Full text data of FASN
FASN
(FAS)
[Confidence: low (only semi-automatic identification from reviews)]
Fatty acid synthase; 2.3.1.85; [Acyl-carrier-protein] S-acetyltransferase; 2.3.1.38; [Acyl-carrier-protein] S-malonyltransferase; 2.3.1.39; 3-oxoacyl-[acyl-carrier-protein] synthase; 2.3.1.41; 3-oxoacyl-[acyl-carrier-protein] reductase; 1.1.1.100; 3-hydroxyacyl-[acyl-carrier-protein] dehydratase; 4.2.1.59; Enoyl-[acyl-carrier-protein] reductase; 1.3.1.39; Oleoyl-[acyl-carrier-protein] hydrolase; 3.1.2.14
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Fatty acid synthase; 2.3.1.85; [Acyl-carrier-protein] S-acetyltransferase; 2.3.1.38; [Acyl-carrier-protein] S-malonyltransferase; 2.3.1.39; 3-oxoacyl-[acyl-carrier-protein] synthase; 2.3.1.41; 3-oxoacyl-[acyl-carrier-protein] reductase; 1.1.1.100; 3-hydroxyacyl-[acyl-carrier-protein] dehydratase; 4.2.1.59; Enoyl-[acyl-carrier-protein] reductase; 1.3.1.39; Oleoyl-[acyl-carrier-protein] hydrolase; 3.1.2.14
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P49327
ID FAS_HUMAN Reviewed; 2511 AA.
AC P49327; Q13479; Q16702; Q4LE83; Q6P4U5; Q6SS02; Q969R1; Q96C68;
read moreAC Q96IT0;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 3.
DT 22-JAN-2014, entry version 157.
DE RecName: Full=Fatty acid synthase;
DE EC=2.3.1.85;
DE Includes:
DE RecName: Full=[Acyl-carrier-protein] S-acetyltransferase;
DE EC=2.3.1.38;
DE Includes:
DE RecName: Full=[Acyl-carrier-protein] S-malonyltransferase;
DE EC=2.3.1.39;
DE Includes:
DE RecName: Full=3-oxoacyl-[acyl-carrier-protein] synthase;
DE EC=2.3.1.41;
DE Includes:
DE RecName: Full=3-oxoacyl-[acyl-carrier-protein] reductase;
DE EC=1.1.1.100;
DE Includes:
DE RecName: Full=3-hydroxyacyl-[acyl-carrier-protein] dehydratase;
DE EC=4.2.1.59;
DE Includes:
DE RecName: Full=Enoyl-[acyl-carrier-protein] reductase;
DE EC=1.3.1.39;
DE Includes:
DE RecName: Full=Oleoyl-[acyl-carrier-protein] hydrolase;
DE EC=3.1.2.14;
GN Name=FASN; Synonyms=FAS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, PHOSPHOPANTETHEINE
RP CONTENT, AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=7567999; DOI=10.1073/pnas.92.19.8695;
RA Jayakumar A., Tai M.-H., Huang W.-Y., Al-Feel W., Hsu M.,
RA Abu-Elheiga L., Chirala S.S., Wakil S.J.;
RT "Human fatty acid synthase: properties and molecular cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:8695-8699(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Hennigar R.A., Jenner K.H., Heine H.S., Kayler A.E., Wood F.D.,
RA Kuhajda F.P., Pasternack G.R.;
RT "Molecular cloning of tumor-associated human fatty acid synthase.";
RL Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Mao J., Wakil S.J.;
RT "Recharacterization of the human fatty acid synthase (FAS) gene.";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Nakajima D., Saito K., Yamakawa H., Kikuno R.F., Nakayama M.,
RA Ohara R., Okazaki N., Koga H., Nagase T., Ohara O.;
RT "Preparation of a set of expression-ready clones of mammalian long
RT cDNAs encoding large proteins by the ORF trap cloning method.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 1-12; 647-666; 791-802; 1242-1255; 1338-1349 AND
RP 2126-2138, ACETYLATION AT MET-1, AND MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (JUL-2005) to UniProtKB.
RN [8]
RP PROTEIN SEQUENCE OF 753-758 AND 1285-1297.
RX PubMed=8022791; DOI=10.1073/pnas.91.14.6379;
RA Kuhajda F.P., Jenner K., Wood F.D., Hennigar R.A., Jacobs L.B.,
RA Dick J.D., Pasternack G.R.;
RT "Fatty acid synthesis: a potential selective target for antineoplastic
RT therapy.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:6379-6383(1994).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2047-2511, AND TISSUE SPECIFICITY.
RX PubMed=7595075;
RA Semenkovich C.F., Coleman T., Fiedorek F.T. Jr.;
RT "Human fatty acid synthase mRNA: tissue distribution, genetic mapping,
RT and kinetics of decay after glucose deprivation.";
RL J. Lipid Res. 36:1507-1521(1995).
RN [10]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2198 AND THR-2204, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-207; SER-2198; THR-2204
RP AND SER-2236, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-2204, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-70; LYS-298; LYS-436;
RP LYS-528; LYS-673; LYS-1704; LYS-1771; LYS-1847 AND LYS-1995, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP 3D-STRUCTURE MODELING, AND STRUCTURE BY ELECTRON CRYOMICROSCOPY.
RX PubMed=11756679; DOI=10.1073/pnas.012589499;
RA Brink J., Ludtke S.J., Yang C.Y., Gu Z.-W., Wakil S.J., Chiu W.;
RT "Quaternary structure of human fatty acid synthase by electron
RT cryomicroscopy.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:138-143(2002).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 2218-2502.
RX PubMed=15507492; DOI=10.1073/pnas.0406901101;
RA Chakravarty B., Gu Z., Chirala S.S., Wakil S.J., Quiocho F.A.;
RT "Human fatty acid synthase: structure and substrate selectivity of the
RT thioesterase domain.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15567-15572(2004).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 2119-2207 IN COMPLEX WITH
RP AASDHPPT AND COENZYME A.
RX PubMed=18022563; DOI=10.1016/j.chembiol.2007.10.013;
RA Bunkoczi G., Pasta S., Joshi A., Wu X., Kavanagh K.L., Smith S.,
RA Oppermann U.;
RT "Mechanism and substrate recognition of human holo ACP synthase.";
RL Chem. Biol. 14:1243-1253(2007).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 2200-2511 IN COMPLEX WITH
RP ORLISTAT, AND ACTIVE SITE FOR THIOESTERASE ACTIVITY.
RX PubMed=17618296; DOI=10.1038/nsmb1265;
RA Pemble C.W. IV, Johnson L.C., Kridel S.J., Lowther W.T.;
RT "Crystal structure of the thioesterase domain of human fatty acid
RT synthase inhibited by Orlistat.";
RL Nat. Struct. Mol. Biol. 14:704-709(2007).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 422-831 IN COMPLEX WITH
RP MALONYL-COENZYME A.
RG Structural genomics consortium (SGC);
RT "Structure of the MAT domain of human FAS with malonyl-CoA.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Fatty acid synthetase catalyzes the formation of long-
CC chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This
CC multifunctional protein has 7 catalytic activities and an acyl
CC carrier protein.
CC -!- CATALYTIC ACTIVITY: Acetyl-CoA + n malonyl-CoA + 2n NADPH = a
CC long-chain fatty acid + (n+1) CoA + n CO(2) + 2n NADP(+).
CC -!- CATALYTIC ACTIVITY: Acetyl-CoA + [acyl-carrier-protein] = CoA +
CC acetyl-[acyl-carrier-protein].
CC -!- CATALYTIC ACTIVITY: Malonyl-CoA + [acyl-carrier-protein] = CoA +
CC malonyl-[acyl-carrier-protein].
CC -!- CATALYTIC ACTIVITY: Acyl-[acyl-carrier-protein] + malonyl-[acyl-
CC carrier-protein] = 3-oxoacyl-[acyl-carrier-protein] + CO(2) +
CC [acyl-carrier-protein].
CC -!- CATALYTIC ACTIVITY: (3R)-3-hydroxyacyl-[acyl-carrier-protein] +
CC NADP(+) = 3-oxoacyl-[acyl-carrier-protein] + NADPH.
CC -!- CATALYTIC ACTIVITY: A (3R)-3-hydroxyacyl-[acyl-carrier protein] =
CC a trans-2-enoyl-[acyl-carrier protein] + H(2)O.
CC -!- CATALYTIC ACTIVITY: An acyl-[acyl-carrier protein] + NADP(+) = a
CC trans-2,3-dehydroacyl-[acyl-carrier protein] + NADPH.
CC -!- CATALYTIC ACTIVITY: Oleoyl-[acyl-carrier-protein] + H(2)O = [acyl-
CC carrier-protein] + oleate.
CC -!- SUBUNIT: Homodimer which is arranged in a head to tail fashion.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Melanosome. Note=Identified by
CC mass spectrometry in melanosome fractions from stage I to stage
CC IV.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Prominent expression in brain,
CC lung, and liver.
CC -!- MISCELLANEOUS: The relatively low beta-ketoacyl synthase activity
CC may be attributable to the low 4'-phosphopantetheine content of
CC the protein.
CC -!- SIMILARITY: Contains 1 acyl carrier domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB35516.1; Type=Erroneous initiation;
CC Sequence=AAC50259.1; Type=Miscellaneous discrepancy; Note=Several sequencing errors;
CC Sequence=BAE06070.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U26644; AAC50259.1; ALT_SEQ; mRNA.
DR EMBL; U29344; AAA73576.1; -; mRNA.
DR EMBL; AY451392; AAS09886.1; -; mRNA.
DR EMBL; AB209988; BAE06070.1; ALT_INIT; mRNA.
DR EMBL; AC135056; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC007267; AAH07267.1; -; mRNA.
DR EMBL; BC007909; AAH07909.1; -; mRNA.
DR EMBL; BC014634; AAH14634.2; -; mRNA.
DR EMBL; BC063242; AAH63242.1; -; mRNA.
DR EMBL; S80437; AAB35516.1; ALT_INIT; mRNA.
DR PIR; A57788; A57788.
DR PIR; G01880; G01880.
DR RefSeq; NP_004095.4; NM_004104.4.
DR UniGene; Hs.83190; -.
DR PDB; 1XKT; X-ray; 2.60 A; A/B=2218-2502.
DR PDB; 2CG5; X-ray; 2.70 A; B=2119-2207.
DR PDB; 2JFD; X-ray; 2.81 A; A/B/C/D=422-823.
DR PDB; 2JFK; X-ray; 2.40 A; A/B/C/D=422-831.
