Fatty acid synthase explained

Fatty acid synthase
Ec Number:2.3.1.85
Cas Number:9045-77-6
Go Code:0004312

Fatty acid synthase (FAS)[1] is an enzyme that in humans is encoded by the FASN gene.[2] [3] [4] [5]

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.[6] [7] [8] [9]

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.[5]

The fatty acids 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 (palmitic 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.[12]

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.

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 (known as the interdomain) of 600 residues from four C-terminal domains (enoyl reductase (ER), -ketoacyl reductase (KR), acyl carrier protein (ACP) and thioesterase (TE)).[13] [14] The interdomain region allows the two monomeric domains to form a dimer.

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.[15] [16] 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.[17] [18] 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.[19] In addition, it has been recently reported that a heterodimeric FAS containing only one competent monomer is capable of palmitate synthesis.[20]

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).[21]

A low resolution X-ray crystallography structure of both pig (homodimer)[22] and yeast FAS (heterododecamer)[23] along with a ~6 Å resolution electron cryo-microscopy (cryo-EM) yeast FAS structure [24] have been solved.

Substrate shuttling mechanism

The solved structures of yeast FAS and mammalian FAS show two distinct organizations 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.[24] The cryo-EM results suggest that the binding of ACP to various sites is asymmetric and stochastic, as also indicated by computer-simulation studies[25]

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.[26] [27]

Although liver X receptors (LXRs) modulate the expression of sterol regulatory element binding protein-1c (SREBP-1c) in feeding, regulation of FAS by SREBP-1c is USF-dependent.[27] [28] [29] [30]

Acylphloroglucinols isolated from the fern Dryopteris crassirhizoma show a fatty acid synthase inhibitory activity.[31]

Clinical significance

The FASN gene has been investigated as a possible oncogene.[32] FAS is upregulated in breast and gastric cancers, as well as being an indicator of poor prognosis, and so may be worthwhile as a chemotherapeutic target.[33] [34] [35] FAS inhibitors are therefore an active area of drug discovery research.[36] [37] [38] [39] [40]

FAS may also be involved in the production of an endogenous ligand for the nuclear receptor PPARalpha, the target of the fibrate drugs for hyperlipidemia,[41] and is being investigated as a possible drug target for treating the metabolic syndrome.[42] Orlistat which is a gastrointestinal lipase inhibitor also inhibits FAS and has a potential as a medicine for cancer.[43] [44]

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.[5]

An association with uterine leiomyomata has been reported.[45]

