Просмотр кода страницы Английская Википедия:Fatty acid synthase

{{Английская Википедия/Панель перехода}}
{{Short description|Class of enzymes}}
{{cs1 config|name-list-style=vanc}}
{{infobox enzyme
| Name       = Fatty acid synthase
| EC_number  = 2.3.1.85
| CAS_number = 9045-77-6
| GO_code    = 0004312
| image      =
| width      = 
| caption    =  
}}
{{infobox gene}}
'''Fatty acid synthase''' ('''FAS''')<ref name=":0">{{Cite journal |last1=Paiva |first1=Pedro |last2=Medina |first2=Fabiola E. |last3=Viegas |first3=Matilde |last4=Ferreira |first4=Pedro |last5=Neves |first5=Rui P. P. |last6=Sousa |first6=João P. M. |last7=Ramos |first7=Maria J. |last8=Fernandes |first8=Pedro A. |date=2021-08-11 |title=Animal Fatty Acid Synthase: A Chemical Nanofactory |url=https://pubs.acs.org/doi/10.1021/acs.chemrev.1c00147 |journal=Chemical Reviews |language=en |volume=121 |issue=15 |pages=9502–9553 |doi=10.1021/acs.chemrev.1c00147 |pmid=34156235 |s2cid=235595027 |issn=0009-2665}}</ref> is an [[enzyme]] that in humans is encoded by the ''FASN'' [[gene]].<ref name="pmid7835891">{{cite journal | vauthors = Jayakumar A, Chirala SS, Chinault AC, Baldini A, Abu-Elheiga L, Wakil SJ | title = Isolation and chromosomal mapping of genomic clones encoding the human fatty acid synthase gene | journal = Genomics | volume = 23 | issue = 2 | pages = 420–424 | date = February 1995 | pmid = 7835891 | doi = 10.1006/geno.1994.1518 }}</ref><ref name="pmid7567999">{{cite journal | vauthors = Jayakumar A, Tai MH, Huang WY, al-Feel W, Hsu M, Abu-Elheiga L, Chirala SS, Wakil SJ | title = Human fatty acid synthase: properties and molecular cloning | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 19 | pages = 8695–8699 | date = Oct 1995 | pmid = 7567999 | pmc = 41033 | doi = 10.1073/pnas.92.19.8695 | bibcode = 1995PNAS...92.8695J | doi-access = free }}</ref><ref name="pmid19027726">{{cite journal | vauthors = 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 | title = The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative | journal = Chemico-Biological Interactions | volume = 178 | issue = 1–3 | pages = 94–98 | date = Feb 2009 | pmid = 19027726 | pmc = 2896744 | doi = 10.1016/j.cbi.2008.10.040 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: FASN fatty acid synthase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2194}}</ref>

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 [[polypeptide]]s, in which [[Substrate (biochemistry)|substrate]]s are handed from one functional domain to the next.<ref name=":0" /><ref name="pmid1060077">{{cite journal | vauthors = Alberts AW, Strauss AW, Hennessy S, Vagelos PR | title = Regulation of synthesis of hepatic fatty acid synthetase: binding of fatty acid synthetase antibodies to polysomes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 72 | issue = 10 | pages = 3956–3960 | date = October 1975 | pmid = 1060077 | pmc = 433116 | doi = 10.1073/pnas.72.10.3956 | bibcode = 1975PNAS...72.3956A | doi-access = free }}</ref><ref name="pmid1098047">{{cite journal | vauthors = Stoops JK, Arslanian MJ, Oh YH, Aune KC, Vanaman TC, Wakil SJ | title = Presence of two polypeptide chains comprising fatty acid synthetase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 72 | issue = 5 | pages = 1940–1944 | date = May 1975 | pmid = 1098047 | pmc = 432664 | doi = 10.1073/pnas.72.5.1940 | bibcode = 1975PNAS...72.1940S | doi-access = free }}</ref><ref name="pmid1063400">{{cite journal | vauthors = Smith S, Agradi E, Libertini L, Dileepan KN | title = Specific release of the thioesterase component of the fatty acid synthetase multienzyme complex by limited trypsinization | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 4 | pages = 1184–1188 | date = April 1976 | pmid = 1063400 | pmc = 430225 | doi = 10.1073/pnas.73.4.1184 | bibcode = 1976PNAS...73.1184S | doi-access = free }}</ref><ref name="pmid12689621">{{cite journal | vauthors = Smith S, Witkowski A, Joshi AK | title = Structural and functional organization of the animal fatty acid synthase | journal = Progress in Lipid Research | volume = 42 | issue = 4 | pages = 289–317 | date = July 2003 | pmid = 12689621 | doi = 10.1016/S0163-7827(02)00067-X }}</ref>