DR PDB; 2PX6; X-ray; 2.30 A; A/B=2200-2511.
DR PDB; 3HHD; X-ray; 2.15 A; A/B/C/D=2-963.
DR PDB; 3TJM; X-ray; 1.48 A; A=2218-2500.
DR PDBsum; 1XKT; -.
DR PDBsum; 2CG5; -.
DR PDBsum; 2JFD; -.
DR PDBsum; 2JFK; -.
DR PDBsum; 2PX6; -.
DR PDBsum; 3HHD; -.
DR PDBsum; 3TJM; -.
DR ProteinModelPortal; P49327; -.
DR SMR; P49327; 2-853, 1220-2114, 2124-2194, 2218-2491.
DR DIP; DIP-33681N; -.
DR IntAct; P49327; 24.
DR MINT; MINT-1146154; -.
DR ChEMBL; CHEMBL4158; -.
DR DrugBank; DB01034; Cerulenin.
DR DrugBank; DB01083; Orlistat.
DR DrugBank; DB00339; Pyrazinamide.
DR PhosphoSite; P49327; -.
DR DMDM; 269849686; -.
DR PaxDb; P49327; -.
DR PRIDE; P49327; -.
DR DNASU; 2194; -.
DR Ensembl; ENST00000306749; ENSP00000304592; ENSG00000169710.
DR GeneID; 2194; -.
DR KEGG; hsa:2194; -.
DR UCSC; uc002kdu.3; human.
DR CTD; 2194; -.
DR GeneCards; GC17M080037; -.
DR H-InvDB; HIX0014269; -.
DR HGNC; HGNC:3594; FASN.
DR HPA; CAB005192; -.
DR HPA; CAB015417; -.
DR HPA; HPA006461; -.
DR MIM; 600212; gene.
DR neXtProt; NX_P49327; -.
DR PharmGKB; PA28006; -.
DR eggNOG; COG3319; -.
DR HOVERGEN; HBG005640; -.
DR InParanoid; P49327; -.
DR KO; K00665; -.
DR OMA; GLRTAQW; -.
DR OrthoDB; EOG71K623; -.
DR PhylomeDB; P49327; -.
DR BioCyc; MetaCyc:HS09992-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; P49327; -.
DR ChiTaRS; FASN; human.
DR EvolutionaryTrace; P49327; -.
DR GeneWiki; Fatty_acid_synthase; -.
DR GenomeRNAi; 2194; -.
DR NextBio; 8869; -.
DR PRO; PR:P49327; -.
DR Bgee; P49327; -.
DR CleanEx; HS_FAS; -.
DR CleanEx; HS_FASN; -.
DR Genevestigator; P49327; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0042587; C:glycogen granule; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0047451; F:3-hydroxyoctanoyl-[acyl-carrier-protein] dehydratase activity; IEA:UniProtKB-EC.
DR GO; GO:0004317; F:3-hydroxypalmitoyl-[acyl-carrier-protein] dehydratase activity; IEA:InterPro.
DR GO; GO:0004316; F:3-oxoacyl-[acyl-carrier-protein] reductase (NADPH) activity; IEA:UniProtKB-EC.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:UniProtKB-EC.
DR GO; GO:0004313; F:[acyl-carrier-protein] S-acetyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0004314; F:[acyl-carrier-protein] S-malonyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0008144; F:drug binding; IEA:Ensembl.
DR GO; GO:0047117; F:enoyl-[acyl-carrier-protein] reductase (NADPH, A-specific) activity; IEA:UniProtKB-EC.
DR GO; GO:0004319; F:enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific) activity; IEA:InterPro.
DR GO; GO:0004312; F:fatty acid synthase activity; TAS:Reactome.
DR GO; GO:0016295; F:myristoyl-[acyl-carrier-protein] hydrolase activity; IEA:UniProtKB-EC.
DR GO; GO:0070402; F:NADPH binding; IEA:Ensembl.
DR GO; GO:0004320; F:oleoyl-[acyl-carrier-protein] hydrolase activity; IEA:UniProtKB-EC.
DR GO; GO:0016296; F:palmitoyl-[acyl-carrier-protein] hydrolase activity; IEA:UniProtKB-EC.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006084; P:acetyl-CoA metabolic process; IEA:Ensembl.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006631; P:fatty acid metabolic process; TAS:ProtInc.
DR GO; GO:0035338; P:long-chain fatty-acyl-CoA biosynthetic process; TAS:Reactome.
DR GO; GO:0015939; P:pantothenate metabolic process; TAS:Reactome.
DR GO; GO:0031325; P:positive regulation of cellular metabolic process; TAS:Reactome.
DR GO; GO:0019432; P:triglyceride biosynthetic process; TAS:Reactome.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 1.10.1470.20; -; 1.
DR Gene3D; 3.40.366.10; -; 2.
DR Gene3D; 3.40.47.10; -; 2.
DR Gene3D; 3.40.50.720; -; 2.
DR InterPro; IPR001227; Ac_transferase_dom.
DR InterPro; IPR009081; Acyl_carrier_prot-like.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR013149; ADH_C.
DR InterPro; IPR002198; DH_sc/Rdtase_SDR.
DR InterPro; IPR023102; Fatty_acid_synthase_dom_2.
DR InterPro; IPR011032; GroES-like.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR013217; Methyltransf_12.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR020842; PKS/FAS_KR.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR006162; PPantetheine_attach_site.
DR InterPro; IPR001031; Thioesterase.
DR InterPro; IPR016039; Thiolase-like.
DR InterPro; IPR016038; Thiolase-like_subgr.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00106; adh_short; 1.
DR Pfam; PF00107; ADH_zinc_N; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF00975; Thioesterase; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00822; PKS_KR; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF52151; SSF52151; 2.
DR SUPFAM; SSF53901; SSF53901; 2.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS50075; ACP_DOMAIN; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Fatty acid biosynthesis;
KW Fatty acid metabolism; Hydrolase; Lipid biosynthesis;
KW Lipid metabolism; Lyase; Multifunctional enzyme; NAD; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein; Polymorphism;
KW Pyridoxal phosphate; Reference proteome; Transferase.
FT CHAIN 1 2511 Fatty acid synthase.
FT /FTId=PRO_0000180276.
FT DOMAIN 2123 2179 Acyl carrier.
FT NP_BIND 1671 1688 NADP (ER) (By similarity).
FT NP_BIND 1886 1901 NADP (KR) (By similarity).
FT REGION 1 414 Beta-ketoacyl synthase (By similarity).
FT REGION 429 817 Acyl and malonyl transferases (By
FT similarity).
FT REGION 1635 1863 Enoyl reductase (By similarity).
FT REGION 1864 2118 Beta-ketoacyl reductase (By similarity).
FT REGION 2207 2511 Thioesterase (By similarity).
FT ACT_SITE 161 161 For beta-ketoacyl synthase activity (By
FT similarity).
FT ACT_SITE 581 581 For malonyltransferase activity (By
FT similarity).
FT ACT_SITE 878 878 For beta-hydroxyacyl dehydratase activity
FT (By similarity).
FT ACT_SITE 2308 2308 For thioesterase activity.
FT ACT_SITE 2481 2481 For thioesterase activity (By
FT similarity).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 70 70 N6-acetyllysine.
FT MOD_RES 207 207 Phosphoserine.
FT MOD_RES 298 298 N6-acetyllysine.
FT MOD_RES 436 436 N6-acetyllysine.
FT MOD_RES 528 528 N6-acetyllysine.
FT MOD_RES 673 673 N6-acetyllysine.
FT MOD_RES 1704 1704 N6-(pyridoxal phosphate)lysine; alternate
FT (By similarity).
FT MOD_RES 1704 1704 N6-acetyllysine; alternate.
FT MOD_RES 1771 1771 N6-acetyllysine.
FT MOD_RES 1847 1847 N6-acetyllysine.
FT MOD_RES 1995 1995 N6-acetyllysine.
FT MOD_RES 2156 2156 O-(pantetheine 4'-phosphoryl)serine (By
FT similarity).
FT MOD_RES 2198 2198 Phosphoserine.
FT MOD_RES 2204 2204 Phosphothreonine.
FT MOD_RES 2236 2236 Phosphoserine.
FT VARIANT 1483 1483 V -> I (in dbSNP:rs2228305).
FT /FTId=VAR_055479.
FT VARIANT 1694 1694 R -> H (in dbSNP:rs2229424).
FT /FTId=VAR_055480.
FT VARIANT 1888 1888 I -> V (in dbSNP:rs2228307).
FT /FTId=VAR_055481.
FT CONFLICT 459 462 AVPA -> LSPT (in Ref. 2; AAA73576).
FT CONFLICT 528 529 KP -> NR (in Ref. 2; AAA73576).
FT CONFLICT 637 637 G -> A (in Ref. 2; AAA73576).
FT CONFLICT 801 801 G -> R (in Ref. 2; AAA73576).
FT CONFLICT 902 902 A -> P (in Ref. 2; AAA73576).
FT CONFLICT 958 958 V -> M (in Ref. 3; AAS09886).
FT CONFLICT 1121 1121 P -> S (in Ref. 2; AAA73576 and 3;
FT AAS09886).
FT CONFLICT 1151 1151 K -> T (in Ref. 6; AAH63242).
FT CONFLICT 1353 1356 LGDI -> SGH (in Ref. 2; AAA73576).
FT CONFLICT 1386 1386 L -> V (in Ref. 2; AAA73576).
FT CONFLICT 1467 1468 NR -> T (in Ref. 2; AAA73576).
FT CONFLICT 1827 1827 K -> E (in Ref. 3; AAS09886).
FT CONFLICT 1934 1934 R -> A (in Ref. 2; AAA73576).
FT CONFLICT 2065 2065 D -> H (in Ref. 9; AAB35516).
FT CONFLICT 2087 2087 R -> A (in Ref. 2; AAA73576).
FT CONFLICT 2363 2363 A -> P (in Ref. 9; AAB35516).
FT CONFLICT 2428 2428 R -> G (in Ref. 2; AAA73576).
FT CONFLICT 2453 2453 A -> T (in Ref. 9; AAB35516).
FT CONFLICT 2456 2456 E -> Q (in Ref. 9; AAB35516).
