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Fatty acid synthase

February 15, 2024

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

Fatty acid synthase
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EC no.2.3.1.85
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fatty acid synthase
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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.[1][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).[1]

Classes edit

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.[10]
  • 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.[11]

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.[10]

Structure edit

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.[13]

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 edit

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]

 
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 edit

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 edit

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 edit

References edit

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  24. ^ a b 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". Proceedings of the National Academy of Sciences of the United States of America. 107 (20): 9164–9169. Bibcode:2010PNAS..107.9164G. doi:10.1073/pnas.0913547107. PMC 2889056. PMID 20231485.
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Further reading edit

  • Wakil SJ (1989). "Fatty acid synthase, a proficient multifunctional enzyme". Biochemistry. 28 (11): 4523–4530. doi:10.1021/bi00437a001. PMID 2669958.
  • Baron A, Migita T, Tang D, Loda M (2004). "Fatty acid synthase: a metabolic oncogene in prostate cancer?". Journal of Cellular Biochemistry. 91 (1): 47–53. doi:10.1002/jcb.10708. PMID 14689581. S2CID 26175683.
  • Lejin D (1978). "[Viscosimetry in clinical practice]". Medicinski Pregled. 30 (9–10): 477–482. PMID 600212.
  • Wronkowski Z (1976). "[Cancer diagnosis of the respiratory system]". Pielȩgniarka I Połozna (12): 7–8. PMID 1044453.
  • Semenkovich CF, Coleman T, Fiedorek FT (1995). "Human fatty acid synthase mRNA: tissue distribution, genetic mapping, and kinetics of decay after glucose deprivation". Journal of Lipid Research. 36 (7): 1507–1521. doi:10.1016/S0022-2275(20)39738-8. PMID 7595075.
  • Kuhajda FP, Jenner K, Wood FD, Hennigar RA, Jacobs LB, Dick JD, Pasternack GR (1994). "Fatty acid synthesis: a potential selective target for antineoplastic therapy". Proceedings of the National Academy of Sciences of the United States of America. 91 (14): 6379–6383. Bibcode:1994PNAS...91.6379K. doi:10.1073/pnas.91.14.6379. PMC 44205. PMID 8022791.
  • Hsu MH, Chirala SS, Wakil SJ (1996). "Human fatty-acid synthase gene. Evidence for the presence of two promoters and their functional interaction". Journal of Biological Chemistry. 271 (23): 13584–13592. doi:10.1074/jbc.271.23.13584. PMID 8662758.
  • Pizer ES, Kurman RJ, Pasternack GR, Kuhajda FP (1997). "Expression of fatty acid synthase is closely linked to proliferation and stromal decidualization in cycling endometrium". International Journal of Gynecological Pathology. 16 (1): 45–51. doi:10.1097/00004347-199701000-00008. PMID 8986532. S2CID 45195801.
  • Jayakumar A, Chirala SS, Wakil SJ (1997). "Human fatty acid synthase: assembling recombinant halves of the fatty acid synthase subunit protein reconstitutes enzyme activity". Proceedings of the National Academy of Sciences of the United States of America. 94 (23): 12326–12330. Bibcode:1997PNAS...9412326J. doi:10.1073/pnas.94.23.12326. PMC 24928. PMID 9356448.
  • Kusakabe T, Maeda M, Hoshi N, Sugino T, Watanabe K, Fukuda T, Suzuki T (2000). "Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells". Journal of Histochemistry and Cytochemistry. 48 (5): 613–622. doi:10.1177/002215540004800505. PMID 10769045.
  • Ye Q, Chung LW, Li S, Zhau HE (2000). "Identification of a novel FAS/ER-alpha fusion transcript expressed in human cancer cells". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1493 (3): 373–377. doi:10.1016/s0167-4781(00)00202-5. PMID 11018265.
  • Rochat-Steiner V, Becker K, Micheau O, Schneider P, Burns K, Tschopp J (2000). "FIST/HIPK3: a Fas/FADD-interacting serine/threonine kinase that induces FADD phosphorylation and inhibits fas-mediated Jun NH(2)-terminal kinase activation". Journal of Experimental Medicine. 192 (8): 1165–1174. doi:10.1084/jem.192.8.1165. PMC 2311455. PMID 11034606.
  • Chirala SS, Jayakumar A, Gu ZW, Wakil SJ (2001). "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. Bibcode:2001PNAS...98.3104C. doi:10.1073/pnas.051635998. PMC 30614. PMID 11248039.
  • Brink J, Ludtke SJ, Yang CY, Gu ZW, Wakil SJ, Chiu W (2002). "Quaternary structure of human fatty acid synthase by electron cryomicroscopy". Proceedings of the National Academy of Sciences of the United States of America. 99 (1): 138–143. Bibcode:2002PNAS...99..138B. doi:10.1073/pnas.012589499. PMC 117528. PMID 11756679.
  • Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P (2002). "Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors". Journal of Biological Chemistry. 277 (13): 11019–11025. doi:10.1074/jbc.M111041200. PMID 11790787.
  • Ming D, Kong Y, Wakil SJ, Brink J, Ma J (2002). "Domain movements in human fatty acid synthase by quantized elastic deformational model". Proceedings of the National Academy of Sciences of the United States of America. 99 (12): 7895–7899. Bibcode:2002PNAS...99.7895M. doi:10.1073/pnas.112222299. PMC 122991. PMID 12060737.
  • Field FJ, Born E, Murthy S, Mathur SN (2003). "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". Biochemical Journal. 368 (Pt 3): 855–864. doi:10.1042/BJ20020731. PMC 1223029. PMID 12213084.