Its main function is to catalyze the synthesis of [[palmitic acid|palmitate]] (C16:0, a long-chain [[Saturated fat|saturated fatty acid]]) from [[acetyl-CoA]] and [[malonyl-CoA]], in the presence of [[nicotinamide adenine dinucleotide phosphate|NADPH]].<ref name="entrez"/>

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 [[Beta-Ketoacyl ACP reductase|ketoreductase]] (KR), [[dehydratase]] (DH), and [[Enoyl-acyl carrier protein reductase|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).<ref name=":0" />

== Classes ==

There are two principal classes of fatty acid synthases. 
* Type I systems utilise a single large, multifunctional polypeptide and are common to both [[animals]] and [[fungi]] (although the structural arrangement of fungal and animal syntheses differ). A Type I fatty acid synthase system is also found in the CMN group of bacteria ([[corynebacteria]], [[mycobacteria]], and [[nocardia]]). In these bacteria, the FAS I system produces palmitic acid, and cooperates with the FAS II system to produce a greater diversity of lipid products.<ref name="pmid15958783">{{cite journal | vauthors = Jenke-Kodama H, Sandmann A, Müller R, Dittmann E | title = Evolutionary implications of bacterial polyketide synthases | journal = Molecular Biology and Evolution | volume = 22 | issue = 10 | pages = 2027–2039 | date = October 2005 | pmid = 15958783 | doi = 10.1093/molbev/msi193 | doi-access = free }}</ref>
* Type II is found in archaea, bacteria and plant plastids, and is characterized by the use of discrete, monofunctional enzymes for fatty acid synthesis. Inhibitors of this pathway (FASII) are being investigated as possible [[antibiotics]].<ref name="Fulmer">{{cite journal | author = Fulmer T | title = Not so FAS | journal = Science-Business EXchange | volume = 2 | issue = 11 |date=March 2009 | doi = 10.1038/scibx.2009.430 | pages = 430| doi-access = free }}</ref>

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.<ref name="isbn0-19-850229-X">{{cite book | vauthors = Stevens L, Price NC | title = Fundamentals of enzymology: the cell and molecular biology of catalytic proteins | publisher = Oxford University Press | location = Oxford [Oxfordshire] | year = 1999 | isbn = 978-0-19-850229-6 }}</ref>

The evolutionary history of fatty acid synthases are very much intertwined with that of [[polyketide synthase]]s (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.<ref name="pmid15958783" />

== 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)).<ref name="pmid11248039">{{cite journal | vauthors = Chirala SS, Jayakumar A, Gu ZW, Wakil SJ | title = Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 6 | pages = 3104–3108 | date = March 2001 | pmid = 11248039 | pmc = 30614 | doi = 10.1073/pnas.051635998 | bibcode = 2001PNAS...98.3104C | doi-access = free }}</ref><ref name="pmid8001737">{{cite journal | author = Smith S | title = The animal fatty acid synthase: one gene, one polypeptide, seven enzymes | journal = FASEB Journal | volume = 8 | issue = 15 | pages = 1248–1259 | date = December 1994 | pmid = 8001737 | doi = 10.1096/fasebj.8.15.8001737| s2cid = 22853095 }}</ref> The interdomain region allows the two monomeric domains to form a dimer.<ref name="pmid11248039" />