FT STRAND 4 13
FT STRAND 16 18
FT HELIX 19 27
FT STRAND 36 40
FT HELIX 44 46
FT TURN 62 66
FT HELIX 69 73
FT HELIX 77 92
FT HELIX 97 100
FT STRAND 106 110
FT HELIX 115 120
FT TURN 124 126
FT HELIX 130 135
FT HELIX 139 148
FT STRAND 154 158
FT HELIX 160 162
FT HELIX 163 176
FT STRAND 181 189
FT HELIX 194 202
FT STRAND 227 235
FT HELIX 236 238
FT STRAND 243 253
FT HELIX 266 279
FT HELIX 284 286
FT STRAND 287 291
FT HELIX 300 312
FT STRAND 320 323
FT HELIX 326 329
FT HELIX 333 335
FT HELIX 336 350
FT HELIX 367 370
FT STRAND 373 376
FT STRAND 387 393
FT STRAND 397 406
FT HELIX 416 419
FT STRAND 422 430
FT HELIX 431 443
FT TURN 444 446
FT HELIX 448 457
FT TURN 462 464
FT STRAND 467 477
FT STRAND 481 484
FT STRAND 492 496
FT TURN 504 509
FT HELIX 510 512
FT HELIX 514 527
FT HELIX 528 530
FT HELIX 534 539
FT HELIX 545 547
FT HELIX 549 569
FT STRAND 575 579
FT HELIX 583 590
FT HELIX 596 611
FT STRAND 618 625
FT HELIX 627 633
FT STRAND 639 645
FT STRAND 648 654
FT HELIX 655 667
FT STRAND 672 675
FT STRAND 677 679
FT HELIX 685 690
FT HELIX 691 701
FT STRAND 702 704
FT STRAND 715 717
FT HELIX 719 721
FT HELIX 725 728
FT HELIX 732 740
FT HELIX 745 749
FT STRAND 757 764
FT HELIX 768 774
FT STRAND 780 783
FT HELIX 792 805
FT HELIX 812 815
FT HELIX 831 833
FT HELIX 847 849
FT HELIX 2127 2134
FT TURN 2149 2153
FT HELIX 2156 2170
FT HELIX 2176 2180
FT HELIX 2184 2192
FT HELIX 2219 2222
FT STRAND 2230 2233
FT STRAND 2239 2241
FT STRAND 2244 2247
FT HELIX 2255 2257
FT HELIX 2258 2263
FT STRAND 2268 2271
FT HELIX 2282 2293
FT TURN 2294 2296
FT STRAND 2303 2307
FT HELIX 2309 2325
FT STRAND 2333 2338
FT HELIX 2343 2352
FT HELIX 2360 2375
FT HELIX 2380 2387
FT STRAND 2390 2392
FT HELIX 2393 2407
FT HELIX 2413 2432
FT STRAND 2443 2447
FT TURN 2459 2463
FT HELIX 2464 2466
FT STRAND 2472 2476
FT HELIX 2483 2485
FT HELIX 2487 2499
SQ SEQUENCE 2511 AA; 273427 MW; 7A07171FEFA3287B CRC64;
MEEVVIAGMS GKLPESENLQ EFWDNLIGGV DMVTDDDRRW KAGLYGLPRR SGKLKDLSRF
DASFFGVHPK QAHTMDPQLR LLLEVTYEAI VDGGINPDSL RGTHTGVWVG VSGSETSEAL
SRDPETLVGY SMVGCQRAMM ANRLSFFFDF RGPSIALDTA CSSSLMALQN AYQAIHSGQC
PAAIVGGINV LLKPNTSVQF LRLGMLSPEG TCKAFDTAGN GYCRSEGVVA VLLTKKSLAR
RVYATILNAG TNTDGFKEQG VTFPSGDIQE QLIRSLYQSA GVAPESFEYI EAHGTGTKVG
DPQELNGITR ALCATRQEPL LIGSTKSNMG HPEPASGLAA LAKVLLSLEH GLWAPNLHFH
SPNPEIPALL DGRLQVVDQP LPVRGGNVGI NSFGFGGSNV HIILRPNTQP PPAPAPHATL
PRLLRASGRT PEAVQKLLEQ GLRHSQDLAF LSMLNDIAAV PATAMPFRGY AVLGGERGGP
EVQQVPAGER PLWFICSGMG TQWRGMGLSL MRLDRFRDSI LRSDEAVKPF GLKVSQLLLS
TDESTFDDIV HSFVSLTAIQ IGLIDLLSCM GLRPDGIVGH SLGEVACGYA DGCLSQEEAV
LAAYWRGQCI KEAHLPPGAM AAVGLSWEEC KQRCPPGVVP ACHNSKDTVT ISGPQAPVFE
FVEQLRKEGV FAKEVRTGGM AFHSYFMEAI APPLLQELKK VIREPKPRSA RWLSTSIPEA
QWHSSLARTS SAEYNVNNLV SPVLFQEALW HVPEHAVVLE IAPHALLQAV LKRGLKPSCT
IIPLMKKDHR DNLEFFLAGI GRLHLSGIDA NPNALFPPVE FPAPRGTPLI SPLIKWDHSL
AWDVPAAEDF PNGSGSPSAA IYNIDTSSES PDHYLVDHTL DGRVLFPATG YLSIVWKTLA
RALGLGVEQL PVVFEDVVLH QATILPKTGT VSLEVRLLEA SRAFEVSENG NLVVSGKVYQ
WDDPDPRLFD HPESPTPNPT EPLFLAQAEV YKELRLRGYD YGPHFQGILE ASLEGDSGRL
LWKDNWVSFM DTMLQMSILG SAKHGLYLPT RVTAIHIDPA THRQKLYTLQ DKAQVADVVV
SRWLRVTVAG GVHISGLHTE SAPRRQQEQQ VPILEKFCFT PHTEEGCLSE RAALQEELQL
CKGLVQALQT KVTQQGLKMV VPGLDGAQIP RDPSQQELPR LLSAACRLQL NGNLQLELAQ
VLAQERPKLP EDPLLSGLLD SPALKACLDT AVENMPSLKM KVVEVLAGHG HLYSRIPGLL
SPHPLLQLSY TATDRHPQAL EAAQAELQQH DVAQGQWDPA DPAPSALGSA DLLVCNCAVA
ALGDPASALS NMVAALREGG FLLLHTLLRG HPLGDIVAFL TSTEPQYGQG ILSQDAWESL
FSRVSLRLVG LKKSFYGSTL FLCRRPTPQD SPIFLPVDDT SFRWVESLKG ILADEDSSRP
VWLKAINCAT SGVVGLVNCL RREPGGNRLR CVLLSNLSST SHVPEVDPGS AELQKVLQGD
LVMNVYRDGA WGAFRHFLLE EDKPEEPTAH AFVSTLTRGD LSSIRWVCSS LRHAQPTCPG
AQLCTVYYAS LNFRDIMLAT GKLSPDAIPG KWTSQDSLLG MEFSGRDASG KRVMGLVPAK
GLATSVLLSP DFLWDVPSNW TLEEAASVPV VYSTAYYALV VRGRVRPGET LLIHSGSGGV
GQAAIAIALS LGCRVFTTVG SAEKRAYLQA RFPQLDSTSF ANSRDTSFEQ HVLWHTGGKG
VDLVLNSLAE EKLQASVRCL ATHGRFLEIG KFDLSQNHPL GMAIFLKNVT FHGVLLDAFF
NESSADWREV WALVQAGIRD GVVRPLKCTV FHGAQVEDAF RYMAQGKHIG KVVVQVLAEE
PEAVLKGAKP KLMSAISKTF CPAHKSYIIA GGLGGFGLEL AQWLIQRGVQ KLVLTSRSGI
RTGYQAKQVR RWRRQGVQVQ VSTSNISSLE GARGLIAEAA QLGPVGGVFN LAVVLRDGLL
ENQTPEFFQD VCKPKYSGTL NLDRVTREAC PELDYFVVFS SVSCGRGNAG QSNYGFANSA
MERICEKRRH EGLPGLAVQW GAIGDVGILV ETMSTNDTIV SGTLPQRMAS CLEVLDLFLN
QPHMVLSSFV LAEKAAAYRD RDSQRDLVEA VAHILGIRDL AAVNLDSSLA DLGLDSLMSV
EVRQTLEREL NLVLSVREVR QLTLRKLQEL SSKADEASEL ACPTPKEDGL AQQQTQLNLR
SLLVNPEGPT LMRLNSVQSS ERPLFLVHPI EGSTTVFHSL ASRLSIPTYG LQCTRAAPLD
SIHSLAAYYI DCIRQVQPEG PYRVAGYSYG ACVAFEMCSQ LQAQQSPAPT HNSLFLFDGS
PTYVLAYTQS YRAKLTPGCE AEAETEAICF FVQQFTDMEH NRVLEALLPL KGLEERVAAA
VDLIIKSHQG LDRQELSFAA RSFYYKLRAA EQYTPKAKYH GNVMLLRAKT GGAYGEDLGA
DYNLSQVCDG KVSVHVIEGD HRTLLEGSGL ESIISIIHSS LAEPRVSVRE G
//
ID FAS_HUMAN Reviewed; 2511 AA.
AC P49327; Q13479; Q16702; Q4LE83; Q6P4U5; Q6SS02; Q969R1; Q96C68;
read moreAC Q96IT0;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 24-NOV-2009, sequence version 3.
DT 22-JAN-2014, entry version 157.
DE RecName: Full=Fatty acid synthase;
DE EC=2.3.1.85;
DE Includes:
DE RecName: Full=[Acyl-carrier-protein] S-acetyltransferase;
DE EC=2.3.1.38;
DE Includes:
DE RecName: Full=[Acyl-carrier-protein] S-malonyltransferase;
DE EC=2.3.1.39;
DE Includes:
DE RecName: Full=3-oxoacyl-[acyl-carrier-protein] synthase;
DE EC=2.3.1.41;
DE Includes:
DE RecName: Full=3-oxoacyl-[acyl-carrier-protein] reductase;
DE EC=1.1.1.100;
DE Includes:
DE RecName: Full=3-hydroxyacyl-[acyl-carrier-protein] dehydratase;
DE EC=4.2.1.59;
DE Includes:
DE RecName: Full=Enoyl-[acyl-carrier-protein] reductase;
DE EC=1.3.1.39;
DE Includes:
DE RecName: Full=Oleoyl-[acyl-carrier-protein] hydrolase;
DE EC=3.1.2.14;
GN Name=FASN; Synonyms=FAS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, PHOSPHOPANTETHEINE
RP CONTENT, AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=7567999; DOI=10.1073/pnas.92.19.8695;
RA Jayakumar A., Tai M.-H., Huang W.-Y., Al-Feel W., Hsu M.,
RA Abu-Elheiga L., Chirala S.S., Wakil S.J.;
RT "Human fatty acid synthase: properties and molecular cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:8695-8699(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Hennigar R.A., Jenner K.H., Heine H.S., Kayler A.E., Wood F.D.,
RA Kuhajda F.P., Pasternack G.R.;
RT "Molecular cloning of tumor-associated human fatty acid synthase.";
RL Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Mao J., Wakil S.J.;
RT "Recharacterization of the human fatty acid synthase (FAS) gene.";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Nakajima D., Saito K., Yamakawa H., Kikuno R.F., Nakayama M.,
RA Ohara R., Okazaki N., Koga H., Nagase T., Ohara O.;
RT "Preparation of a set of expression-ready clones of mammalian long
RT cDNAs encoding large proteins by the ORF trap cloning method.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 1-12; 647-666; 791-802; 1242-1255; 1338-1349 AND
RP 2126-2138, ACETYLATION AT MET-1, AND MASS SPECTROMETRY.