External links edit

  • Fatty+Acid+Synthase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • Fatty Acid Synthase: RCSB PDB Molecule of the Month 2014-07-14 at the Wayback Machine
  • 3D electron microscopy structures of fatty acid synthase from the EM Data Bank(EMDB)
  • PDBe-KB provides an overview of all the structure information available in the PDB for Human Fatty acid synthase

February 15, 2024
fatty, acid, synthase, enzyme, that, humans, encoded, fasn, gene, identifiersec, 85cas, 9045, 6databasesintenzintenz, viewbrendabrenda, entryexpasynicezyme, viewkeggkegg, entrymetacycmetabolic, pathwaypriamprofilepdb, structuresrcsb, pdbe, pdbsumgene, ontology. Fatty acid synthase FAS 1 is an enzyme that in humans is encoded by the FASN gene 2 3 4 5 Fatty acid synthaseIdentifiersEC no 2 3 1 85CAS no 9045 77 6DatabasesIntEnzIntEnz viewBRENDABRENDA entryExPASyNiceZyme viewKEGGKEGG entryMetaCycmetabolic pathwayPRIAMprofilePDB structuresRCSB PDB PDBe PDBsumGene OntologyAmiGO QuickGOSearchPMCarticlesPubMedarticlesNCBIproteinsfatty acid synthaseIdentifiersAliasesfatty acid synthasesExternal IDsGeneCards 1 OrthologsSpeciesHumanMouseEntrezn an aEnsembln an aUniProtnan aRefSeq mRNA n an aRefSeq protein n an aLocation UCSC n an aPubMed searchn an aWikidataView Edit HumanFatty 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 1 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 1 Contents 1 Classes 2 Structure 3 Substrate shuttling mechanism 4 Regulation 5 Clinical significance 6 See also 7 References 8 Further reading 9 External linksClasses editThere 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 10 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 11 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 10 Structure editMammalian 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 13 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 A resolution electron cryo microscopy cryo EM yeast FAS structure 24 have been solved Substrate shuttling mechanism editThe 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 nbsp 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 nbsp FAS head to tail model with positions of polypeptides three catalytic domains and their corresponding reactions visualization by Kosi Gramatikoff Regulation editMetabolism 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 editThe 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 edit nbsp Biology portalDiscovery 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 disordersReferences edit a b c Paiva P Medina FE Viegas M Ferreira P Neves RP Sousa JP Ramos MJ Fernandes PA 2021 08 11 Animal Fatty Acid Synthase A Chemical Nanofactory Chemical Reviews 121 15 9502 9553 doi 10 1021 acs chemrev 1c00147 ISSN 0009 2665 PMID 34156235 S2CID 235595027 Jayakumar A Chirala SS Chinault AC Baldini A Abu Elheiga L Wakil SJ February 1995 Isolation and chromosomal mapping of genomic clones encoding the human fatty acid synthase gene Genomics 23 2 420 424 doi 10 1006 geno 1994 1518 PMID 7835891 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 Proceedings of the National Academy of Sciences of the United States of America 92 19 8695 8699 Bibcode 1995PNAS 92 8695J doi 10 1073 pnas 92 19 8695 PMC 41033 PMID 7567999 Persson B Kallberg Y Bray JE Bruford E Dellaporta SL Favia AD Duarte RG Jornvall 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 Chemico Biological Interactions 178 1 3 94 98 doi 10 1016 j cbi 2008 10 040 PMC 2896744 PMID 19027726 a b c Entrez Gene FASN fatty acid synthase 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 Proceedings of the National Academy of Sciences of the United States of America 72 10 3956 3960 Bibcode 1975PNAS 72 3956A doi 10 1073 pnas 72 10 3956 PMC 433116 PMID 1060077 Stoops JK Arslanian MJ Oh YH Aune KC Vanaman TC Wakil SJ May 1975 