See also

Further reading

External links

Notes and References

  1. Paiva . Pedro . Medina . Fabiola E. . Viegas . Matilde . Ferreira . Pedro . Neves . Rui P. P. . Sousa . João P. M. . Ramos . Maria J. . Fernandes . Pedro A. . 2021-08-11 . Animal Fatty Acid Synthase: A Chemical Nanofactory . Chemical Reviews . en . 121 . 15 . 9502–9553 . 10.1021/acs.chemrev.1c00147 . 34156235 . 235595027 . 0009-2665.
  2. Jayakumar A, Chirala SS, Chinault AC, Baldini A, Abu-Elheiga L, Wakil SJ . Isolation and chromosomal mapping of genomic clones encoding the human fatty acid synthase gene . Genomics . 23 . 2 . 420–424 . February 1995 . 7835891 . 10.1006/geno.1994.1518 .
  3. Jayakumar A, Tai MH, Huang WY, al-Feel W, Hsu M, Abu-Elheiga L, Chirala SS, Wakil SJ . Human fatty acid synthase: properties and molecular cloning . Proceedings of the National Academy of Sciences of the United States of America . 92 . 19 . 8695–8699 . Oct 1995 . 7567999 . 41033 . 10.1073/pnas.92.19.8695 . 1995PNAS...92.8695J . free .
  4. 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 . The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative . Chemico-Biological Interactions . 178 . 1–3 . 94–98 . Feb 2009 . 19027726 . 2896744 . 10.1016/j.cbi.2008.10.040 . 2009CBI...178...94P .
  5. Web site: Entrez Gene: FASN fatty acid synthase.
  6. Alberts AW, Strauss AW, Hennessy S, Vagelos PR . Regulation of synthesis of hepatic fatty acid synthetase: binding of fatty acid synthetase antibodies to polysomes . Proceedings of the National Academy of Sciences of the United States of America . 72 . 10 . 3956–3960 . October 1975 . 1060077 . 433116 . 10.1073/pnas.72.10.3956 . 1975PNAS...72.3956A . free .
  7. Stoops JK, Arslanian MJ, Oh YH, Aune KC, Vanaman TC, Wakil SJ . Presence of two polypeptide chains comprising fatty acid synthetase . Proceedings of the National Academy of Sciences of the United States of America . 72 . 5 . 1940–1944 . May 1975 . 1098047 . 432664 . 10.1073/pnas.72.5.1940 . 1975PNAS...72.1940S . free .
  8. Smith S, Agradi E, Libertini L, Dileepan KN . Specific release of the thioesterase component of the fatty acid synthetase multienzyme complex by limited trypsinization . Proceedings of the National Academy of Sciences of the United States of America . 73 . 4 . 1184–1188 . April 1976 . 1063400 . 430225 . 10.1073/pnas.73.4.1184 . 1976PNAS...73.1184S . free .
  9. Smith S, Witkowski A, Joshi AK . Structural and functional organization of the animal fatty acid synthase . Progress in Lipid Research . 42 . 4 . 289–317 . July 2003 . 12689621 . 10.1016/S0163-7827(02)00067-X .
  10. Jenke-Kodama H, Sandmann A, Müller R, Dittmann E . Evolutionary implications of bacterial polyketide synthases . Molecular Biology and Evolution . 22 . 10 . 2027–2039 . October 2005 . 15958783 . 10.1093/molbev/msi193 . free .
  11. Fulmer T . Not so FAS . Science-Business EXchange . 2 . 11 . March 2009 . 10.1038/scibx.2009.430 . 430. free .
  12. Book: Stevens L, Price NC . Fundamentals of enzymology: the cell and molecular biology of catalytic proteins . Oxford University Press . Oxford [Oxfordshire] . 1999 . 978-0-19-850229-6 .
  13. Chirala SS, Jayakumar A, Gu ZW, Wakil SJ . Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer . Proceedings of the National Academy of Sciences of the United States of America . 98 . 6 . 3104–3108 . March 2001 . 11248039 . 30614 . 10.1073/pnas.051635998 . 2001PNAS...98.3104C . free .
  14. Smith S . The animal fatty acid synthase: one gene, one polypeptide, seven enzymes . FASEB Journal . 8 . 15 . 1248–1259 . December 1994 . 8001737 . 10.1096/fasebj.8.15.8001737. free . 22853095 .
  15. Stoops JK, Wakil SJ . Animal fatty acid synthetase. A novel arrangement of the beta-ketoacyl synthetase sites comprising domains of the two subunits . Journal of Biological Chemistry . 256 . 10 . 5128–5133 . May 1981 . 10.1016/S0021-9258(19)69376-2 . 6112225 . free .
