Fatty acid synthase

Fatty acid synthase
Identifiers
EC number 2.3.1.85
CAS number 9045-77-6
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
FASN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFASN, fatty acid synthase, Fasn, A630082H08Rik, FAS, OA-519, SDR27X1, Fatty acid synthase
External IDsMGI: 95485 HomoloGene: 55800 GeneCards: FASN
RNA expression pattern


More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

2194

14104

Ensembl

ENSG00000169710

ENSMUSG00000025153

UniProt

P49327

P19096

RefSeq (mRNA)

NM_004104

NM_007988

RefSeq (protein)

NP_004095

NP_032014

Location (UCSC)Chr 17: 82.08 – 82.1 MbChr 11: 120.81 – 120.82 Mb
PubMed search[1][2]
Wikidata
View/Edit HumanView/Edit Mouse

Fatty acid synthase (FAS) is an enzyme that in humans is encoded by the FASN gene.[3][4][5][6]

Fatty acid synthase is a multi-enzyme protein that catalyzes fatty acid synthesis. It is not a single enzyme but a whole enzymatic system composed of two identical 272 kDa multifunctional polypeptides, in which substrates are handed from one functional domain to the next.[7][8][9][10]

Its main function is to catalyze the synthesis of palmitate (C16:0, a long-chain saturated fatty acid) from acetyl-CoA and malonyl-CoA, in the presence of NADPH.[6]

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 synthesized by a series of decarboxylative Claisen condensation reactions from acetyl-CoA and malonyl-CoA. Following each round of elongation the beta keto group is reduced to the fully saturated carbon chain by the sequential action of a ketoreductase (KR), dehydratase (DH), and enoyl reductase (ER). The growing fatty acid chain is carried between these active sites while attached covalently to the phosphopantetheine prosthetic group of an acyl carrier protein (ACP), and is released by the action of a thioesterase (TE) upon reaching a carbon chain length of 16 (palmitidic acid).

Classes

There are two principal classes of fatty acid synthases.

The mechanism of FAS I and FAS II elongation and reduction is the same, as the domains of the FAS II enzymes are largely homologous to their domain counterparts in FAS I multienzyme polypeptides. However, the differences in the organization of the enzymes - integrated in FAS I, discrete in FAS II - gives rise to many important biochemical differences.[13]

The evolutionary history of fatty acid synthases are very much intertwined with that of polyketide synthases (PKS). Polyketide synthases use a similar mechanism and homologous domains to produce secondary metabolite lipids. Furthermore, polyketide synthases also exhibit a Type I and Type II organization. FAS I in animals is thought to have arisen through modification of PKS I in fungi, whereas FAS I in fungi and the CMN group of bacteria seem to have arisen separately through the fusion of FAS II genes.[11]

Structure

Mammalian FAS consists of a homodimer of two identical protein subunits, 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)).[14][15]

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.[16][17] 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.[18][19] 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.[20] In addition, it has been recently reported that a heterodimeric FAS containing only one competent monomer is capable of palmitate synthesis.[21]

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 (see figure on the top right).[22]

A low resolution X-ray crystallography structure of both pig (homodimer)[23] and yeast FAS (heterododecamer)[24] along with a ~6 Å resolution electron cryo-microscopy (cryo-EM) yeast FAS structure [25] have been solved.

Substrate shuttling mechanism

The solved structures of yeast FAS and mammalian FAS show two distinct organization of highly conserved catalytic domains/enzymes in this multi-enzyme cellular machine. Yeast FAS has a highly efficient rigid barrel-like structure with 6 reaction chambers which synthesize fatty acids independently, while the mammalian FAS has an open flexible structure with only two reaction chambers. However, in both cases the conserved ACP acts as the mobile domain responsible for shuttling the intermediate fatty acid substrates to various catalytic sites. A first direct structural insight into this substrate shuttling mechanism was obtained by cryo-EM analysis, where ACP is observed bound to the various catalytic domains in the barrel-shaped yeast fatty acid synthase.[25] The cryo-EM results suggest that the binding of ACP to various sites is asymmetric and stochastic, as also indicated by computer-simulation studies[26]

FAS revised model with positions of polypeptides, three catalytic domains and their corresponding reactions, visualization by Kosi Gramatikoff. Note that FAS is only active as a homodimer rather than the monomer pictured.
FAS 'head-to-tail' model with positions of polypeptides, three catalytic domains and their corresponding reactions, visualization by Kosi Gramatikoff.