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 Bibcode 1975PNAS 72 1940S doi 10 1073 pnas 72 5 1940 PMC 432664 PMID 1098047 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 Proceedings of the National Academy of Sciences of the United States of America 73 4 1184 1188 Bibcode 1976PNAS 73 1184S doi 10 1073 pnas 73 4 1184 PMC 430225 PMID 1063400 Smith S Witkowski A Joshi AK July 2003 Structural and functional organization of the animal fatty acid synthase Progress in Lipid Research 42 4 289 317 doi 10 1016 S0163 7827 02 00067 X PMID 12689621 a b Jenke Kodama H Sandmann A Muller R Dittmann E October 2005 Evolutionary implications of bacterial polyketide synthases Molecular Biology and Evolution 22 10 2027 2039 doi 10 1093 molbev msi193 PMID 15958783 Fulmer T March 2009 Not so FAS Science Business EXchange 2 11 430 doi 10 1038 scibx 2009 430 Stevens L Price NC 1999 Fundamentals of enzymology the cell and molecular biology of catalytic proteins Oxford Oxfordshire Oxford University Press ISBN 978 0 19 850229 6 a b 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 Proceedings of the National Academy of Sciences of the United States of America 98 6 3104 3108 Bibcode 2001PNAS 98 3104C doi 10 1073 pnas 051635998 PMC 30614 PMID 11248039 Smith S December 1994 The animal fatty acid synthase one gene one polypeptide seven enzymes FASEB Journal 8 15 1248 1259 doi 10 1096 fasebj 8 15 8001737 PMID 8001737 S2CID 22853095 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 Journal of Biological Chemistry 256 10 5128 5133 doi 10 1016 S0021 9258 19 69376 2 PMID 6112225 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 Journal of Biological Chemistry 257 6 3230 3235 doi 10 1016 S0021 9258 19 81100 6 PMID 7061475 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 Journal of Biological Chemistry 273 9 4937 4943 doi 10 1074 jbc 273 9 4937 PMID 9478938 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 18799 doi 10 1021 bi015535z PMID 11535054 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 Journal of Biological Chemistry 274 17 11557 11563 doi 10 1074 jbc 274 17 11557 PMID 10206962 Joshi AK Rangan VS Witkowski A Smith S February 2003 Engineering of an active animal fatty acid synthase dimer with only one competent subunit Chemistry and Biology 10 2 169 173 doi 10 1016 S1074 5521 03 00023 1 PMID 12618189 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 Nature Structural and Molecular Biology 12 3 225 232 doi 10 1038 nsmb899 PMID 15711565 S2CID 6132878 Maier T Leibundgut M Ban N September 2008 The crystal structure of a mammalian fatty acid synthase Science 321 5894 1315 1322 Bibcode 2008Sci 321 1315M doi 10 1126 science 1161269 PMID 18772430 S2CID 3168991 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 2 319 332 doi 10 1016 j cell 2007 03 013 PMID 17448991 S2CID 8209424 a b Gipson P Mills DJ Wouts R Grininger M Vonck J Kuhlbrandt W May 2010 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 Bibcode 2010PNAS 107 9164G doi 10 1073 pnas 0913547107 PMC 2889056 PMID 20231485 Anselmi C Grininger M Gipson P Faraldo Gomez JD September 2010 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 doi 10 1021 ja103354w PMID 20704262 Paulauskis JD Sul HS January 1989 Hormonal regulation of mouse fatty acid synthase gene transcription in liver Journal of Biological Chemistry 264 1 574 577 doi 10 1016 S0021 9258 17 31298 X PMID 2535847 a b 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 Molecular and Cellular Biology 23 16 5896 5907 doi 10 1128 MCB 23 16 5896 5907 2003 PMC 166350 PMID 12897158 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 Journal of Biological Chemistry 282 8 5453 5467 doi 10 1074 jbc M610566200 PMID 17197698 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 Molecular and Cellular Biology 21 9 2991 3000 doi 10 1128 MCB 21 9 