Fatty acid synthases (FAS) is enzymatic system composed of 272 kDa multifunctional polypeptide, in which substrates are handed from one functional domain to the next.
Additional recommended knowledge
Fatty acids are aliphatic acids fundamental to energy production and storage, cellular structure and as intermediates in the biosynthesis of hormones and other biologically important molecules. They are synthesised by a series of decarboxylative Claisen condensation reactions from Acetyl-CoA and Malonyl-CoA (see fatty acid synthesis). Following each round of elongation the beta keto group is reduced to the fully saturated carbon chain by the action of a ketoreductase (KR), enol reductase (ER) and dehydratase (DH). The growing fatty acid chain is carried as an acyl carrier protein (ACP) linked substrate, and is released by the action of a thioesterase (TE) (see positions of the polypeptides in the 3D models on the right).
There are two principal classes of fatty acid synthases.
- Type I systems utilise a single large, multifunctional polypeptide and are common to both mammals and fungi (although the structural arrangement of fungal and mamallian synthases differ).
- Type II, or bacterial systems, use discrete, monofunctional enzymes which are used iteratively to elongate and reduce the fatty acid chain.
Mammalian FAS consists of two identical multifunctional polypeptides, in which three catalytic domains in the N-terminal section (-ketoacyl synthase (KS), malonyl/acetyltransferase (MAT), and dehydrase (DH)), are separated by a core region of 600 residues from four C-terminal domains (enoyl reductase (ER), -ketoacyl reductase (KR), acyl carrier protein (ACP) and thioesterase (TE)).
The conventional model for organization of FAS (see the 'head-to-tail' model on the right) is largely based on the observations that the bifunctional reagent 1,3-dibromopropanone (DBP) is able to crosslink the active site cysteine thiol of the KS domain in one FAS monomer with the phosphopantetheine prosthetic group of the ACP domain in the other monomer. Complementation analysis of FAS dimers carrying different mutations on each monomer has established that the KS and MAT domains can cooperate with the ACP of either monomer and a reinvestigation of the DBP crosslinking experiments revealed that the KS active site Cys161 thiol could be crosslinked to the ACP 4'-phosphopantetheine thiol of either monomer. In addition, it has been recently reported that a heterodimeric FAS containing only one competent monomer is capable of palmitate synthesis.
Thee above observations seemed incompatible with the classical 'head-to-tail' model for FAS organization, and an alternative model has been proposed, predicting that the KS and MAT domains of both monomers lie closer to the center of the FAS dimer, where they can access the ACP of either subunit (see figure on the top right).
Metabolism and homeostasis of fatty acid is regulated by liver X receptor (LXRs). LXRs regulate fatty acid synthesis by modulating the expression of sterol regulatory element binding protein-1c (SREBP-1c).
It has been investigated as a possible oncogene. FAS is up-regulated in breast cancers and as well as being an indicator of poor prognosis may also be worthwhile as a chemotherapeutic target.
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|Metabolism: lipid metabolism|
|Lipid production||Acetyl-CoA carboxylase - Fatty acid synthesis: Beta-ketoacyl-ACP synthase - Β-Ketoacyl ACP reductase - 3-Hydroxyacyl ACP dehydrase - Enoyl ACP reductase|
unsaturated (Enoyl CoA isomerase, 2,4 Dienoyl-CoA reductase) - odd chain (Propionyl-CoA carboxylase) - Fatty acid synthase - Long fatty acyl CoA synthetase
|Lipid degradation||Acyl transport: Carnitine palmitoyltransferase I - Carnitine-acylcarnitine translocase - Carnitine palmitoyltransferase II|
Beta oxidation: Acyl CoA dehydrogenase (ACADL, ACADM, ACADS, ACADVL) - Enoyl-CoA hydratase - 3-Hydroxyacyl CoA dehydrogenase - Acetyl-CoA C-acyltransferase - Mitochondrial trifunctional protein
Ketogenesis: HMG-CoA synthase - HMG-CoA lyase - Other: Malonyl-CoA decarboxylase
|Steroids||HMG-CoA reductase - Farnesyl-diphosphate farnesyltransferase - Squalene monooxygenase - Lanosterol synthase - CYP51A1|
|Prostanoids||Cyclooxygenase - Thromboxane-A synthase - Prostacyclin synthase - Prostaglandin E synthase - Prostaglandin D2 synthase|
|Leukotrienes||Arachidonate 5-lipoxygenase - 5-Lipoxygenase activating protein - Leukotriene A4 hydrolase - Leukotriene C4 synthase|
|Bile acids||Cholesterol 7 alpha-hydroxylase|