Regulation

Metabolism and homeostasis of fatty acid synthase is transcriptionally regulated by Upstream Stimulatory Factors (USF1 and USF2) and sterol regulatory element binding protein-1c (SREBP-1c) in response to feeding/insulin in living animals.[27][28]

Although liver X receptor (LXRs) modulate the expression of sterol regulatory element binding protein-1c (SREBP-1c) in feeding, regulation of FAS by SREBP-1c is USF-dependent.[28][29][30][31]

Acylphloroglucinols isolated from the fern Dryopteris crassirhizoma show a fatty acid synthase inhibitory activity.[32]

Clinical significance

The gene that codes for FAS has been investigated as a possible oncogene.[33] FAS is upregulated in breast cancers and as well as being an indicator of poor prognosis may also be worthwhile as a chemotherapeutic target.[34][35] FAS may also be involved in the production of an endogenous ligand (biochemistry) for the nuclear receptor PPARalpha, the target of the fibrate drugs for hyperlipidemia,[36] and is being investigated as a possible drug target for treating the metabolic syndrome.[37] Orlistat which is a gastrointenstinal inhibitor also inhibits FAS and has a potential as a medicine for cancer. [38][39]

In some cancer cell lines, this protein has been found to be fused with estrogen receptor alpha (ER-alpha), in which the N-terminus of FAS is fused in-frame with the C-terminus of ER-alpha.[6]

An association with uterine leiomyomata has been reported.[40]