2991 3000 2001 PMC 86928 PMID 11287605 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 amp Development 14 22 2819 2830 doi 10 1101 gad 844900 PMC 317055 PMID 11090130 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 Bioorganic amp Medicinal Chemistry Letters 16 18 4738 4742 doi 10 1016 j bmcl 2006 07 018 PMID 16870425 Baron A Migita T Tang D Loda M January 2004 Fatty acid synthase a metabolic oncogene in prostate cancer Journal of Cellular Biochemistry 91 1 47 53 doi 10 1002 jcb 10708 PMID 14689581 S2CID 26175683 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 Research 27 1A 27 34 PMID 17352212 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 Human Pathology 28 6 686 692 doi 10 1016 S0046 8177 97 90177 5 PMID 9191002 Ezzeddini R Taghikhani M Somi MH Samadi N Rasaee MJ May 2019 Clinical importance of FASN in relation to HIF 1a and SREBP 1c in gastric adenocarcinoma Life Sciences 224 169 176 doi 10 1016 j lfs 2019 03 056 PMID 30914315 S2CID 85532042 First Human Study Taking Place With Fatty Acid Synthase Inhibitor oncotherapynetwork com April 7 2017 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 May 2018 Design and synthesis of a series of bioavailable fatty acid synthase FASN KR domain inhibitors for cancer therapy Bioorganic amp Medicinal Chemistry Letters 28 12 2159 2164 doi 10 1016 j bmcl 2018 05 014 PMID 29779975 S2CID 29159508 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 September 2014 A human fatty acid synthase inhibitor binds b ketoacyl reductase in the keto substrate site Nature Chemical Biology 10 9 774 779 doi 10 1038 nchembio 1603 PMID 25086508 Vander Heiden MG DeBerardinis RJ February 2017 Understanding the Intersections between Metabolism and Cancer Biology Cell 168 4 657 669 doi 10 1016 j cell 2016 12 039 PMC 5329766 PMID 28187287 Sgro CD 2009 01 01 An investigation into the interdomain region of Caenorhabditis elegans fatty acid synthase and its implications as a drug target thesis thesis La Trobe 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 3 476 488 doi 10 1016 j cell 2009 05 036 PMC 2725194 PMID 19646743 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 Proceedings of the National Academy of Sciences of the United States of America 108 13 5378 5383 Bibcode 2011PNAS 108 5378W doi 10 1073 pnas 1002588108 PMC 3069196 PMID 21389266 Flavin R Peluso S Nguyen PL Loda M April 2010 Fatty acid synthase as a potential therapeutic target in cancer Future Oncology 6 4 551 562 doi 10 2217 fon 10 11 PMC 3197858 PMID 20373869 Richardson RD Ma G Oyola Y Zancanella M Knowles LM Cieplak P Romo D Smith JW September 2008 Synthesis of novel beta lactone inhibitors of fatty acid synthase Journal of Medicinal Chemistry 51 17 5285 5296 doi 10 1021 jm800321h PMC 3172131 PMID 18710210 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 American Journal of Human Genetics 91 4 621 628 doi 10 1016 j ajhg 2012 08 009 PMC 3484658 PMID 23040493 Further reading editWakil SJ 1989 Fatty acid synthase a proficient multifunctional enzyme Biochemistry 28 11 4523 4530 doi 10 1021 bi00437a001 PMID 2669958 Baron A Migita T Tang D Loda M 2004 Fatty acid synthase a metabolic oncogene in prostate cancer Journal of Cellular Biochemistry 91 1 47 53 doi 10 1002 jcb 10708 PMID 14689581 S2CID 26175683 Lejin D 1978 Viscosimetry in clinical practice Medicinski Pregled 30 9 10 477 482 PMID 600212 Wronkowski Z 1976 Cancer diagnosis of the respiratory system Pielȩgniarka I Polozna 12 7 8 PMID 1044453 Semenkovich CF Coleman T Fiedorek FT 1995 Human fatty acid synthase mRNA tissue distribution genetic mapping and kinetics of decay after glucose deprivation Journal of Lipid Research 36 7 1507 1521 doi 10 1016 S0022 2275 20 39738 8 PMID 7595075 Kuhajda FP Jenner K Wood FD Hennigar RA Jacobs LB Dick JD Pasternack GR 1994 Fatty acid synthesis a potential