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.<ref name="pmid6112225">{{cite journal | vauthors = Stoops JK, Wakil SJ | title = Animal fatty acid synthetase. A novel arrangement of the beta-ketoacyl synthetase sites comprising domains of the two subunits | journal = Journal of Biological Chemistry | volume = 256 | issue = 10 | pages = 5128–5133 | date = May 1981 | doi = 10.1016/S0021-9258(19)69376-2 | pmid = 6112225 | doi-access = free }}</ref><ref name="pmid7061475">{{cite journal | vauthors = Stoops JK, Wakil SJ | title = 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 = Journal of Biological Chemistry | volume = 257 | issue = 6 | pages = 3230–3235 | date = March 1982 | doi = 10.1016/S0021-9258(19)81100-6 | pmid = 7061475 | doi-access = free }}</ref> 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.<ref name="pmid9478938">{{cite journal | vauthors = Joshi AK, Rangan VS, Smith S | title = 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 = Journal of Biological Chemistry | volume = 273 | issue = 9 | pages = 4937–4943 | date = February 1998 | pmid = 9478938 | doi = 10.1074/jbc.273.9.4937 | doi-access = free }}</ref><ref name="pmid11535054">{{cite journal | vauthors = Rangan VS, Joshi AK, Smith S | title = Mapping the functional topology of the animal fatty acid synthase by mutant complementation in vitro | journal = Biochemistry | volume = 40 | issue = 36 | pages = 10792–18799 | date = September 2001 | pmid = 11535054 | doi = 10.1021/bi015535z }}</ref> 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.<ref name="pmid10206962">{{cite journal | vauthors = Witkowski A, Joshi AK, Rangan VS, Falick AM, Witkowska HE, Smith S | title = 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 = Journal of Biological Chemistry | volume = 274 | issue = 17 | pages = 11557–11563 | date = April 1999 | pmid = 10206962 | doi = 10.1074/jbc.274.17.11557 | doi-access = free }}</ref> In addition, it has been recently reported that a [[heterodimeric]] FAS containing only one competent monomer is capable of palmitate synthesis.<ref name="pmid12618189">{{cite journal | vauthors = Joshi AK, Rangan VS, Witkowski A, Smith S | title = Engineering of an active animal fatty acid synthase dimer with only one competent subunit | journal = Chemistry and Biology | volume = 10 | issue = 2 | pages = 169–173 | date = February 2003 | pmid = 12618189 | doi = 10.1016/S1074-5521(03)00023-1 | doi-access = free }}</ref>

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).<ref name="pmid15711565">{{cite journal | vauthors = Asturias FJ, Chadick JZ, Cheung IK, Stark H, Witkowski A, Joshi AK, Smith S | s2cid = 6132878 | title = Structure and molecular organization of mammalian fatty acid synthase | journal = Nature Structural and Molecular Biology | volume = 12 | issue = 3 | pages = 225–232 | date = March 2005 | pmid = 15711565 | doi = 10.1038/nsmb899 }}</ref>

A low resolution X-ray crystallography structure of both pig (homodimer)<ref name="pmid18772430">{{cite journal | vauthors = Maier T, Leibundgut M, Ban N | title = The crystal structure of a mammalian fatty acid synthase | journal = Science | volume = 321 | issue = 5894 | pages = 1315–1322 | date = September 2008 | pmid = 18772430 | doi = 10.1126/science.1161269 | bibcode = 2008Sci...321.1315M | s2cid = 3168991 }}</ref> and yeast FAS (heterododecamer)<ref name="pmid17448991">{{cite journal | vauthors = Lomakin IB, Xiong Y, Steitz TA | title = The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together | journal = Cell | volume = 129 | issue = 2 | pages = 319–332 | date = April 2007 | pmid = 17448991 | doi = 10.1016/j.cell.2007.03.013 | s2cid = 8209424 | doi-access = free }}</ref> along with a ~6 Å resolution electron cryo-microscopy (cryo-EM) yeast FAS structure <ref name="GipsonMills2010">{{cite journal | vauthors = Gipson P, Mills DJ, Wouts R, Grininger M, Vonck J, Kühlbrandt W | title = Direct structural insight into the substrate-shuttling mechanism of yeast fatty acid synthase by electron cryomicroscopy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 20 | pages = 9164–9169 | date = May 2010 | pmid = 20231485 | pmc = 2889056 | doi = 10.1073/pnas.0913547107 | bibcode = 2010PNAS..107.9164G | doi-access = free }}</ref> 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.<ref name="GipsonMills2010"/> The cryo-EM results suggest that the binding of ACP to various sites is asymmetric and stochastic, as also indicated by computer-simulation studies<ref name="AnselmiGrininger2010">{{cite journal | vauthors = Anselmi C, Grininger M, Gipson P, Faraldo-Gómez JD | title = Mechanism of substrate shuttling by the acyl-carrier protein within the fatty acid mega-synthase | journal = Journal of the American Chemical Society | volume = 132 | issue = 35 | pages = 12357–12364 | date = September 2010 | pmid = 20704262 | doi = 10.1021/ja103354w }}</ref>

{|
|[[Image:FASmodel2.jpg|thumb|right|250px|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.]]
|[[Image:FASmodel1.jpg|thumb|right|250px|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.<ref name="pmid2535847">{{cite journal | vauthors = Paulauskis JD, Sul HS | title = Hormonal regulation of mouse fatty acid synthase gene transcription in liver | journal = Journal of Biological Chemistry | volume = 264 | issue = 1 | pages = 574–577 | date = January 1989 | doi = 10.1016/S0021-9258(17)31298-X | pmid = 2535847 | doi-access = free }}</ref><ref name="pmid12897158">{{cite journal | vauthors = Latasa MJ, Griffin MJ, Moon YS, Kang C, Sul HS | title = 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 | journal = Molecular and Cellular Biology | volume = 23 | issue = 16 | pages = 5896–5907 | date = August 2003 | pmid = 12897158 | pmc = 166350 | doi = 10.1128/MCB.23.16.5896-5907.2003 }}</ref>

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.<ref name="pmid12897158"/><ref name="pmid17197698">{{cite journal | vauthors = Griffin MJ, Wong RH, Pandya N, Sul HS | title = Direct interaction between USF and SREBP-1c mediates synergistic activation of the fatty-acid synthase promoter | journal = Journal of Biological Chemistry | volume = 282 | issue = 8 | pages = 5453–5467 | date = February 2007 | pmid = 17197698 | doi = 10.1074/jbc.M610566200 | doi-access = free }}</ref><ref name="pmid11287605">{{cite journal | vauthors = 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 | title = Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter | journal = Molecular and Cellular Biology | volume = 21 | issue = 9 | pages = 2991–3000 | date = May 2001 | pmid = 11287605 | pmc = 86928 | doi = 10.1128/MCB.21.9.2991-3000.2001 }}</ref><ref name="pmid11090130">{{cite journal | vauthors = Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ | title = Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta | journal = Genes & Development | volume = 14 | issue = 22 | pages = 2819–2830 | date = November 2000 | pmid = 11090130 | pmc = 317055 | doi = 10.1101/gad.844900 }}</ref>

Acyl[[phloroglucinol]]s isolated from the fern ''[[Dryopteris crassirhizoma]]'' show a fatty acid synthase inhibitory activity.<ref name="pmid16870425">{{cite journal | vauthors = Na M, Jang J, Min BS, Lee SJ, Lee MS, Kim BY, Oh WK, Ahn JS | title = Fatty acid synthase inhibitory activity of acylphloroglucinols isolated from Dryopteris crassirhizoma | journal = Bioorganic & Medicinal Chemistry Letters | volume = 16 | issue = 18 | pages = 4738–4742 | date = September 2006 | pmid = 16870425 | doi = 10.1016/j.bmcl.2006.07.018 }}</ref>