RC TISSUE=B-cell lymphoma;
RA Bienvenut W.V.;
RL Submitted (JUL-2005) to UniProtKB.
RN [8]
RP PROTEIN SEQUENCE OF 753-758 AND 1285-1297.
RX PubMed=8022791; DOI=10.1073/pnas.91.14.6379;
RA Kuhajda F.P., Jenner K., Wood F.D., Hennigar R.A., Jacobs L.B.,
RA Dick J.D., Pasternack G.R.;
RT "Fatty acid synthesis: a potential selective target for antineoplastic
RT therapy.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:6379-6383(1994).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2047-2511, AND TISSUE SPECIFICITY.
RX PubMed=7595075;
RA Semenkovich C.F., Coleman T., Fiedorek F.T. Jr.;
RT "Human fatty acid synthase mRNA: tissue distribution, genetic mapping,
RT and kinetics of decay after glucose deprivation.";
RL J. Lipid Res. 36:1507-1521(1995).
RN [10]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-2198 AND THR-2204, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-207; SER-2198; THR-2204
RP AND SER-2236, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [13]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-2204, AND MASS
RP SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-70; LYS-298; LYS-436;
RP LYS-528; LYS-673; LYS-1704; LYS-1771; LYS-1847 AND LYS-1995, AND MASS
RP SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [18]
RP 3D-STRUCTURE MODELING, AND STRUCTURE BY ELECTRON CRYOMICROSCOPY.
RX PubMed=11756679; DOI=10.1073/pnas.012589499;
RA Brink J., Ludtke S.J., Yang C.Y., Gu Z.-W., Wakil S.J., Chiu W.;
RT "Quaternary structure of human fatty acid synthase by electron
RT cryomicroscopy.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:138-143(2002).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 2218-2502.
RX PubMed=15507492; DOI=10.1073/pnas.0406901101;
RA Chakravarty B., Gu Z., Chirala S.S., Wakil S.J., Quiocho F.A.;
RT "Human fatty acid synthase: structure and substrate selectivity of the
RT thioesterase domain.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:15567-15572(2004).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 2119-2207 IN COMPLEX WITH
RP AASDHPPT AND COENZYME A.
RX PubMed=18022563; DOI=10.1016/j.chembiol.2007.10.013;
RA Bunkoczi G., Pasta S., Joshi A., Wu X., Kavanagh K.L., Smith S.,
RA Oppermann U.;
RT "Mechanism and substrate recognition of human holo ACP synthase.";
RL Chem. Biol. 14:1243-1253(2007).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 2200-2511 IN COMPLEX WITH
RP ORLISTAT, AND ACTIVE SITE FOR THIOESTERASE ACTIVITY.
RX PubMed=17618296; DOI=10.1038/nsmb1265;
RA Pemble C.W. IV, Johnson L.C., Kridel S.J., Lowther W.T.;
RT "Crystal structure of the thioesterase domain of human fatty acid
RT synthase inhibited by Orlistat.";
RL Nat. Struct. Mol. Biol. 14:704-709(2007).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 422-831 IN COMPLEX WITH
RP MALONYL-COENZYME A.
RG Structural genomics consortium (SGC);
RT "Structure of the MAT domain of human FAS with malonyl-CoA.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Fatty acid synthetase catalyzes the formation of long-
CC chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This
CC multifunctional protein has 7 catalytic activities and an acyl
CC carrier protein.
CC -!- CATALYTIC ACTIVITY: Acetyl-CoA + n malonyl-CoA + 2n NADPH = a
CC long-chain fatty acid + (n+1) CoA + n CO(2) + 2n NADP(+).
CC -!- CATALYTIC ACTIVITY: Acetyl-CoA + [acyl-carrier-protein] = CoA +
CC acetyl-[acyl-carrier-protein].
CC -!- CATALYTIC ACTIVITY: Malonyl-CoA + [acyl-carrier-protein] = CoA +
CC malonyl-[acyl-carrier-protein].
CC -!- CATALYTIC ACTIVITY: Acyl-[acyl-carrier-protein] + malonyl-[acyl-
CC carrier-protein] = 3-oxoacyl-[acyl-carrier-protein] + CO(2) +
CC [acyl-carrier-protein].
CC -!- CATALYTIC ACTIVITY: (3R)-3-hydroxyacyl-[acyl-carrier-protein] +
CC NADP(+) = 3-oxoacyl-[acyl-carrier-protein] + NADPH.
CC -!- CATALYTIC ACTIVITY: A (3R)-3-hydroxyacyl-[acyl-carrier protein] =
CC a trans-2-enoyl-[acyl-carrier protein] + H(2)O.
CC -!- CATALYTIC ACTIVITY: An acyl-[acyl-carrier protein] + NADP(+) = a
CC trans-2,3-dehydroacyl-[acyl-carrier protein] + NADPH.
CC -!- CATALYTIC ACTIVITY: Oleoyl-[acyl-carrier-protein] + H(2)O = [acyl-
CC carrier-protein] + oleate.
CC -!- SUBUNIT: Homodimer which is arranged in a head to tail fashion.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Melanosome. Note=Identified by
CC mass spectrometry in melanosome fractions from stage I to stage
CC IV.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Prominent expression in brain,
CC lung, and liver.
CC -!- MISCELLANEOUS: The relatively low beta-ketoacyl synthase activity
CC may be attributable to the low 4'-phosphopantetheine content of
CC the protein.
CC -!- SIMILARITY: Contains 1 acyl carrier domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAB35516.1; Type=Erroneous initiation;
CC Sequence=AAC50259.1; Type=Miscellaneous discrepancy; Note=Several sequencing errors;
CC Sequence=BAE06070.1; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U26644; AAC50259.1; ALT_SEQ; mRNA.
DR EMBL; U29344; AAA73576.1; -; mRNA.
DR EMBL; AY451392; AAS09886.1; -; mRNA.
DR EMBL; AB209988; BAE06070.1; ALT_INIT; mRNA.
DR EMBL; AC135056; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC007267; AAH07267.1; -; mRNA.
DR EMBL; BC007909; AAH07909.1; -; mRNA.
DR EMBL; BC014634; AAH14634.2; -; mRNA.
DR EMBL; BC063242; AAH63242.1; -; mRNA.
DR EMBL; S80437; AAB35516.1; ALT_INIT; mRNA.
DR PIR; A57788; A57788.
DR PIR; G01880; G01880.
DR RefSeq; NP_004095.4; NM_004104.4.
DR UniGene; Hs.83190; -.
DR PDB; 1XKT; X-ray; 2.60 A; A/B=2218-2502.
DR PDB; 2CG5; X-ray; 2.70 A; B=2119-2207.
DR PDB; 2JFD; X-ray; 2.81 A; A/B/C/D=422-823.
DR PDB; 2JFK; X-ray; 2.40 A; A/B/C/D=422-831.
DR PDB; 2PX6; X-ray; 2.30 A; A/B=2200-2511.
DR PDB; 3HHD; X-ray; 2.15 A; A/B/C/D=2-963.
DR PDB; 3TJM; X-ray; 1.48 A; A=2218-2500.
DR PDBsum; 1XKT; -.
DR PDBsum; 2CG5; -.
DR PDBsum; 2JFD; -.
DR PDBsum; 2JFK; -.
DR PDBsum; 2PX6; -.
DR PDBsum; 3HHD; -.
DR PDBsum; 3TJM; -.
DR ProteinModelPortal; P49327; -.
DR SMR; P49327; 2-853, 1220-2114, 2124-2194, 2218-2491.
DR DIP; DIP-33681N; -.
DR IntAct; P49327; 24.
DR MINT; MINT-1146154; -.
DR ChEMBL; CHEMBL4158; -.
DR DrugBank; DB01034; Cerulenin.
DR DrugBank; DB01083; Orlistat.
DR DrugBank; DB00339; Pyrazinamide.
DR PhosphoSite; P49327; -.
DR DMDM; 269849686; -.
DR PaxDb; P49327; -.
DR PRIDE; P49327; -.
DR DNASU; 2194; -.
DR Ensembl; ENST00000306749; ENSP00000304592; ENSG00000169710.
DR GeneID; 2194; -.
DR KEGG; hsa:2194; -.
DR UCSC; uc002kdu.3; human.
DR CTD; 2194; -.
DR GeneCards; GC17M080037; -.
DR H-InvDB; HIX0014269; -.
DR HGNC; HGNC:3594; FASN.
DR HPA; CAB005192; -.
DR HPA; CAB015417; -.
DR HPA; HPA006461; -.
DR MIM; 600212; gene.
DR neXtProt; NX_P49327; -.
DR PharmGKB; PA28006; -.
DR eggNOG; COG3319; -.
DR HOVERGEN; HBG005640; -.
DR InParanoid; P49327; -.
DR KO; K00665; -.
DR OMA; GLRTAQW; -.
DR OrthoDB; EOG71K623; -.
DR PhylomeDB; P49327; -.
DR BioCyc; MetaCyc:HS09992-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; P49327; -.
DR ChiTaRS; FASN; human.
DR EvolutionaryTrace; P49327; -.
DR GeneWiki; Fatty_acid_synthase; -.
DR GenomeRNAi; 2194; -.
DR NextBio; 8869; -.
DR PRO; PR:P49327; -.
DR Bgee; P49327; -.
DR CleanEx; HS_FAS; -.
DR CleanEx; HS_FASN; -.
DR Genevestigator; P49327; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0042587; C:glycogen granule; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0047451; F:3-hydroxyoctanoyl-[acyl-carrier-protein] dehydratase activity; IEA:UniProtKB-EC.
DR GO; GO:0004317; F:3-hydroxypalmitoyl-[acyl-carrier-protein] dehydratase activity; IEA:InterPro.