See also

References

  1. ↑ "Human PubMed Reference:".
  2. ↑ "Mouse PubMed Reference:".
  3. ↑ Jayakumar A, Chirala SS, Chinault AC, Baldini A, Abu-Elheiga L, Wakil SJ (Feb 1995). "Isolation and chromosomal mapping of genomic clones encoding the human fatty acid synthase gene". Genomics. 23 (2): 420–4. PMID 7835891. doi:10.1006/geno.1994.1518.
  4. ↑ Jayakumar A, Tai MH, Huang WY, al-Feel W, Hsu M, Abu-Elheiga L, Chirala SS, Wakil SJ (Oct 1995). "Human fatty acid synthase: properties and molecular cloning". Proc Natl Acad Sci U S A. 92 (19): 8695–9. PMC 41033 Freely accessible. PMID 7567999. doi:10.1073/pnas.92.19.8695.
  5. ↑ Persson B, Kallberg Y, Bray JE, Bruford E, Dellaporta SL, Favia AD, Duarte RG, Jörnvall H, Kavanagh KL, Kedishvili N, Kisiela M, Maser E, Mindnich R, Orchard S, Penning TM, Thornton JM, Adamski J, Oppermann U (Feb 2009). "The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative". Chem Biol Interact. 178 (1–3): 94–8. PMC 2896744 Freely accessible. PMID 19027726. doi:10.1016/j.cbi.2008.10.040.
  6. 1 2 3 "Entrez Gene: FASN fatty acid synthase".
  7. ↑ Alberts AW, Strauss AW, Hennessy S, Vagelos PR (October 1975). "Regulation of synthesis of hepatic fatty acid synthetase: binding of fatty acid synthetase antibodies to polysomes". Proc. Natl. Acad. Sci. U.S.A. 72 (10): 3956–60. PMC 433116 Freely accessible. PMID 1060077. doi:10.1073/pnas.72.10.3956.
  8. ↑ Stoops JK, Arslanian MJ, Oh YH, Aune KC, Vanaman TC, Wakil SJ (May 1975). "Presence of two polypeptide chains comprising fatty acid synthetase". Proc. Natl. Acad. Sci. U.S.A. 72 (5): 1940–4. PMC 432664 Freely accessible. PMID 1098047. doi:10.1073/pnas.72.5.1940.
  9. ↑ Smith S, Agradi E, Libertini L, Dileepan KN (April 1976). "Specific release of the thioesterase component of the fatty acid synthetase multienzyme complex by limited trypsinization". Proc. Natl. Acad. Sci. U.S.A. 73 (4): 1184–8. PMC 430225 Freely accessible. PMID 1063400. doi:10.1073/pnas.73.4.1184.
  10. ↑ Smith S, Witkowski A, Joshi AK (July 2003). "Structural and functional organization of the animal fatty acid synthase". Prog. Lipid Res. 42 (4): 289–317. PMID 12689621. doi:10.1016/S0163-7827(02)00067-X.
  11. 1 2 Jenke-Kodama H, Sandmann A, Müller R, Dittmann E (October 2005). "Evolutionary implications of bacterial polyketide synthases". Mol. Biol. Evol. 22 (10): 2027–39. PMID 15958783. doi:10.1093/molbev/msi193.
  12. ↑ Fulmer T (March 2009). "Not so FAS". SciBX. 2 (11): 1. doi:10.1038/scibx.2009.430.
  13. ↑ Stevens L, Price NC (1999). Fundamentals of enzymology: the cell and molecular biology of catalytic proteins. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-850229-X.
  14. ↑ Chirala SS, Jayakumar A, Gu ZW, Wakil SJ (March 2001). "Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer". Proc. Natl. Acad. Sci. U.S.A. 98 (6): 3104–8. PMC 30614 Freely accessible. PMID 11248039. doi:10.1073/pnas.051635998.
  15. ↑ Smith S (December 1994). "The animal fatty acid synthase: one gene, one polypeptide, seven enzymes". FASEB J. 8 (15): 1248–59. PMID 8001737.
  16. ↑ Stoops JK, Wakil SJ (May 1981). "Animal fatty acid synthetase. A novel arrangement of the beta-ketoacyl synthetase sites comprising domains of the two subunits". J. Biol. Chem. 256 (10): 5128–33. PMID 6112225.
  17. ↑ Stoops JK, Wakil SJ (March 1982). "Animal fatty acid synthetase. Identification of the residues comprising the novel arrangement of the beta-ketoacyl synthetase site and their role in its cold inactivation". J. Biol. Chem. 257 (6): 3230–5. PMID 7061475.
  18. ↑ Joshi AK, Rangan VS, Smith S (February 1998). "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 (9): 4937–43. PMID 9478938. doi:10.1074/jbc.273.9.4937.
  19. ↑ Rangan VS, Joshi AK, Smith S (September 2001). "Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro". Biochemistry. 40 (36): 10792–9. PMID 11535054. doi:10.1021/bi015535z.
  20. ↑ Witkowski A, Joshi AK, Rangan VS, Falick AM, Witkowska HE, Smith S (April 1999). "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 (17): 11557–63. PMID 10206962. doi:10.1074/jbc.274.17.11557.
  21. ↑ Joshi AK, Rangan VS, Witkowski A, Smith S (February 2003). "Engineering of an active animal fatty acid synthase dimer with only one competent subunit". Chem. Biol. 10 (2): 169–73. PMID 12618189. doi:10.1016/S1074-5521(03)00023-1.
  22. ↑ Asturias FJ, Chadick JZ, Cheung IK, Stark H, Witkowski A, Joshi AK, Smith S (March 2005). "Structure and molecular organization of mammalian fatty acid synthase". Nat. Struct. Mol. Biol. 12 (3): 225–32. PMID 15711565. doi:10.1038/nsmb899.