== Clinical significance ==

The ''FASN'' gene has been investigated as a possible [[oncogene]].<ref name="pmid14689581">{{cite journal | vauthors = Baron A, Migita T, Tang D, Loda M | title = Fatty acid synthase: a metabolic oncogene in prostate cancer? | journal = Journal of Cellular Biochemistry | volume = 91 | issue = 1 | pages = 47–53 | date = January 2004 | pmid = 14689581 | doi = 10.1002/jcb.10708 | s2cid = 26175683 }}</ref> FAS is [[Downregulation and upregulation|upregulated]] in breast and gastric cancers, as well as being an indicator of poor prognosis, and so may be worthwhile as a chemotherapeutic target.<ref name="pmid17352212">{{cite journal | vauthors = Hunt DA, Lane HM, Zygmont ME, Dervan PA, Hennigar RA | title = MRNA stability and overexpression of fatty acid synthase in human breast cancer cell lines | journal = Anticancer Research | volume = 27 | issue = 1A | pages = 27–34 | year = 2007 | pmid = 17352212 }}</ref><ref name="pmid9191002">{{cite journal | vauthors = Gansler TS, Hardman W, Hunt DA, Schaffel S, Hennigar RA | title = Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival | journal = Human Pathology | volume = 28 | issue = 6 | pages = 686–692 | date = June 1997 | pmid = 9191002 | doi = 10.1016/S0046-8177(97)90177-5 }}</ref><ref name="pmid130914315">{{cite journal | vauthors = Ezzeddini R, Taghikhani M, Somi MH, Samadi N, Rasaee, MJ | title = Clinical importance of FASN in relation to HIF-1α and SREBP-1c in gastric adenocarcinoma | journal = Life Sciences | volume = 224 | pages = 169–176 | date = May 2019 | pmid = 30914315 | doi = 10.1016/j.lfs.2019.03.056 | s2cid = 85532042 | url = https://www.sciencedirect.com/science/article/abs/pii/S0024320519302206 }}</ref> FAS [[enzyme inhibitor|inhibitors]] are therefore an active area of [[drug discovery]] research.<ref>{{cite web | url = http://www.oncotherapynetwork.com/breast-cancer-targets/first-human-study-taking-place-fatty-acid-synthase-inhibitor | title = First Human Study Taking Place With Fatty Acid Synthase Inhibitor | publisher = oncotherapynetwork.com | date = April 7, 2017}}</ref><ref>{{cite journal | vauthors = 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 | title = Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy | journal = Bioorganic & Medicinal Chemistry Letters | volume = 28 | issue = 12 | pages = 2159–2164 | date = May 2018 | pmid = 29779975 | doi = 10.1016/j.bmcl.2018.05.014 | s2cid = 29159508 }}</ref><ref>{{cite journal | vauthors = 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 | title = A human fatty acid synthase inhibitor binds β-ketoacyl reductase in the keto-substrate site | journal = Nature Chemical Biology | volume = 10 | issue = 9 | pages = 774–779 | date = September 2014 | pmid = 25086508 | doi = 10.1038/nchembio.1603 }}</ref><ref name="Vander_Heiden_2017">{{cite journal | vauthors = Vander Heiden MG, DeBerardinis RJ | title = Understanding the Intersections between Metabolism and Cancer Biology | journal = Cell | volume = 168 | issue = 4 | pages = 657–669 | date = February 2017 | pmid = 28187287 | pmc = 5329766 | doi = 10.1016/j.cell.2016.12.039 }}</ref><ref>{{Cite thesis |title=An investigation into the interdomain region of Caenorhabditis elegans fatty acid synthase and its implications as a drug target |url=https://opal.latrobe.edu.au/articles/thesis/An_investigation_into_the_interdomain_region_of_Caenorhabditis_elegans_fatty_acid_synthase_and_its_implications_as_a_drug_target/21841695/1 |publisher=La Trobe |date=2009-01-01 |degree=thesis |language=en |first=Christopher David |last=Sgro}}</ref>

FAS may also be involved in the production of an endogenous [[ligand (biochemistry)|ligand]] for the nuclear receptor [[Peroxisome proliferator-activated receptor alpha|PPARalpha]], the target of the [[fibrate]] drugs for hyperlipidemia,<ref name="pmid19646743">{{cite journal | vauthors = Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J, Semenkovich CF | title = Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. | journal = Cell | volume = 138 | issue = 3 | pages = 476–488 | date = August 2009 | pmid = 19646743 | pmc = 2725194 | doi = 10.1016/j.cell.2009.05.036 }}</ref> and is being investigated as a possible drug target for treating the metabolic syndrome.<ref name="pmid21389266">{{cite journal | vauthors = 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 | title = Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes. | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 13 | pages = 5378–5383 | date = March 2011 | pmid = 21389266 | pmc = 3069196 | doi = 10.1073/pnas.1002588108 | bibcode = 2011PNAS..108.5378W | doi-access = free }}</ref> [[Orlistat]] which is a gastrointestinal lipase inhibitor also inhibits FAS and has a [[Discovery and development of gastrointestinal lipase inhibitors#Shift towards cancer treatment|potential as a medicine for cancer]].<ref name="FlavinR">{{cite journal | vauthors = Flavin R, Peluso S, Nguyen PL, Loda M | title = Fatty acid synthase as a potential therapeutic target in cancer | journal = Future Oncology | volume = 6 | issue = 4 | pages = 551–562 | date = April 2010 | pmid = 20373869 | pmc = 3197858 | doi = 10.2217/fon.10.11 }}</ref><ref name="RichardsonRD">{{cite journal | vauthors = Richardson RD, Ma G, Oyola Y, Zancanella M, Knowles LM, Cieplak P, Romo D, Smith JW | title = Synthesis of novel beta-lactone inhibitors of fatty acid synthase | journal = Journal of Medicinal Chemistry | volume = 51 | issue = 17 | pages = 5285–5296 | date = September 2008 | pmid = 18710210 | pmc = 3172131 | doi = 10.1021/jm800321h }}</ref>

