Fatty acid synthesis

Apart from two polyunsaturated fatty acids (linoleic acid, C18:2; and alpha-linolenic acid, C18:3) the human body is able to synthesize all other fatty acids required either for structural lipids in membranes or for storage purpose. Fatty acid synthesis and their further use for phospholipids and triglycerides is referred to as lipogenesis. Any metabolite that yields acetyl-CoA during its degradation is a potential supplier for lipogenesis, the most important being carbohydrates. In general, it can be understood that excess carbohydrates beyond the body s energy needs will be converted into fat. Lipogenesis is not a simple reversal of beta oxidation, but uses an entirely different pathway for the regeneration of fatty acids from acetyl-CoA precursors. The reductive synthesis of fatty acids is a cytoplasmic process carried out by a multienzyme complex called the acyl carrier protein (ACP). The acyl chain is covalently linked to the sulfhydryl prosthetic group of ACP. The reduction-oxidation steps require NADPH (rather than FADH2 and NADH found during beta-oxidation).

There are three major processes involved in the reductive synthesis of fatty acids. First, acetyl-CoA has to be transported across the inner mitochondrial membrane into the cytoplasm. Second, the true substrate for ACP is malonyl-CoA, a C3 acyl thioester that is formed by the carboxylation of acetyl-CoA to malonyl-CoA. Third, the first end product and intermediate for further lipid biosynthesis is palmitic acid, the C16 acyl derivative. For all other lipogenetic processes, protein complexes other than ACP are required.

Fatty acid synthesis is a cytoplasmic process. All acetyl-CoA must be exported from the mitochondrial matrix via citrate (first step in Krebs cycle). In the cytoplasm, citrate is split into acetyl-CoA and oxaloacetate. The latter, if not used for gluconeogenesis, is transported back into the mitochondrial matrix. Oxaloacetate concentration, thus, plays a crucial role in connecting carbohydrate, lipid, and energy metabolism. In the cytoplasm acetyl-CoA is activated by acetyl-CoA-carboxylase (EC 6.4.1.2) to malonyl-CoA (C00083). This C3 acyl intermediate is the immediate precursor for fatty acid synthesis. The enzyme contains biotin as prosthetic group catalyzing the following two reactions: