Fatty acid elongation (WP380)

Fatty acids are essential to all organisms except for archaea; they are major constituents of cellular membranes, and are used for energy storage and for posttranslational protein modifications. Most organisms are capable of synthesizing long chain (C12:0-C16:0) saturated fatty acids de novo. Although the initiation and termination reactions may vary, the cyclic series of chain-lengthening reactions are essentially the same across all organisms. The fatty acid chain, which starts as a 2-carbon chain from acetyl-CoA, is extended two carbons at a time by the addition of an acetyl group from malonyl-CoA. When the final length of the fatty acid is achieved, fatty acid synthesis is terminated. Each cycle of chain elongation involves 5 reactions with the following enzymatic activities: malonyl transferase (EC: 2.3.1.39), ketoacyl synthase (EC: 2.3.1.41), ketoacyl reductase (EC: 1.1.1.100), 3-hydroxyacyl dehydratase (EC: 4.2.1.58, 4.2.1.59, and 4.2.1.61), and enoyl-acyl reductase (EC: 1.3.1.10). In yeast, fatty acid biosynthesis is terminated with the release of fatty acyl-CoAs from fatty acid synthase (FAS), the enzyme complex that carries out de novo fatty acid biosynthesis. Palmitoyl- (C16) and stearoyl-CoA (C18) are the main products in yeast, while myristoyl-CoA (C14) is only produced in small amounts. To synthesize palmitoyl-CoA (C16) one acetyl-CoA and 7 malonyl-CoA molecules are required. The elongation substrate, malonyl-CoA is synthesized from the carboxylation of acetyl-CoA (EC 6.4.1.2) by the biotin-containing enzyme, acetyl-CoA carboxylase (Acc1p). Acetyl-CoA carboxylase is activated by the biotin:apoprotein ligase (Bpl1p). The yeast FAS complex catalyzes a total of 8 reactions. The alpha subunit(Fas2p) catalyzes 3 reactions, ketoacyl synthase (EC: 2.3.1.41),ketoacyl reductase (EC: 1.1.1.100) and self pantetheinylation and the yeast beta subunit (Fas1p) catalyzes 5 reactions, acetyltransferase (EC 2.3.1.38), malonyl transferase (EC: 2.3.1.39),3-hydroxyacyl dehydratase (EC: 4.2.1.58, 4.2.1.59, and 4.2.1.61),enoyl-acyl reductase (EC: 1.3.1.10), and palmitoyl transferase (EC:2.3.1.-). FASs are regulated at the transcriptional and translational level as well as posttranslationally. In yeast, FAS is a housekeeping enzyme that is expressed constitutively at a low level, but its expression is also activated by the general yeast transcription factors Rap1, Abf1 and Reb1 and theinositol/choline-responsive transcription factor heterodimer, Ino2p-Ino4p. The coordinate expression of the two subunits also appears to be regulated by Fas1p controlling the expression of FAS2. The FAS subunits are further regulated by proteolytic degradation of excess subunits. While the intact FAS multimeric complex (alpha6beta6) is stable, its individual subunits are rapidly degraded. Description source: YeastPathways.

Participants