  16. Stoops JK, Wakil SJ . 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 . Journal of Biological Chemistry . 257 . 6 . 3230–3235 . March 1982 . 10.1016/S0021-9258(19)81100-6 . 7061475 . free .
  17. Joshi AK, Rangan VS, 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 . Journal of Biological Chemistry . 273 . 9 . 4937–4943 . February 1998 . 9478938 . 10.1074/jbc.273.9.4937 . free .
  18. Rangan VS, Joshi AK, Smith S . Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro . Biochemistry . 40 . 36 . 10792–18799 . September 2001 . 11535054 . 10.1021/bi015535z .
  19. Witkowski A, Joshi AK, Rangan VS, Falick AM, Witkowska HE, Smith S . 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 . Journal of Biological Chemistry . 274 . 17 . 11557–11563 . April 1999 . 10206962 . 10.1074/jbc.274.17.11557 . free .
  20. Joshi AK, Rangan VS, Witkowski A, Smith S . Engineering of an active animal fatty acid synthase dimer with only one competent subunit . Chemistry and Biology . 10 . 2 . 169–173 . February 2003 . 12618189 . 10.1016/S1074-5521(03)00023-1 . free .
  21. Asturias FJ, Chadick JZ, Cheung IK, Stark H, Witkowski A, Joshi AK, Smith S . 6132878 . Structure and molecular organization of mammalian fatty acid synthase . Nature Structural and Molecular Biology . 12 . 3 . 225–232 . March 2005 . 15711565 . 10.1038/nsmb899 .
  22. Maier T, Leibundgut M, Ban N . The crystal structure of a mammalian fatty acid synthase . Science . 321 . 5894 . 1315–1322 . September 2008 . 18772430 . 10.1126/science.1161269 . 2008Sci...321.1315M . 3168991 .
  23. Lomakin IB, Xiong Y, Steitz TA . The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together . Cell . 129 . 2 . 319–332 . April 2007 . 17448991 . 10.1016/j.cell.2007.03.013 . 8209424 . free .
  24. Gipson P, Mills DJ, Wouts R, Grininger M, Vonck J, Kühlbrandt W . Direct structural insight into the substrate-shuttling mechanism of yeast fatty acid synthase by electron cryomicroscopy . Proceedings of the National Academy of Sciences of the United States of America . 107 . 20 . 9164–9169 . May 2010 . 20231485 . 2889056 . 10.1073/pnas.0913547107 . 2010PNAS..107.9164G . free .
  25. Anselmi C, Grininger M, Gipson P, Faraldo-Gómez JD . Mechanism of substrate shuttling by the acyl-carrier protein within the fatty acid mega-synthase . Journal of the American Chemical Society . 132 . 35 . 12357–12364 . September 2010 . 20704262 . 10.1021/ja103354w .
  26. Paulauskis JD, Sul HS . Hormonal regulation of mouse fatty acid synthase gene transcription in liver . Journal of Biological Chemistry . 264 . 1 . 574–577 . January 1989 . 10.1016/S0021-9258(17)31298-X . 2535847 . free .
  27. Latasa MJ, Griffin MJ, Moon YS, Kang C, Sul HS . 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 . Molecular and Cellular Biology . 23 . 16 . 5896–5907 . August 2003 . 12897158 . 166350 . 10.1128/MCB.23.16.5896-5907.2003 .
  28. Griffin MJ, Wong RH, Pandya N, Sul HS . Direct interaction between USF and SREBP-1c mediates synergistic activation of the fatty-acid synthase promoter . Journal of Biological Chemistry . 282 . 8 . 5453–5467 . February 2007 . 17197698 . 10.1074/jbc.M610566200 . free .
  29. 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 . Molecular and Cellular Biology . 21 . 9 . 2991–3000 . May 2001 . 11287605 . 86928 . 10.1128/MCB.21.9.2991-3000.2001 .
  30. 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 & Development . 14 . 22 . 2819–2830 . November 2000 . 11090130 . 317055 . 10.1101/gad.844900 .
  31. Na M, Jang J, Min BS, Lee SJ, Lee MS, Kim BY, Oh WK, Ahn JS . Fatty acid synthase inhibitory activity of acylphloroglucinols isolated from Dryopteris crassirhizoma . Bioorganic & Medicinal Chemistry Letters . 16 . 18 . 4738–4742 . September 2006 . 16870425 . 10.1016/j.bmcl.2006.07.018 .
