and an extra polyunsaturated FA (PUFA) ELO needed to synthesize C22:5n-6 and C22:6n-3 from C18. By contrast, the two trypanosomes seem to have lost the portion of their PUFA pathway that converts 18:2n-6 to 20:4n-6 and 20:5n-3. T. cruzi and Leishmania spp. have additional TbELO1–3 homologues that are probably involved in synthesis of the very-long-chain saturated acyl and alkyl groups that are found on surface GPI anchors and glycoconjugates. These GPIs, depending on the fatty chain length and degree of saturation, are involved in immunity and inflammation in different life-cycle stages. The selective regulation of the various ELOs could explain how these parasites produce the various FAs needed during different life-cycle stages, as happens in T. brucei . Other eukaryotic parasitic protozoans such as the mucosal parasites and apicomplexans use mechanisms apparently dissimilar to those in trypanosomatids to make or acquire their bulk FAs. Trypanosomatid mitochondrial type II and ELO pathways are apparently essential for parasite survival and could serve as potential drug targets. The ELO pathway seems to have evolved to accommodate the complex and parasitic life-style of the trypanosomatids, allowing it to produce the different FAs that are needed as it migrates between different compartments in the vector and host. Rather than using a conventional type I or II fatty-acid synthase, Trypanosoma brucei synthesize most of their fatty acids by an unpreceden