Fatty acid synthase

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Image:FASmodel2.jpg
FAS revised model with positions of polypeptides, three catalytic domains and their corresponding reactions, visualization by Kosi Gramatikoff.

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[1][1][1][1][1].

Metabolic function

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 ob the right).

Classes

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.

Structure

Image:FASmodel1.jpg
FAS 'head-to-tail' model with positions of polypeptides, three catalytic domains and their corresponding reactions, visualization by Kosi Gramatikoff.

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))[1][1].

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[1][1]. 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[1][1] 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[1]. In addition, it has been recently reported that a heterodimeric FAS containing only one competent monomer is capable of palmitate synthesis[1].

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 [1](see figure on the top right).

Regulation

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).[1][1]

Clinical significance

It has been investigated as a possible oncogene.[1] 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.[1][1]

See also

References

External links

Template:Metabolic pathway stub

v • d • e
Enzymes: multienzyme complexes
CAD (Carbamoyl phosphate synthase II, Aspartate carbamoyltransferase, Dihydroorotase) - Cholesterol side-chain cleavage enzyme - Cytochrome b6f complex - Electron transport chain - Fatty acid synthetase complex - Glycine decarboxylase complex - Mitochondrial trifunctional protein (HADHA, HADHB) - Oxoglutarate dehydrogenase - Phosphoenolpyruvate sugar phosphotransferase system - Photosynthetic reaction center complex proteins - Photosystem - Polyketide synthase - Pyruvate dehydrogenase complex (E1, E2, E3) - Sucrase-isomaltase complex -Tryptophan synthase
v • d • e
Metabolism: lipid metabolism
Lipid productionAcetyl-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 degradationAcyl 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
PhospholipidsDiacylglycerol kinase
SteroidsHMG-CoA reductase - Farnesyl-diphosphate farnesyltransferase - Squalene monooxygenase - Lanosterol synthase - CYP51A1
ProstanoidsCyclooxygenase - Thromboxane-A synthase - Prostacyclin synthase - Prostaglandin E synthase - Prostaglandin D2 synthase
LeukotrienesArachidonate 5-lipoxygenase - 5-Lipoxygenase activating protein - Leukotriene A4 hydrolase - Leukotriene C4 synthase
Bile acidsCholesterol 7 alpha-hydroxylase
fr:Acide gras synthase


Acknowledgement and Attribution Regarding Sources of Content

Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .

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