DR GO; GO:0004316; F:3-oxoacyl-[acyl-carrier-protein] reductase (NADPH) activity; IEA:UniProtKB-EC.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:UniProtKB-EC.
DR GO; GO:0004313; F:[acyl-carrier-protein] S-acetyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0004314; F:[acyl-carrier-protein] S-malonyltransferase activity; IEA:UniProtKB-EC.
DR GO; GO:0008144; F:drug binding; IEA:Ensembl.
DR GO; GO:0047117; F:enoyl-[acyl-carrier-protein] reductase (NADPH, A-specific) activity; IEA:UniProtKB-EC.
DR GO; GO:0004319; F:enoyl-[acyl-carrier-protein] reductase (NADPH, B-specific) activity; IEA:InterPro.
DR GO; GO:0004312; F:fatty acid synthase activity; TAS:Reactome.
DR GO; GO:0016295; F:myristoyl-[acyl-carrier-protein] hydrolase activity; IEA:UniProtKB-EC.
DR GO; GO:0070402; F:NADPH binding; IEA:Ensembl.
DR GO; GO:0004320; F:oleoyl-[acyl-carrier-protein] hydrolase activity; IEA:UniProtKB-EC.
DR GO; GO:0016296; F:palmitoyl-[acyl-carrier-protein] hydrolase activity; IEA:UniProtKB-EC.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006084; P:acetyl-CoA metabolic process; IEA:Ensembl.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006631; P:fatty acid metabolic process; TAS:ProtInc.
DR GO; GO:0035338; P:long-chain fatty-acyl-CoA biosynthetic process; TAS:Reactome.
DR GO; GO:0015939; P:pantothenate metabolic process; TAS:Reactome.
DR GO; GO:0031325; P:positive regulation of cellular metabolic process; TAS:Reactome.
DR GO; GO:0019432; P:triglyceride biosynthetic process; TAS:Reactome.
DR Gene3D; 1.10.1200.10; -; 1.
DR Gene3D; 1.10.1470.20; -; 1.
DR Gene3D; 3.40.366.10; -; 2.
DR Gene3D; 3.40.47.10; -; 2.
DR Gene3D; 3.40.50.720; -; 2.
DR InterPro; IPR001227; Ac_transferase_dom.
DR InterPro; IPR009081; Acyl_carrier_prot-like.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR013149; ADH_C.
DR InterPro; IPR002198; DH_sc/Rdtase_SDR.
DR InterPro; IPR023102; Fatty_acid_synthase_dom_2.
DR InterPro; IPR011032; GroES-like.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR013217; Methyltransf_12.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR InterPro; IPR020842; PKS/FAS_KR.
DR InterPro; IPR020843; PKS_ER.
DR InterPro; IPR006162; PPantetheine_attach_site.
DR InterPro; IPR001031; Thioesterase.
DR InterPro; IPR016039; Thiolase-like.
DR InterPro; IPR016038; Thiolase-like_subgr.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00106; adh_short; 1.
DR Pfam; PF00107; ADH_zinc_N; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF00550; PP-binding; 1.
DR Pfam; PF00975; Thioesterase; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00822; PKS_KR; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF52151; SSF52151; 2.
DR SUPFAM; SSF53901; SSF53901; 2.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS50075; ACP_DOMAIN; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Fatty acid biosynthesis;
KW Fatty acid metabolism; Hydrolase; Lipid biosynthesis;
KW Lipid metabolism; Lyase; Multifunctional enzyme; NAD; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein; Polymorphism;
KW Pyridoxal phosphate; Reference proteome; Transferase.
FT CHAIN 1 2511 Fatty acid synthase.
FT /FTId=PRO_0000180276.
FT DOMAIN 2123 2179 Acyl carrier.
FT NP_BIND 1671 1688 NADP (ER) (By similarity).
FT NP_BIND 1886 1901 NADP (KR) (By similarity).
FT REGION 1 414 Beta-ketoacyl synthase (By similarity).
FT REGION 429 817 Acyl and malonyl transferases (By
FT similarity).
FT REGION 1635 1863 Enoyl reductase (By similarity).
FT REGION 1864 2118 Beta-ketoacyl reductase (By similarity).
FT REGION 2207 2511 Thioesterase (By similarity).
FT ACT_SITE 161 161 For beta-ketoacyl synthase activity (By
FT similarity).
FT ACT_SITE 581 581 For malonyltransferase activity (By
FT similarity).
FT ACT_SITE 878 878 For beta-hydroxyacyl dehydratase activity
FT (By similarity).
FT ACT_SITE 2308 2308 For thioesterase activity.
FT ACT_SITE 2481 2481 For thioesterase activity (By
FT similarity).
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 70 70 N6-acetyllysine.
FT MOD_RES 207 207 Phosphoserine.
FT MOD_RES 298 298 N6-acetyllysine.
FT MOD_RES 436 436 N6-acetyllysine.
FT MOD_RES 528 528 N6-acetyllysine.
FT MOD_RES 673 673 N6-acetyllysine.
FT MOD_RES 1704 1704 N6-(pyridoxal phosphate)lysine; alternate
FT (By similarity).
FT MOD_RES 1704 1704 N6-acetyllysine; alternate.
FT MOD_RES 1771 1771 N6-acetyllysine.
FT MOD_RES 1847 1847 N6-acetyllysine.
FT MOD_RES 1995 1995 N6-acetyllysine.
FT MOD_RES 2156 2156 O-(pantetheine 4'-phosphoryl)serine (By
FT similarity).
FT MOD_RES 2198 2198 Phosphoserine.
FT MOD_RES 2204 2204 Phosphothreonine.
FT MOD_RES 2236 2236 Phosphoserine.
FT VARIANT 1483 1483 V -> I (in dbSNP:rs2228305).
FT /FTId=VAR_055479.
FT VARIANT 1694 1694 R -> H (in dbSNP:rs2229424).
FT /FTId=VAR_055480.
FT VARIANT 1888 1888 I -> V (in dbSNP:rs2228307).
FT /FTId=VAR_055481.
FT CONFLICT 459 462 AVPA -> LSPT (in Ref. 2; AAA73576).
FT CONFLICT 528 529 KP -> NR (in Ref. 2; AAA73576).
FT CONFLICT 637 637 G -> A (in Ref. 2; AAA73576).
FT CONFLICT 801 801 G -> R (in Ref. 2; AAA73576).
FT CONFLICT 902 902 A -> P (in Ref. 2; AAA73576).
FT CONFLICT 958 958 V -> M (in Ref. 3; AAS09886).
FT CONFLICT 1121 1121 P -> S (in Ref. 2; AAA73576 and 3;
FT AAS09886).
FT CONFLICT 1151 1151 K -> T (in Ref. 6; AAH63242).
FT CONFLICT 1353 1356 LGDI -> SGH (in Ref. 2; AAA73576).
FT CONFLICT 1386 1386 L -> V (in Ref. 2; AAA73576).
FT CONFLICT 1467 1468 NR -> T (in Ref. 2; AAA73576).
FT CONFLICT 1827 1827 K -> E (in Ref. 3; AAS09886).
FT CONFLICT 1934 1934 R -> A (in Ref. 2; AAA73576).
FT CONFLICT 2065 2065 D -> H (in Ref. 9; AAB35516).
FT CONFLICT 2087 2087 R -> A (in Ref. 2; AAA73576).
FT CONFLICT 2363 2363 A -> P (in Ref. 9; AAB35516).
FT CONFLICT 2428 2428 R -> G (in Ref. 2; AAA73576).
FT CONFLICT 2453 2453 A -> T (in Ref. 9; AAB35516).
FT CONFLICT 2456 2456 E -> Q (in Ref. 9; AAB35516).