selective target for antineoplastic therapy Proceedings of the National Academy of Sciences of the United States of America 91 14 6379 6383 Bibcode 1994PNAS 91 6379K doi 10 1073 pnas 91 14 6379 PMC 44205 PMID 8022791 Hsu MH Chirala SS Wakil SJ 1996 Human fatty acid synthase gene Evidence for the presence of two promoters and their functional interaction Journal of Biological Chemistry 271 23 13584 13592 doi 10 1074 jbc 271 23 13584 PMID 8662758 Pizer ES Kurman RJ Pasternack GR Kuhajda FP 1997 Expression of fatty acid synthase is closely linked to proliferation and stromal decidualization in cycling endometrium International Journal of Gynecological Pathology 16 1 45 51 doi 10 1097 00004347 199701000 00008 PMID 8986532 S2CID 45195801 Jayakumar A Chirala SS Wakil SJ 1997 Human fatty acid synthase assembling recombinant halves of the fatty acid synthase subunit protein reconstitutes enzyme activity Proceedings of the National Academy of Sciences of the United States of America 94 23 12326 12330 Bibcode 1997PNAS 9412326J doi 10 1073 pnas 94 23 12326 PMC 24928 PMID 9356448 Kusakabe T Maeda M Hoshi N Sugino T Watanabe K Fukuda T Suzuki T 2000 Fatty acid synthase is expressed mainly in adult hormone sensitive cells or cells with high lipid metabolism and in proliferating fetal cells Journal of Histochemistry and Cytochemistry 48 5 613 622 doi 10 1177 002215540004800505 PMID 10769045 Ye Q Chung LW Li S Zhau HE 2000 Identification of a novel FAS ER alpha fusion transcript expressed in human cancer cells Biochimica et Biophysica Acta BBA Gene Structure and Expression 1493 3 373 377 doi 10 1016 s0167 4781 00 00202 5 PMID 11018265 Rochat Steiner V Becker K Micheau O Schneider P Burns K Tschopp J 2000 FIST HIPK3 a Fas FADD interacting serine threonine kinase that induces FADD phosphorylation and inhibits fas mediated Jun NH 2 terminal kinase activation Journal of Experimental Medicine 192 8 1165 1174 doi 10 1084 jem 192 8 1165 PMC 2311455 PMID 11034606 Chirala SS Jayakumar A Gu ZW Wakil SJ 2001 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 Bibcode 2001PNAS 98 3104C doi 10 1073 pnas 051635998 PMC 30614 PMID 11248039 Brink J Ludtke SJ Yang CY Gu ZW Wakil SJ Chiu W 2002 Quaternary structure of human fatty acid synthase by electron cryomicroscopy Proceedings of the National Academy of Sciences of the United States of America 99 1 138 143 Bibcode 2002PNAS 99 138B doi 10 1073 pnas 012589499 PMC 117528 PMID 11756679 Joseph SB Laffitte BA Patel PH Watson MA Matsukuma KE Walczak R Collins JL Osborne TF Tontonoz P 2002 Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors Journal of Biological Chemistry 277 13 11019 11025 doi 10 1074 jbc M111041200 PMID 11790787 Ming D Kong Y Wakil SJ Brink J Ma J 2002 Domain movements in human fatty acid synthase by quantized elastic deformational model Proceedings of the National Academy of Sciences of the United States of America 99 12 7895 7899 Bibcode 2002PNAS 99 7895M doi 10 1073 pnas 112222299 PMC 122991 PMID 12060737 Field FJ Born E Murthy S Mathur SN 2003 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 Biochemical Journal 368 Pt 3 855 864 doi 10 1042 BJ20020731 PMC 1223029 PMID 12213084 External links editFatty Acid Synthase at the U S National Library of Medicine Medical Subject Headings MeSH Fatty Acid Synthesis Rensselaer Polytechnic Institute Fatty Acid Synthase RCSB PDB Molecule of the Month Archived 2014 07 14 at the Wayback Machine 3D electron microscopy structures of fatty acid synthase from the EM Data Bank EMDB PDBe KB provides an overview of all the structure information available in the PDB for Human Fatty acid synthase Retrieved from https en wikipedia org w index php title Fatty acid synthase amp oldid 1193472167, wikipedia, wiki, book, books, library,

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