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.<ref name="entrez"/>

An association with [[uterine leiomyomata]] has been reported.<ref name=Eggert2012>{{cite journal | vauthors = 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 | title = Genome-wide linkage and association analyses implicate FASN in predisposition to uterine leiomyomata | journal = American Journal of Human Genetics | volume = 91 | issue = 4 | pages = 621–628 | year = 2012 | pmid = 23040493 | pmc = 3484658 | doi = 10.1016/j.ajhg.2012.08.009 }}</ref>

==See also==
{{Portal|Biology}}
* [[Discovery and development of gastrointestinal lipase inhibitors]]
* [[Fatty acid synthesis]]
* [[Fatty acid metabolism]]
* [[Fatty acid degradation]]
* [[Enoyl-acyl carrier protein reductase]]
* [[List of fatty acid metabolism disorders]]

==References==
{{reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal | author = Wakil SJ | title = Fatty acid synthase, a proficient multifunctional enzyme | journal = Biochemistry | volume = 28 | issue = 11 | pages = 4523–4530 | year = 1989 | pmid = 2669958 | doi = 10.1021/bi00437a001 }}
*{{cite journal | vauthors = Baron A, Migita T, Tang D, Loda M | title = Fatty acid synthase: a metabolic oncogene in prostate cancer? | journal = Journal of Cellular Biochemistry | volume = 91 | issue = 1 | pages = 47–53 | year = 2004 | pmid = 14689581 | doi = 10.1002/jcb.10708 | s2cid = 26175683 }}
*{{cite journal | author = Lejin D | title = [Viscosimetry in clinical practice] | journal = Medicinski Pregled | volume = 30 | issue = 9–10 | pages = 477–482 | year = 1978 | pmid = 600212 }}
*{{cite journal | author = Wronkowski Z | title = [Cancer diagnosis of the respiratory system] | journal = Pielȩgniarka I Połozna | issue = 12 | pages = 7–8 | year = 1976 | pmid = 1044453 }}
*{{cite journal | vauthors = Semenkovich CF, Coleman T, Fiedorek FT | title = Human fatty acid synthase mRNA: tissue distribution, genetic mapping, and kinetics of decay after glucose deprivation | journal = Journal of Lipid Research | volume = 36 | issue = 7 | pages = 1507–1521 | year = 1995 | doi = 10.1016/S0022-2275(20)39738-8 | pmid = 7595075 | doi-access = free }}
*{{cite journal | vauthors = Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR | title = Fatty acid synthesis: a potential selective target for antineoplastic therapy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 14 | pages = 6379–6383 | year = 1994 | pmid = 8022791 | pmc = 44205 | doi = 10.1073/pnas.91.14.6379 | bibcode = 1994PNAS...91.6379K | doi-access = free }}
*{{cite journal | vauthors = Hsu MH, Chirala SS, Wakil SJ | title = Human fatty-acid synthase gene. Evidence for the presence of two promoters and their functional interaction | journal = Journal of Biological Chemistry | volume = 271 | issue = 23 | pages = 13584–13592 | year = 1996 | pmid = 8662758 | doi = 10.1074/jbc.271.23.13584 | doi-access = free }}
*{{cite journal | vauthors = Pizer ES, Kurman RJ, Pasternack GR, Kuhajda FP | title = Expression of fatty acid synthase is closely linked to proliferation and stromal decidualization in cycling endometrium | journal =   International Journal of Gynecological Pathology| volume = 16 | issue = 1 | pages = 45–51 | year = 1997 | pmid = 8986532 | doi = 10.1097/00004347-199701000-00008 | s2cid = 45195801 }}
*{{cite journal | vauthors = Jayakumar A, Chirala SS, Wakil SJ | title = Human fatty acid synthase: assembling recombinant halves of the fatty acid synthase subunit protein reconstitutes enzyme activity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 23 | pages = 12326–12330 | year = 1997 | pmid = 9356448 | pmc = 24928 | doi = 10.1073/pnas.94.23.12326 | bibcode = 1997PNAS...9412326J | doi-access = free }}
*{{cite journal | vauthors = Kusakabe T, Maeda M, Hoshi N, Sugino T, Watanabe K, Fukuda T, Suzuki T | title = Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells | journal = Journal of Histochemistry and Cytochemistry | volume = 48 | issue = 5 | pages = 613–622 | year = 2000 | pmid = 10769045 | doi = 10.1177/002215540004800505 | doi-access = free }}