FT STRAND 4 13
FT STRAND 16 18
FT HELIX 19 27
FT STRAND 36 40
FT HELIX 44 46
FT TURN 62 66
FT HELIX 69 73
FT HELIX 77 92
FT HELIX 97 100
FT STRAND 106 110
FT HELIX 115 120
FT TURN 124 126
FT HELIX 130 135
FT HELIX 139 148
FT STRAND 154 158
FT HELIX 160 162
FT HELIX 163 176
FT STRAND 181 189
FT HELIX 194 202
FT STRAND 227 235
FT HELIX 236 238
FT STRAND 243 253
FT HELIX 266 279
FT HELIX 284 286
FT STRAND 287 291
FT HELIX 300 312
FT STRAND 320 323
FT HELIX 326 329
FT HELIX 333 335
FT HELIX 336 350
FT HELIX 367 370
FT STRAND 373 376
FT STRAND 387 393
FT STRAND 397 406
FT HELIX 416 419
FT STRAND 422 430
FT HELIX 431 443
FT TURN 444 446
FT HELIX 448 457
FT TURN 462 464
FT STRAND 467 477
FT STRAND 481 484
FT STRAND 492 496
FT TURN 504 509
FT HELIX 510 512
FT HELIX 514 527
FT HELIX 528 530
FT HELIX 534 539
FT HELIX 545 547
FT HELIX 549 569
FT STRAND 575 579
FT HELIX 583 590
FT HELIX 596 611
FT STRAND 618 625
FT HELIX 627 633
FT STRAND 639 645
FT STRAND 648 654
FT HELIX 655 667
FT STRAND 672 675
FT STRAND 677 679
FT HELIX 685 690
FT HELIX 691 701
FT STRAND 702 704
FT STRAND 715 717
FT HELIX 719 721
FT HELIX 725 728
FT HELIX 732 740
FT HELIX 745 749
FT STRAND 757 764
FT HELIX 768 774
FT STRAND 780 783
FT HELIX 792 805
FT HELIX 812 815
FT HELIX 831 833
FT HELIX 847 849
FT HELIX 2127 2134
FT TURN 2149 2153
FT HELIX 2156 2170
FT HELIX 2176 2180
FT HELIX 2184 2192
FT HELIX 2219 2222
FT STRAND 2230 2233
FT STRAND 2239 2241
FT STRAND 2244 2247
FT HELIX 2255 2257
FT HELIX 2258 2263
FT STRAND 2268 2271
FT HELIX 2282 2293
FT TURN 2294 2296
FT STRAND 2303 2307
FT HELIX 2309 2325
FT STRAND 2333 2338
FT HELIX 2343 2352
FT HELIX 2360 2375
FT HELIX 2380 2387
FT STRAND 2390 2392
FT HELIX 2393 2407
FT HELIX 2413 2432
FT STRAND 2443 2447
FT TURN 2459 2463
FT HELIX 2464 2466
FT STRAND 2472 2476
FT HELIX 2483 2485
FT HELIX 2487 2499
SQ SEQUENCE 2511 AA; 273427 MW; 7A07171FEFA3287B CRC64;
MEEVVIAGMS GKLPESENLQ EFWDNLIGGV DMVTDDDRRW KAGLYGLPRR SGKLKDLSRF
DASFFGVHPK QAHTMDPQLR LLLEVTYEAI VDGGINPDSL RGTHTGVWVG VSGSETSEAL
SRDPETLVGY SMVGCQRAMM ANRLSFFFDF RGPSIALDTA CSSSLMALQN AYQAIHSGQC
PAAIVGGINV LLKPNTSVQF LRLGMLSPEG TCKAFDTAGN GYCRSEGVVA VLLTKKSLAR
RVYATILNAG TNTDGFKEQG VTFPSGDIQE QLIRSLYQSA GVAPESFEYI EAHGTGTKVG
DPQELNGITR ALCATRQEPL LIGSTKSNMG HPEPASGLAA LAKVLLSLEH GLWAPNLHFH
SPNPEIPALL DGRLQVVDQP LPVRGGNVGI NSFGFGGSNV HIILRPNTQP PPAPAPHATL
PRLLRASGRT PEAVQKLLEQ GLRHSQDLAF LSMLNDIAAV PATAMPFRGY AVLGGERGGP
EVQQVPAGER PLWFICSGMG TQWRGMGLSL MRLDRFRDSI LRSDEAVKPF GLKVSQLLLS
TDESTFDDIV HSFVSLTAIQ IGLIDLLSCM GLRPDGIVGH SLGEVACGYA DGCLSQEEAV
LAAYWRGQCI KEAHLPPGAM AAVGLSWEEC KQRCPPGVVP ACHNSKDTVT ISGPQAPVFE
FVEQLRKEGV FAKEVRTGGM AFHSYFMEAI APPLLQELKK VIREPKPRSA RWLSTSIPEA
QWHSSLARTS SAEYNVNNLV SPVLFQEALW HVPEHAVVLE IAPHALLQAV LKRGLKPSCT
IIPLMKKDHR DNLEFFLAGI GRLHLSGIDA NPNALFPPVE FPAPRGTPLI SPLIKWDHSL
AWDVPAAEDF PNGSGSPSAA IYNIDTSSES PDHYLVDHTL DGRVLFPATG YLSIVWKTLA
RALGLGVEQL PVVFEDVVLH QATILPKTGT VSLEVRLLEA SRAFEVSENG NLVVSGKVYQ
WDDPDPRLFD HPESPTPNPT EPLFLAQAEV YKELRLRGYD YGPHFQGILE ASLEGDSGRL
LWKDNWVSFM DTMLQMSILG SAKHGLYLPT RVTAIHIDPA THRQKLYTLQ DKAQVADVVV
SRWLRVTVAG GVHISGLHTE SAPRRQQEQQ VPILEKFCFT PHTEEGCLSE RAALQEELQL
CKGLVQALQT KVTQQGLKMV VPGLDGAQIP RDPSQQELPR LLSAACRLQL NGNLQLELAQ
VLAQERPKLP EDPLLSGLLD SPALKACLDT AVENMPSLKM KVVEVLAGHG HLYSRIPGLL
SPHPLLQLSY TATDRHPQAL EAAQAELQQH DVAQGQWDPA DPAPSALGSA DLLVCNCAVA
ALGDPASALS NMVAALREGG FLLLHTLLRG HPLGDIVAFL TSTEPQYGQG ILSQDAWESL
FSRVSLRLVG LKKSFYGSTL FLCRRPTPQD SPIFLPVDDT SFRWVESLKG ILADEDSSRP
VWLKAINCAT SGVVGLVNCL RREPGGNRLR CVLLSNLSST SHVPEVDPGS AELQKVLQGD
LVMNVYRDGA WGAFRHFLLE EDKPEEPTAH AFVSTLTRGD LSSIRWVCSS LRHAQPTCPG
AQLCTVYYAS LNFRDIMLAT GKLSPDAIPG KWTSQDSLLG MEFSGRDASG KRVMGLVPAK
GLATSVLLSP DFLWDVPSNW TLEEAASVPV VYSTAYYALV VRGRVRPGET LLIHSGSGGV
GQAAIAIALS LGCRVFTTVG SAEKRAYLQA RFPQLDSTSF ANSRDTSFEQ HVLWHTGGKG
VDLVLNSLAE EKLQASVRCL ATHGRFLEIG KFDLSQNHPL GMAIFLKNVT FHGVLLDAFF
NESSADWREV WALVQAGIRD GVVRPLKCTV FHGAQVEDAF RYMAQGKHIG KVVVQVLAEE
PEAVLKGAKP KLMSAISKTF CPAHKSYIIA GGLGGFGLEL AQWLIQRGVQ KLVLTSRSGI
RTGYQAKQVR RWRRQGVQVQ VSTSNISSLE GARGLIAEAA QLGPVGGVFN LAVVLRDGLL
ENQTPEFFQD VCKPKYSGTL NLDRVTREAC PELDYFVVFS SVSCGRGNAG QSNYGFANSA
MERICEKRRH EGLPGLAVQW GAIGDVGILV ETMSTNDTIV SGTLPQRMAS CLEVLDLFLN
QPHMVLSSFV LAEKAAAYRD RDSQRDLVEA VAHILGIRDL AAVNLDSSLA DLGLDSLMSV
EVRQTLEREL NLVLSVREVR QLTLRKLQEL SSKADEASEL ACPTPKEDGL AQQQTQLNLR
SLLVNPEGPT LMRLNSVQSS ERPLFLVHPI EGSTTVFHSL ASRLSIPTYG LQCTRAAPLD
SIHSLAAYYI DCIRQVQPEG PYRVAGYSYG ACVAFEMCSQ LQAQQSPAPT HNSLFLFDGS
PTYVLAYTQS YRAKLTPGCE AEAETEAICF FVQQFTDMEH NRVLEALLPL KGLEERVAAA
VDLIIKSHQG LDRQELSFAA RSFYYKLRAA EQYTPKAKYH GNVMLLRAKT GGAYGEDLGA
DYNLSQVCDG KVSVHVIEGD HRTLLEGSGL ESIISIIHSS LAEPRVSVRE G
//
MIM
600212
*RECORD*
*FIELD* NO
600212
*FIELD* TI
*600212 FATTY ACID SYNTHASE; FASN
*FIELD* TX
DESCRIPTION
Fatty acid synthase (EC 2.3.1.85) catalyzes the conversion of acetyl-CoA
read moreand malonyl-CoA, in the presence of NADPH, into long-chain saturated
fatty acids (Wakil, 1989). In prokaryotes and plants, FASN consists of
an acyl carrier protein and 7 structurally independent monofunctional
enzymes. In animals, however, all of the component enzymatic activities
of FASN and acyl carrier protein are organized in one large polypeptide
chain.
CLONING
Jayakumar et al. (1994) isolated and sequenced cDNA clones representing
the 2 ends of the human FASN gene and also isolated overlapping genomic
clones from human YAC libraries.
Jayakumar et al. (1995) purified fatty acid synthase to near homogeneity
from a human hepatoma cell line, HepG2. The specific activity of the
enzyme was found to be half that of chicken liver enzyme. They also
cloned the human brain FASN cDNA. The cDNA sequence had an open reading
frame of 7,512 bp that encoded a 2504-amino acid protein with relative
mass of 272,516. The amino acid sequence of the human enzyme had 79% and
63% identity, respectively, with the sequences of the rat and chicken
enzymes. Northern analysis revealed that human FASN mRNA is about 9.3 kb
in size and that its level varies among human tissues, with brain, lung,
and liver tissues showing prominent expression. Sequence variants of
unknown origin and significance were found in the enzyme derived from
HepG2.
GENE FUNCTION
Ye et al. (2000) investigated the expression of ESR1 in prostate cancer
cell lines and unexpectedly found a FASN/ESR1 fusion transcript. Using
semi-nested RT-PCR analysis of ESR1 and its variants, Ye et al. (2000)
found that the N-terminal coding region of FASN containing domain 1 was
fused to the C-terminal coding region of the ESR1 ligand binding domain.
Nested RT-PCR also detected the fusion transcript in breast, cervical,
and bladder cancer cell lines.
Loftus et al. (2000) identified a link between anabolic energy
metabolism and appetite control. Both systemic and
intracerebroventricular treatment of mice with fatty acid synthase
inhibitors (cerulenin and C75, a synthetic compound) led to inhibition
of feeding and dramatic weight loss. C75 inhibited expression of the
prophagic signal neuropeptide Y (162640) in the hypothalamus and acted
in a leptin (164160)-independent manner that appears to be mediated by
malonyl-CoA. Loftus et al. (2000) suggested that FASN may represent an
important link in feeding regulation and may be a potential therapeutic
target for obesity.
Camassei et al. (2003) found that FAS activation increased with
increased retinoblastoma (180200) aggressiveness and postulated that FAS
inhibition could represent an alternative treatment strategy in advanced
and resistant retinoblastomas.
Menendez et al. (2004) identified a molecular link between FASN and the
HER2 oncogene (164870), a marker for poor prognosis that is
overexpressed in 30% of breast and ovarian cancers. Pharmacologic FASN
inhibitors were found to suppress p185(HER2) oncoprotein expression and
tyrosine kinase activity in breast and ovarian cancers overexpressing
HER2. Similar suppression was observed when FASN gene expression was
silenced by using the highly sequence-specific mechanism of RNA
interference (RNAi).
Using a focused RNAi analysis, followed by validation with pharmacologic
inhibitors, Heaton et al. (2010) identified 3 cellular pathways required
for dengue virus (DENV; see 614371) replication: autophagy, actin
polymerization, and fatty acid biosynthesis. They identified FASN as a
key enzyme in the fatty acid biosynthetic pathway and showed that FASN
relocalized to sites of DENV replication. DENV nonstructural protein-3
(NS3) colocalized with FASN and interacted with FASN in a 2-hybrid
assay. Purified recombinant NS3 stimulated FASN activity in vitro.
Heaton et al. (2010) proposed that DENV co-opts the fatty acid
biosynthesis pathway to establish replication complexes.
