Fatty acid synthase

Fatty acid synthase (FAS) is enzymatic system composed of 272 kDa multifunctional polypeptide, in which substrates are handed from one functional domain to the next [Alberts, A.W., Strauss, A.W., Hennessy, S. & Vagelos, P.R. Regulation of synthesis of hepatic fatty acid synthetase: binding of fatty acid synthetase antibodies to polysomes. Proc. Natl. Acad. Sci. USA 72, 3956−3960] [Stoops, J.K. et al. Presence of two polypeptide chains comprising fatty acid synthetase. Proc. Natl. Acad. Sci. USA 72, 1940−1944 (1975)] [Smith, S., Agradi, E., Libertini, L. & Dileepan, K.N. Specific release of the thioesterase component of the fatty acid synthetase multienzyme complex by limited trypsinization. Proc. Natl. Acad. Sci. USA 73, 1184−1188 (1976)] [Wakil, S.J. Fatty acid synthase, a proficient multifunctional enzyme. Biochemistry 28, 4523−4530 (1989)] [Smith, S., Witkowski, A. & Joshi, A.K. Structural and functional organization of the animal fatty acid synthase. Prog. Lipid Res. 42, 289−317] .

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 on 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 mammalian synthases differ).
* Type II, or bacterial systems, use discrete, monofunctional enzymes which are used iteratively to elongate and reduce the fatty acid chain.

tructure

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)) [Chirala, S.S., Jayakumar, A., Gu, Z.W. & Wakil, S.J. Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer. Proc. Natl. Acad. Sci. USA 98, 3104−3108 (2001)] [Smith, S. The animal fatty acid synthase: one gene, one polypeptide, seven enzymes. FASEB J. 8, 1248−1259 (1994)] .

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 [Stoops, J.K. & Wakil, S.J. Animal fatty acid synthetase. A novel arrangement of the -ketoacyl synthetase sites comprising domains of the two subunits. J. Biol. Chem. 256, 5128−5133 (1981)] [Stoops, J.K. & Wakil, S.J. Animal fatty acid synthetase. Identification of the residues comprising the novel arrangement of the -ketoacyl synthetase site and their role in its cold inactivation. J. Biol. Chem. 257, 3230−3235] . 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 [Joshi, A.K., Rangan, V.S. & Smith, S. Differential affinity labeling of the two subunits of the homodimeric animal fatty acid synthase allows isolation of heterodimers consisting of subunits that have been independently modified. J. Biol. Chem. 273, 4937−4943 (1998)] [Rangan, V.S., Joshi, A.K. & Smith, S. Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro. Biochemistry 40, 10792−10799 (2001)] 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 [Witkowski, A. et al. Dibromopropanone cross-linking of the phosphopantetheine and active-site cysteine thiols of the animal fatty acid synthase can occur both inter- and intrasubunit. Reevaluation of the side-by-side, antiparallel subunit model. J. Biol. Chem. 274, 11557−11563 (1999)] . In addition, it has been recently reported that a heterodimeric FAS containing only one competent monomer is capable of palmitate synthesis [Joshi, A.K., Rangan, V.S., Witkowski, A. & Smith, S. Engineering of an active animal fatty acid synthase dimer with only one competent subunit. Chem. Biol. 10, 169−173 (2003)] .

The 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 [Asturias FJ et al., Structure and molecular organization of mammalian fatty acid synthase. Nature Structural & Molecular Biology 12, 225 - 232 (2005) PMID 15711565] (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). [Yoshikawa T, Shimano H, Amemiya-Kudo M, Yahagi N, Hasty AH, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Kimura S, Ishibashi S, Yamada N. Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol. 2001 May;21(9):2991-3000. PMID 11287605] [Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. 2000 Nov 15;14(22):2819-30. PMID 11090130]

Clinical significance

It has been investigated as a possible oncogene. [cite journal |author=Baron A, Migita T, Tang D, Loda M |title=Fatty acid synthase: a metabolic oncogene in prostate cancer? |journal=J Cell Biochem |volume=91 |issue=1 |pages=47–53 |year=2004 |pmid=14689581 |doi=10.1002/jcb.10708] 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. [Hunt DA. Lane HM. Zygmont ME. Dervan PA. Hennigar RA. MRNA stability and overexpression of fatty acid synthase in human breast cancer cell lines. [Journal Article] Anticancer Research. 27(1A):27-34, 2007 Jan-Feb.UI: 17352212] [Gansler TS. Hardman W 3rd. Hunt DA. Schaffel S. Hennigar RA. Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. [Journal Article] Human Pathology. 28(6):686-92, 1997 Jun.UI: 9191002]

ee also

* Fatty acid synthesis
* Fatty acid metabolism
* Fatty acid degradation
* Fatty acid
* Essential fatty acid
* Enoyl-acyl carrier protein reductase
* List of fatty acid metabolism disorders
* FASN, the human gene encoding the fatty acid synthase protein

References

External links

*
* http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#synthesis
* http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/fasynthesis.htm