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20-September-2008 09:55:58 - synthase FAS revised model with positions of polypeptides, three catalytic domains and their corresponding reactions, visualization by Kosi Gramatikoff. 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 next12345. Contents 1 Metabolic function 2 Classes 3 Structure 4 Regulation 5 Clinical significance 6 See also 7 References 8 External links 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. Structure FAS 'head-to-tail' model with positions of polypeptides, three catalytic domains and their corresponding reactions, visualization by Kosi Gramatikoff. 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 TE67. 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 monomer89. 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 monomer1011 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 monomer12. In addition, it has been recently reported that a heterodimeric FAS containing only one competent monomer is capable of palmitate synthesis13. 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 14see 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.1516 Clinical significance It has been investigated as a possible oncogene.17 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.1819 See 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 ^ 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 ^ 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 ^ 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 ^ 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 ^ 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 ^ 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 ^ Asturias FJ et al., Structure and molecular organization of mammalian fatty acid synthase. Nature Structural Molecular Biology 12, 225 - 232 2005 PMID 15711565 ^ 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;219:2991-3000. 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;1422:2819-30. PMID 11090130 ^ Baron A, Migita T, Tang D, Loda M 2004. Fatty acid synthase: a metabolic oncogene in prostate cancer?. J Cell Biochem 91 1: 47-53. doi:10.1002/jcb.10708. PMID 14689581. ^ 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. 271A: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. 286:686-92, 1997 Jun. UI: 9191002 External links MeSH Fatty+Acid+Synthase http://web.indstate.edu/thcme/mwking/lipid-synthesis.html#synthesis http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/fasynthesis.htm This article about metabolism is a 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 - triglyceride and fatty acid enzymes Lipid production ATP citrate lyase - Acetyl-CoA carboxylase Fatty acid synthesis/Fatty acid synthase: Beta-ketoacyl-ACP synthase - Î’-Ketoacyl ACP reductase - 3-Hydroxyacyl ACP dehydrase - Enoyl ACP reductase triacyl glycerol: Glycerol-3-phosphate dehydrogenase - Thiokinase Lipid degradation Acyl transport: Carnitine palmitoyltransferase I - Carnitine-acylcarnitine translocase - Carnitine palmitoyltransferase II Beta oxidation/Mitochondrial trifunctional protein: Acyl CoA dehydrogenase ACADL, ACADM, ACADS, ACADVL - Enoyl-CoA hydratase - 3-Hydroxyacyl CoA dehydrogenase - Acetyl-CoA C-acyltransferase to acetyl-CoA: Malonyl-CoA decarboxylase unsaturated Enoyl CoA isomerase, 2,4 Dienoyl-CoA reductase odd chain Propionyl-CoA carboxylase aldehydes Long-chain-aldehyde dehydrogenase see also disorders Retrieved from http://en..org/wiki/Fatty_acid_synthase Categories: Biochemistry stubs | Transferases | EC 2.3.1 | Metabolism | Fatty acids Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Français РуÑ?Ñ?кий This page was last modified on 28 June 2008, at 11:0
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