Knobloch et al. (2013) demonstrated that Fasn, the key enzyme of de novo
lipogenesis, is highly active in adult neural stem and progenitor cells
(NSPCs) and that conditional deletion of Fasn in mouse NSPCs impairs
adult neurogenesis. The rate of de novo lipid synthesis and subsequent
proliferation of NSPCs is regulated by Spot14 (601926), a gene
implicated in lipid metabolism, that Knobloch et al. (2013) found to be
selectively expressed in low proliferating adult NSPCs. Spot14 reduces
the availability of malonyl-CoA, which is an essential substrate for
Fasn to fuel lipogenesis. Knobloch et al. (2013) concluded that they
identified a functional coupling between the regulation of lipid
metabolism and adult NSPC proliferation.
BIOCHEMICAL FEATURES
- Crystal Structure
Maier et al. (2008) determined the crystal structure of fatty acid
synthase at 3.2-angstrom resolution covering 5 catalytic domains,
whereas the flexibly tethered acyl carrier protein and thioesterase
domains remain unresolved. The structure revealed a complex architecture
of alternating linkers and enzymatic domains. Substrate shuttling is
facilitated by flexible tethering of the acyl carrier protein domain and
by the limited contact between the condensing and modifying portions of
the multienzyme, which are mainly connected by linkers rather than
direct interaction. The structure identified 2 additional nonenzymatic
domains: a pseudoketoreductase and a peripheral pseudomethyltransferase
that is probably a remnant of an ancestral methyltransferase domain
maintained in some related polyketide synthases. The structural
comparison of mammalian fatty acid synthase with modular polyketide
synthases showed how their segmental construction allows the variation
of domain composition to achieve diverse product synthesis.
MAPPING
By fluorescence in situ hybridization, Jayakumar et al. (1994) mapped
the FASN gene to 17q25. Southern analyses suggested that a single 40-kb
cosmid clone encompasses the entire coding region of the gene.
MOLECULAR GENETICS
- Associations Pending Confirmation
To detect a genetic component to uterine leiomyomata (150699)
predisposition, Eggert et al. (2012) performed genomewide association
studies in 2 independent cohorts of white women and conducted a
metaanalysis. They identified 1 SNP (dbSNP rs4247357) with significant
association (p = 3.05 x 10(-8), odds ratio = 1.299) under a linkage peak
and in a block of linkage disequilibrium in 17q25.3 that included the
FASN gene. By tissue microarray immunohistochemistry, Eggert et al.
(2012) found elevated (3-fold) FAS levels in uterine
leiomyomata-affected tissue compared to matched myometrial tissue. FAS
transcripts and/or protein levels are upregulated in various neoplasms
and implicated in tumor cell survival.
ANIMAL MODEL
In animals, including humans, the source of long chain saturated fatty
acids is either de novo synthesis, which is mediated by fatty acid
synthase, ingested food, or both. To understand the importance of de
novo fatty acid synthesis, Chirala et al. (2003) generated Fasn knockout
mice. The heterozygous mutant mice were ostensibly normal; however,
levels of Fasn mRNA and activity were approximately 50% and 35% lower,
respectively, than those of wildtype mice. When the heterozygous mutant
mice were interbred, no null mice were produced; thus, Fasn is essential
during embryonic development. Furthermore, the number of heterozygous
progeny was 70% less than predicted by Mendelian inheritance, indicating
partial haploid insufficiency. Even when 1 parent was wildtype and the
other heterozygous, the estimated loss of heterozygous progeny was 60%.
Most of the Fasn-null embryos died before implantation and the
heterozygous embryos died at various stages of development. Feeding the
breeders a diet rich in saturated fatty acids did not prevent the loss
of homo- or heterozygotes.
Casado et al. (1999) stated that the E box within the FASN promoter is
regulated by USF1 (191523), USF2 (600390), and SREBP1 (184756). They
analyzed the glucose responsiveness of hepatic Fasn gene expression in
Usf1 and Usf2 knockout mice and found that in both types of mutant mice,
induction of the Fasn gene by refeeding a carbohydrate-rich diet was
severely delayed. In contrast, expression of Srebp1 was almost normal,
and insulin response was unchanged. Casado et al. (1999) concluded that
the USF transactivators, and especially USF1/USF2 heterodimers, are
essential to sustain the dietary induction of the FASN gene in liver.
*FIELD* RF
1. Camassei, F. D.; Cozza, R.; Acquaviva, A.; Jerkner, A.; Rava, L.;
Gareri, R.; Donfrancesco, A.; Basman, C.; Vadala, P.; Hadjistilianou,
T.; Boldrini, R.: Expression of the lipogenic enzyme fatty acid synthase
(FAS) in retinoblastoma and its correlation with tumor aggressiveness. Invest.
Ophthal. Vis. Sci. 44: 2399-2403, 2003.
2. Casado, M.; Vallet, V. S.; Kahn, A.; Vaulont, S.: Essential role
in vivo of upstream stimulatory factors for a normal dietary response
of the fatty acid synthase gene in the liver. J. Biol. Chem. 274:
2009-2013, 1999.
3. Chirala, S. S.; Chang, H.; Matzuk, M.; Abu-Elheiga, L.; Mao, J.;
Mahon, K.; Finegold, M.; Wakil, S. J.: Fatty acid synthesis is essential
in embryonic development: fatty acid synthase null mutants and most
of the heterozygotes die in utero. Proc. Nat. Acad. Sci. 100: 6358-6363,
2003.
4. Eggert, S. L.; Huyck, K. L.; Somasundaram, P.; Kavalla, R.; Stewart,
E. A.; Lu, A. T.; Painter, J. N.; Montgomery, G. W.; Medland, S. E.;
Nyholt, D. R.; Treloar, S. A.; Zondervan, K. T.: and 9 others:
Genome-wide linkage and association analyses implicate FASN in predisposition
to uterine leiomyomata. Am. J. Hum. Genet. 91: 621-628, 2012.
5. Heaton, N. S.; Perera, R.; Berger, K. L.; Khadka, S.; LaCount,
D. J.; Kuhn, R. J.; Randall, G.: Dengue virus nonstructural protein
3 redistributes fatty acid synthase to sites of viral replication
and increases cellular fatty acid synthesis. Proc. Nat. Acad. Sci. 107:
17345-17350, 2010.
6. Jayakumar, A.; Chirala, S. S.; Chinault, A. C.; Baldini, A.; Abu-Elheiga,
L.; Wakil, S. J.: Isolation and chromosomal mapping of genomic clones
encoding the human fatty acid synthase gene. Genomics 23: 420-424,
1994.
7. Jayakumar, A.; Tai, M.-H.; Huang, W.-Y.; Al-Feel, W.; Hsu, M.;
Abu-Elheiga, L.; Chirala, S. S.; Wakil, S. J.: Human fatty acid synthase:
properties and molecular cloning. Proc. Nat. Acad. Sci. 92: 8695-8699,
1995.
8. Knobloch, M.; Braun, S. M. G.; Zurkirchen, L.; von Schoultz, C.;
Zamboni, N.; Arauzo-Bravo, M. J; Kovacs, W. J.; Karalay, O.; Suter,
U.; Machado, R. A. C.; Roccio, M.; Lutolf, M. P.; Semenkovich, C.
F.; Jessberger, S.: Metabolic control of adult neural stem cell activity
by Fasn-dependent lipogenesis. Nature 493: 226-230, 2013.
9. Loftus, T. M.; Jaworsky, D. E.; Frehywot, G. L.; Townsend, C. A.;
Ronnett, G. V.; Lane, M. D.; Kuhajda, F. P.: Reduced food intake
and body weight in mice treated with fatty acid synthase inhibitors. Science 288:
2379-2381, 2000.
10. Maier, T.; Leibundgut, M.; Ban, N.: The crystal structure of
a mammalian fatty acid synthase. Science 321: 1315-1322, 2008.
11. Menendez, J. A.; Vellon, L.; Mehmi, I.; Oza, B. P.; Ropero, S.;
Colomer, R.; Lupu, R.: Inhibition of fatty acid synthase (FAS) suppresses
HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc.
Nat. Acad. Sci. 101: 10715-10720, 2004.
12. Wakil, S. J.: Fatty acid synthase, a proficient multifunctional
enzyme. Biochemistry 28: 4523-4530, 1989.
13. Ye, Q.; Chung, L. W. K.; Li, S.; Zhau, H. E.: Identification
of a novel FAS/ER-alpha fusion transcript expressed in human cancer
cells. Biochim. Biophys. Acta 1493: 373-377, 2000.
*FIELD* CN
Ada Hamosh - updated: 05/16/2013
Ada Hamosh - updated: 2/7/2013
Paul J. Converse - updated: 6/14/2012
Ada Hamosh - updated: 10/1/2008
Victor A. McKusick - updated: 9/23/2004
Patricia A. Hartz - updated: 5/7/2004
Jane Kelly - updated: 10/22/2003
Victor A. McKusick - updated: 6/25/2003
Ada Hamosh - updated: 5/29/2001
Paul J. Converse - updated: 2/6/2001
*FIELD* CD
Victor A. McKusick: 12/1/1994
*FIELD* ED
alopez: 05/16/2013
alopez: 3/5/2013
terry: 2/7/2013
mgross: 6/19/2012
terry: 6/14/2012
alopez: 10/2/2008
terry: 10/1/2008
tkritzer: 9/23/2004
mgross: 5/7/2004
cwells: 10/22/2003
tkritzer: 6/26/2003
tkritzer: 6/25/2003
alopez: 10/31/2001
cwells: 6/4/2001
cwells: 5/29/2001
terry: 5/29/2001
cwells: 2/6/2001
carol: 2/5/2001
alopez: 6/13/1997
mark: 9/28/1995
carol: 1/10/1995
carol: 12/1/1994
*RECORD*
*FIELD* NO
600212
*FIELD* TI
*600212 FATTY ACID SYNTHASE; FASN
*FIELD* TX
DESCRIPTION
Fatty acid synthase (EC 2.3.1.85) catalyzes the conversion of acetyl-CoA
read moreand malonyl-CoA, in the presence of NADPH, into long-chain saturated
fatty acids (Wakil, 1989). In prokaryotes and plants, FASN consists of
an acyl carrier protein and 7 structurally independent monofunctional
enzymes. In animals, however, all of the component enzymatic activities
of FASN and acyl carrier protein are organized in one large polypeptide
chain.
CLONING
Jayakumar et al. (1994) isolated and sequenced cDNA clones representing
the 2 ends of the human FASN gene and also isolated overlapping genomic
clones from human YAC libraries.