  32. Baron A, Migita T, Tang D, Loda M . Fatty acid synthase: a metabolic oncogene in prostate cancer? . Journal of Cellular Biochemistry . 91 . 1 . 47–53 . January 2004 . 14689581 . 10.1002/jcb.10708 . 26175683 .
  33. Hunt DA, Lane HM, Zygmont ME, Dervan PA, Hennigar RA . MRNA stability and overexpression of fatty acid synthase in human breast cancer cell lines . Anticancer Research . 27 . 1A . 27–34 . 2007 . 17352212 .
  34. Gansler TS, Hardman W, Hunt DA, Schaffel S, Hennigar RA . Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival . Human Pathology . 28 . 6 . 686–692 . June 1997 . 9191002 . 10.1016/S0046-8177(97)90177-5 .
  35. Ezzeddini R, Taghikhani M, Somi MH, Samadi N, Rasaee, MJ . Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma . Life Sciences . 224 . 169–176 . May 2019 . 30914315 . 10.1016/j.lfs.2019.03.056 . 85532042 .
  36. Web site: First Human Study Taking Place With Fatty Acid Synthase Inhibitor . oncotherapynetwork.com . April 7, 2017 . June 4, 2018 . April 15, 2019 . https://web.archive.org/web/20190415121500/https://www.oncotherapynetwork.com/breast-cancer-targets/first-human-study-taking-place-fatty-acid-synthase-inhibitor . dead .
  37. Lu T, Schubert C, Cummings MD, Bignan G, Connolly PJ, Smans K, Ludovici D, Parker MH, Meyer C, Rocaboy C, Alexander R, Grasberger B, De Breucker S, Esser N, Fraiponts E, Gilissen R, Janssens B, Peeters D, Van Nuffel L, Vermeulen P, Bischoff J, Meerpoel L . Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy . Bioorganic & Medicinal Chemistry Letters . 28 . 12 . 2159–2164 . May 2018 . 29779975 . 10.1016/j.bmcl.2018.05.014 . 29159508 .
  38. Hardwicke MA, Rendina AR, Williams SP, Moore ML, Wang L, Krueger JA, Plant RN, Totoritis RD, Zhang G, Briand J, Burkhart WA, Brown KK, Parrish CA . A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site . Nature Chemical Biology . 10 . 9 . 774–779 . September 2014 . 25086508 . 10.1038/nchembio.1603 .
  39. Vander Heiden MG, DeBerardinis RJ . Understanding the Intersections between Metabolism and Cancer Biology . Cell . 168 . 4 . 657–669 . February 2017 . 28187287 . 5329766 . 10.1016/j.cell.2016.12.039 .
  40. An investigation into the interdomain region of Caenorhabditis elegans fatty acid synthase and its implications as a drug target . La Trobe . 2009-01-01 . thesis . en . Christopher David . Sgro.
  41. Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J, Semenkovich CF . Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. . Cell . 138 . 3 . 476–488 . August 2009 . 19646743 . 2725194 . 10.1016/j.cell.2009.05.036 .
  42. 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 . Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes. . Proceedings of the National Academy of Sciences of the United States of America . 108 . 13 . 5378–5383 . March 2011 . 21389266 . 3069196 . 10.1073/pnas.1002588108 . 2011PNAS..108.5378W . free .
  43. Flavin R, Peluso S, Nguyen PL, Loda M . Fatty acid synthase as a potential therapeutic target in cancer . Future Oncology . 6 . 4 . 551–562 . April 2010 . 20373869 . 3197858 . 10.2217/fon.10.11 .
  44. Richardson RD, Ma G, Oyola Y, Zancanella M, Knowles LM, Cieplak P, Romo D, Smith JW . Synthesis of novel beta-lactone inhibitors of fatty acid synthase . Journal of Medicinal Chemistry . 51 . 17 . 5285–5296 . September 2008 . 18710210 . 3172131 . 10.1021/jm800321h .
  45. 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 . Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata . American Journal of Human Genetics . 91 . 4 . 621–628 . 2012 . 23040493 . 3484658 . 10.1016/j.ajhg.2012.08.009 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Fatty acid synthase".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.