*{{cite journal | vauthors = Ye Q, Chung LW, Li S, Zhau HE | title = Identification of a novel FAS/ER-alpha fusion transcript expressed in human cancer cells | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1493 | issue = 3 | pages = 373–377 | year = 2000 | pmid = 11018265 | doi = 10.1016/s0167-4781(00)00202-5 }}
*{{cite journal | vauthors = Rochat-Steiner V, Becker K, Micheau O, Schneider P, Burns K, Tschopp J | title = FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that induces FADD phosphorylation and inhibits fas-mediated Jun NH(2)-terminal kinase activation | journal = Journal of Experimental Medicine | volume = 192 | issue = 8 | pages = 1165–1174 | year = 2000 | pmid = 11034606 | pmc = 2311455 | doi = 10.1084/jem.192.8.1165 }}
*{{cite journal | vauthors = Chirala SS, Jayakumar A, Gu ZW, Wakil SJ | title = Human fatty acid synthase: role of interdomain in the formation of catalytically active synthase dimer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 6 | pages = 3104–3108 | year = 2001 | pmid = 11248039 | pmc = 30614 | doi = 10.1073/pnas.051635998 | bibcode = 2001PNAS...98.3104C | doi-access = free }}
*{{cite journal | vauthors = Brink J, Ludtke SJ, Yang CY, Gu ZW, Wakil SJ, Chiu W | title = Quaternary structure of human fatty acid synthase by electron cryomicroscopy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 1 | pages = 138–143 | year = 2002 | pmid = 11756679 | pmc = 117528 | doi = 10.1073/pnas.012589499 | bibcode = 2002PNAS...99..138B | doi-access = free }}
*{{cite journal | vauthors = Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P | title = Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors | journal = Journal of Biological Chemistry | volume = 277 | issue = 13 | pages = 11019–11025 | year = 2002 | pmid = 11790787 | doi = 10.1074/jbc.M111041200 | doi-access = free }}
*{{cite journal | vauthors = Ming D, Kong Y, Wakil SJ, Brink J, Ma J | title = Domain movements in human fatty acid synthase by quantized elastic deformational model | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 12 | pages = 7895–7899 | year = 2002 | pmid = 12060737 | pmc = 122991 | doi = 10.1073/pnas.112222299 | bibcode = 2002PNAS...99.7895M | doi-access = free }}
*{{cite journal | vauthors = Field FJ, Born E, Murthy S, Mathur SN | title = Polyunsaturated fatty acids decrease the expression of sterol regulatory element-binding protein-1 in CaCo-2 cells: effect on fatty acid synthesis and triacylglycerol transport | journal = Biochemical Journal | volume = 368 | issue = Pt 3 | pages = 855–864 | year = 2003 | pmid = 12213084 | pmc = 1223029 | doi = 10.1042/BJ20020731 }}
{{refend}}

==External links==
* {{MeshName|Fatty+Acid+Synthase}}
* [https://web.archive.org/web/20070420081705/http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/fasynthesis.htm Fatty Acid Synthesis: Rensselaer Polytechnic Institute]
* [http://www.rcsb.org/pdb/101/motm.do?momID=90 Fatty Acid Synthase: RCSB PDB Molecule of the Month] {{Webarchive|url=https://web.archive.org/web/20140714181017/http://www.rcsb.org/pdb/101/motm.do?momID=90 |date=2014-07-14 }} 
* [http://www.pdbe.org/emsearch/fatty%20acid%20synthase 3D electron microscopy structures of fatty acid synthase from the EM Data Bank(EMDB)]
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P49327 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Fatty acid synthase

{{PDB Gallery|geneid=2194}}
{{Multienzyme complexes}}
{{Lipid metabolism enzymes}}
{{Acyltransferases}}
{{Enzymes}}

[[Category:Transferases]]
[[Category:EC 2.3.1]]
[[Category:Metabolism]]
[[Category:Fatty acids]]
[[Category:NADPH-dependent enzymes]]
[[Category:Enzymes of known structure]]
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