In highly lipogenic tissues such as the liver, adipose and lactating breast, the Fatty acid synthase (FAS) catalyzed fatty acid synthesis pathway has three main functions: 1) the conversion of excess caloric intake into triacylglycerols for storage, 2) synthesis of fat from carbohydrate and protein when dietary sources of fat are lacking, and 3) synthesis of fat in the breast during lactation.
Palmitate, the major endproduct of the FAS pathway, is primarily esterified and stored as a triacylglycerol in liver and adipose tissue. When needed, triacylglycerols are exported to other sites where they are used for energy in metabolic functions such as cell repair and cell cycling. In the lactating breast, fatty acids are produced to provide energy for the baby, but shorter chain fatty acids such as myristate are produced instead for ease of digestion. Aside from being utilized as a source of energy, palmitate and other minor fatty acids have been shown to be involved in cell signaling. For example, acute exposure of human pancreatic islets to palmitate causes an up-regulation of tyrosine phosphorylation of insulin receptors. As well, protein palmitoylation has been implicated in the modification of several different proteins, particularly in G-protein coupled receptors. These G-proteins are crucial in cellular signaling processes and palmitoylation is thought to modify G-protein phosphorylation and membrane translocation, In addition, many palmitoylated proteins are found to be concentrated in lipid rafts. In special lipid rafts called caveolae, palmitate is also present and is thought to contribute to processes such as ras and raf signaling as well as caveolae stability and cholesterol transport.
Despite the important role palmitate plays in the cellular activities, it is not an essential fatty acid. A person consuming an adequately balanced diet will obtain sufficient amounts of fat, and therefore undergo minimal endogenous fatty acid synthesis. Even in tissues with high cellular turnover, circulating fatty acids are preferentially used as structural lipids over endogenously produced ones. Because of the low activity, there are few diseases that directly involve the fatty acid synthesis pathway, although variations of FAS activity still may have an influence on diseases such as obesity and diabetes. Nonetheless, fatty acid synthesis is crucial for development. In mice, FAS homozygous knockouts are non-viable, with most of the embryos dying before implantation. As well, most heterozygous FAS knockout mice die at various stages of embryonic development. Surviving heterozygous mice possess 50% and 35% lower FAS mRNA and activity compared to wild types, suggesting that the lack of FAS
gene has significant teratogenic consequences. Additionally, conditional knockout FASKOL (FAS knockout in liver) mice develop fatty livers and liver disease when consuming fat free diets. In these mice, fatty acids are mobilized from the adipose tissue to the liver. However, due to the liver’s inability to synthesize new fatty acids, the incoming fatty acids are not oxidized and build up. This suggests that FAS, is necessary to maintain normal health and that a basal level of de novo fatty acid synthesis is required.
Production of endogenous fatty acids begins with the substrate acetyl-CoA that is available in the cytosol. The other critical starting substrate is malonyl-CoA, and its production from acetyl-CoA is the initial rate-limiting step in fatty acid synthesis. In the presence of bicarbonate and ATP, acetyl-CoA is converted to malonyl-CoA by acetyl-CoA carboxylase. In a two-step reaction, the enzyme transfers a carboxyl group from the bicarbonate to acetyl-CoA, forming malonyl-CoA. Both of these substrates are then used in fatty acid chain elongation, a multi-step process that is completely catalyzed by FAS. Initially, acetyl-CoA, acting as a primer molecule, combines with the cysteine SH group on the FAS molecule, catalyzed by acetyl transacylase. Malonyl-CoA is then transferred to the adjacent SH group (which is located on ACP), catalyzed by malonyl transacylase, forming an acyl(acetyl)-malonyl enzyme. Next, 3-ketoacyl synthase liberates CO2 from the acyl chain, decarboxylating the chain and driving the reaction further downstream. The chain is then reduced (3-ketoacyl reductase), dehydrated (dehydratase) and reduced again (enoyl reductase) to form a saturated four-carbon acyl enzyme. The chain then enters this sequence of reactions six more times, with a new malonyl-CoA being incorporated into the chain each sequence until a saturated 16-carbon palmitate is formed. The fatty acid is then cleaved from FAS by thioesterase, and is activated by the addition of a CoA residue before it is utilized for metabolic functions. Although the major endproduct is palmitate, in some tissues there are separate thioesterase enzymes that specifically cleave fatty acids of length 8, 10, 12, or 18 carbon atoms, resulting in a variety of fatty acids being produced by FAS.
Lau, Dominic Sze Yan. Fatty Acid Synthase and Cancer: Expression and Interaction with Conjugated Linoleic Acid. ProQuest, 2007.