  23. ↑ Maier T, Leibundgut M, Ban N (September 2008). "The crystal structure of a mammalian fatty acid synthase". Science. 321 (5894): 1315–22. PMID 18772430. doi:10.1126/science.1161269.
  24. ↑ Lomakin IB, Xiong Y, Steitz TA (April 2007). "The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together". Cell. 129 (2): 319–32. PMID 17448991. doi:10.1016/j.cell.2007.03.013.
  25. 1 2 Gipson P, Mills DJ, Wouts R, Grininger M, Vonck J, Kühlbrandt W (May 2010). "Direct structural insight into the substrate-shuttling mechanism of yeast fatty acid synthase by electron cryomicroscopy". Proc. Natl. Acad. Sci. U.S.A. 107 (20): 9164–9. PMC 2889056 Freely accessible. PMID 20231485. doi:10.1073/pnas.0913547107.
  26. ↑ Anselmi C, Grininger M, Gipson P, Faraldo-Gómez JD (September 2010). "Mechanism of substrate shuttling by the acyl-carrier protein within the fatty acid mega-synthase". J. Am. Chem. Soc. 132 (35): 12357–64. PMID 20704262. doi:10.1021/ja103354w.
  27. ↑ Paulauskis JD, Sul HS (January 1989). "Hormonal regulation of mouse fatty acid synthase gene transcription in liver". J. Biol. Chem. 264 (1): 574–7. PMID 2535847.
  28. 1 2 Latasa MJ, Griffin MJ, Moon YS, Kang C, Sul HS (August 2003). "Occupancy and function of the -150 sterol regulatory element and -65 E-box in nutritional regulation of the fatty acid synthase gene in living animals". Mol. Cell. Biol. 23 (16): 5896–907. PMC 166350 Freely accessible. PMID 12897158. doi:10.1128/MCB.23.16.5896-5907.2003.
  29. ↑ Griffin MJ, Wong RH, Pandya N, Sul HS (February 2007). "Direct interaction between USF and SREBP-1c mediates synergistic activation of the fatty-acid synthase promoter". J. Biol. Chem. 282 (8): 5453–67. PMID 17197698. doi:10.1074/jbc.M610566200.
  30. ↑ 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 (May 2001). "Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter". Mol. Cell. Biol. 21 (9): 2991–3000. PMC 86928 Freely accessible. PMID 11287605. doi:10.1128/MCB.21.9.2991-3000.2001.
  31. ↑ Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ (November 2000). "Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta". Genes Dev. 14 (22): 2819–30. PMC 317055 Freely accessible. PMID 11090130. doi:10.1101/gad.844900.
  32. ↑ Na M, Jang J, Min BS, Lee SJ, Lee MS, Kim BY, Oh WK, Ahn JS (September 2006). "Fatty acid synthase inhibitory activity of acylphloroglucinols isolated from Dryopteris crassirhizoma". Bioorg. Med. Chem. Lett. 16 (18): 4738–42. PMID 16870425. doi:10.1016/j.bmcl.2006.07.018.
  33. ↑ Baron A, Migita T, Tang D, Loda M (January 2004). "Fatty acid synthase: a metabolic oncogene in prostate cancer?". J. Cell. Biochem. 91 (1): 47–53. PMID 14689581. doi:10.1002/jcb.10708.
  34. ↑ Hunt DA, Lane HM, Zygmont ME, Dervan PA, Hennigar RA (2007). "MRNA stability and overexpression of fatty acid synthase in human breast cancer cell lines". Anticancer Res. 27 (1A): 27–34. PMID 17352212.
  35. ↑ Gansler TS, Hardman W, Hunt DA, Schaffel S, Hennigar RA (June 1997). "Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival". Hum. Pathol. 28 (6): 686–92. PMID 9191002. doi:10.1016/S0046-8177(97)90177-5.
  36. ↑ Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J, Semenkovich CF (August 2009). "Identification of a physiologically relevant endogenous ligand for PPARalpha in liver.". Cell. 138 (3): 476–88. PMC 2725194 Freely accessible. PMID 19646743. doi:10.1016/j.cell.2009.05.036.
  37. ↑ Wu M, Singh SB, Wang J, Chung CC, Salituro G, Karanam BV, Lee SH, Powles M, Ellsworth KP, Lassman ME, Miller C, Myers RW, Tota MR, Zhang BB, Li C (March 2011). "Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes.". Proc Natl Acad Sci U S A. 108 (13): 5378–83. PMC 3069196 Freely accessible. PMID 21389266. doi:10.1073/pnas.1002588108.
  38. ↑ Flavin, R., et al., Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol, 2010. 6(4): p. 551-562.
  39. ↑ Richardson, R.D., et al., Synthesis of Novel β-Lactone Inhibitors of Fatty Acid Synthase. Journal of medicinal chemistry, 2008. 51(17): p. 5285-5296.
  40. ↑ Eggert SL, Huyck KL, Somasundaram P, Kavalla R, Stewart EA, Lu AT, Painter JN, Montgomery GW, Medland SE, Nyholt DR, Treloar SA, Zondervan KT, Heath AC, Madden PA, Rose L, Buring JE, Ridker PM, Chasman DI, Martin NG, Cantor RM, Morton CC (2012). "Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata". Am J Hum Genet. 91 (4): 621–8. PMC 3484658 Freely accessible. PMID 23040493. doi:10.1016/j.ajhg.2012.08.009.

Further reading

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