Jayakumar et al. (1995) purified fatty acid synthase to near homogeneity
from a human hepatoma cell line, HepG2. The specific activity of the
enzyme was found to be half that of chicken liver enzyme. They also
cloned the human brain FASN cDNA. The cDNA sequence had an open reading
frame of 7,512 bp that encoded a 2504-amino acid protein with relative
mass of 272,516. The amino acid sequence of the human enzyme had 79% and
63% identity, respectively, with the sequences of the rat and chicken
enzymes. Northern analysis revealed that human FASN mRNA is about 9.3 kb
in size and that its level varies among human tissues, with brain, lung,
and liver tissues showing prominent expression. Sequence variants of
unknown origin and significance were found in the enzyme derived from
HepG2.
GENE FUNCTION
Ye et al. (2000) investigated the expression of ESR1 in prostate cancer
cell lines and unexpectedly found a FASN/ESR1 fusion transcript. Using
semi-nested RT-PCR analysis of ESR1 and its variants, Ye et al. (2000)
found that the N-terminal coding region of FASN containing domain 1 was
fused to the C-terminal coding region of the ESR1 ligand binding domain.
Nested RT-PCR also detected the fusion transcript in breast, cervical,
and bladder cancer cell lines.
Loftus et al. (2000) identified a link between anabolic energy
metabolism and appetite control. Both systemic and
intracerebroventricular treatment of mice with fatty acid synthase
inhibitors (cerulenin and C75, a synthetic compound) led to inhibition
of feeding and dramatic weight loss. C75 inhibited expression of the
prophagic signal neuropeptide Y (162640) in the hypothalamus and acted
in a leptin (164160)-independent manner that appears to be mediated by
malonyl-CoA. Loftus et al. (2000) suggested that FASN may represent an
important link in feeding regulation and may be a potential therapeutic
target for obesity.
Camassei et al. (2003) found that FAS activation increased with
increased retinoblastoma (180200) aggressiveness and postulated that FAS
inhibition could represent an alternative treatment strategy in advanced
and resistant retinoblastomas.
Menendez et al. (2004) identified a molecular link between FASN and the
HER2 oncogene (164870), a marker for poor prognosis that is
overexpressed in 30% of breast and ovarian cancers. Pharmacologic FASN
inhibitors were found to suppress p185(HER2) oncoprotein expression and
tyrosine kinase activity in breast and ovarian cancers overexpressing
HER2. Similar suppression was observed when FASN gene expression was
silenced by using the highly sequence-specific mechanism of RNA
interference (RNAi).
Using a focused RNAi analysis, followed by validation with pharmacologic
inhibitors, Heaton et al. (2010) identified 3 cellular pathways required
for dengue virus (DENV; see 614371) replication: autophagy, actin
polymerization, and fatty acid biosynthesis. They identified FASN as a
key enzyme in the fatty acid biosynthetic pathway and showed that FASN
relocalized to sites of DENV replication. DENV nonstructural protein-3
(NS3) colocalized with FASN and interacted with FASN in a 2-hybrid
assay. Purified recombinant NS3 stimulated FASN activity in vitro.
Heaton et al. (2010) proposed that DENV co-opts the fatty acid
biosynthesis pathway to establish replication complexes.
Knobloch et al. (2013) demonstrated that Fasn, the key enzyme of de novo
lipogenesis, is highly active in adult neural stem and progenitor cells
(NSPCs) and that conditional deletion of Fasn in mouse NSPCs impairs
adult neurogenesis. The rate of de novo lipid synthesis and subsequent
proliferation of NSPCs is regulated by Spot14 (601926), a gene
implicated in lipid metabolism, that Knobloch et al. (2013) found to be
selectively expressed in low proliferating adult NSPCs. Spot14 reduces
the availability of malonyl-CoA, which is an essential substrate for
Fasn to fuel lipogenesis. Knobloch et al. (2013) concluded that they
identified a functional coupling between the regulation of lipid
metabolism and adult NSPC proliferation.
BIOCHEMICAL FEATURES
- Crystal Structure
Maier et al. (2008) determined the crystal structure of fatty acid
synthase at 3.2-angstrom resolution covering 5 catalytic domains,
whereas the flexibly tethered acyl carrier protein and thioesterase
domains remain unresolved. The structure revealed a complex architecture
of alternating linkers and enzymatic domains. Substrate shuttling is
facilitated by flexible tethering of the acyl carrier protein domain and
by the limited contact between the condensing and modifying portions of
the multienzyme, which are mainly connected by linkers rather than
direct interaction. The structure identified 2 additional nonenzymatic
domains: a pseudoketoreductase and a peripheral pseudomethyltransferase
that is probably a remnant of an ancestral methyltransferase domain
maintained in some related polyketide synthases. The structural
comparison of mammalian fatty acid synthase with modular polyketide
synthases showed how their segmental construction allows the variation
of domain composition to achieve diverse product synthesis.
MAPPING
By fluorescence in situ hybridization, Jayakumar et al. (1994) mapped
the FASN gene to 17q25. Southern analyses suggested that a single 40-kb
cosmid clone encompasses the entire coding region of the gene.
MOLECULAR GENETICS
- Associations Pending Confirmation
To detect a genetic component to uterine leiomyomata (150699)
predisposition, Eggert et al. (2012) performed genomewide association
studies in 2 independent cohorts of white women and conducted a
metaanalysis. They identified 1 SNP (dbSNP rs4247357) with significant
association (p = 3.05 x 10(-8), odds ratio = 1.299) under a linkage peak
and in a block of linkage disequilibrium in 17q25.3 that included the
FASN gene. By tissue microarray immunohistochemistry, Eggert et al.
(2012) found elevated (3-fold) FAS levels in uterine
leiomyomata-affected tissue compared to matched myometrial tissue. FAS
transcripts and/or protein levels are upregulated in various neoplasms
and implicated in tumor cell survival.
ANIMAL MODEL
In animals, including humans, the source of long chain saturated fatty
acids is either de novo synthesis, which is mediated by fatty acid
synthase, ingested food, or both. To understand the importance of de
novo fatty acid synthesis, Chirala et al. (2003) generated Fasn knockout
mice. The heterozygous mutant mice were ostensibly normal; however,
levels of Fasn mRNA and activity were approximately 50% and 35% lower,
respectively, than those of wildtype mice. When the heterozygous mutant
mice were interbred, no null mice were produced; thus, Fasn is essential
during embryonic development. Furthermore, the number of heterozygous
progeny was 70% less than predicted by Mendelian inheritance, indicating
partial haploid insufficiency. Even when 1 parent was wildtype and the
other heterozygous, the estimated loss of heterozygous progeny was 60%.
Most of the Fasn-null embryos died before implantation and the
heterozygous embryos died at various stages of development. Feeding the
breeders a diet rich in saturated fatty acids did not prevent the loss
of homo- or heterozygotes.
Casado et al. (1999) stated that the E box within the FASN promoter is
regulated by USF1 (191523), USF2 (600390), and SREBP1 (184756). They
analyzed the glucose responsiveness of hepatic Fasn gene expression in
Usf1 and Usf2 knockout mice and found that in both types of mutant mice,
induction of the Fasn gene by refeeding a carbohydrate-rich diet was
severely delayed. In contrast, expression of Srebp1 was almost normal,
and insulin response was unchanged. Casado et al. (1999) concluded that
the USF transactivators, and especially USF1/USF2 heterodimers, are
essential to sustain the dietary induction of the FASN gene in liver.
*FIELD* RF
1. Camassei, F. D.; Cozza, R.; Acquaviva, A.; Jerkner, A.; Rava, L.;
Gareri, R.; Donfrancesco, A.; Basman, C.; Vadala, P.; Hadjistilianou,
T.; Boldrini, R.: Expression of the lipogenic enzyme fatty acid synthase
(FAS) in retinoblastoma and its correlation with tumor aggressiveness. Invest.
Ophthal. Vis. Sci. 44: 2399-2403, 2003.
2. Casado, M.; Vallet, V. S.; Kahn, A.; Vaulont, S.: Essential role
in vivo of upstream stimulatory factors for a normal dietary response
of the fatty acid synthase gene in the liver. J. Biol. Chem. 274:
2009-2013, 1999.
3. Chirala, S. S.; Chang, H.; Matzuk, M.; Abu-Elheiga, L.; Mao, J.;
Mahon, K.; Finegold, M.; Wakil, S. J.: Fatty acid synthesis is essential
in embryonic development: fatty acid synthase null mutants and most
of the heterozygotes die in utero. Proc. Nat. Acad. Sci. 100: 6358-6363,
2003.
4. Eggert, S. L.; Huyck, K. L.; Somasundaram, P.; Kavalla, R.; Stewart,
E. A.; Lu, A. T.; Painter, J. N.; Montgomery, G. W.; Medland, S. E.;
Nyholt, D. R.; Treloar, S. A.; Zondervan, K. T.: and 9 others:
Genome-wide linkage and association analyses implicate FASN in predisposition
to uterine leiomyomata. Am. J. Hum. Genet. 91: 621-628, 2012.
5. Heaton, N. S.; Perera, R.; Berger, K. L.; Khadka, S.; LaCount,
D. J.; Kuhn, R. J.; Randall, G.: Dengue virus nonstructural protein
3 redistributes fatty acid synthase to sites of viral replication
and increases cellular fatty acid synthesis. Proc. Nat. Acad. Sci. 107:
17345-17350, 2010.
6. Jayakumar, A.; Chirala, S. S.; Chinault, A. C.; Baldini, A.; Abu-Elheiga,
L.; Wakil, S. J.: Isolation and chromosomal mapping of genomic clones
encoding the human fatty acid synthase gene. Genomics 23: 420-424,
1994.
7. Jayakumar, A.; Tai, M.-H.; Huang, W.-Y.; Al-Feel, W.; Hsu, M.;
Abu-Elheiga, L.; Chirala, S. S.; Wakil, S. J.: Human fatty acid synthase:
properties and molecular cloning. Proc. Nat. Acad. Sci. 92: 8695-8699,
1995.
8. Knobloch, M.; Braun, S. M. G.; Zurkirchen, L.; von Schoultz, C.;
Zamboni, N.; Arauzo-Bravo, M. J; Kovacs, W. J.; Karalay, O.; Suter,
U.; Machado, R. A. C.; Roccio, M.; Lutolf, M. P.; Semenkovich, C.
F.; Jessberger, S.: Metabolic control of adult neural stem cell activity
by Fasn-dependent lipogenesis. Nature 493: 226-230, 2013.
9. Loftus, T. M.; Jaworsky, D. E.; Frehywot, G. L.; Townsend, C. A.;
Ronnett, G. V.; Lane, M. D.; Kuhajda, F. P.: Reduced food intake
and body weight in mice treated with fatty acid synthase inhibitors. Science 288:
2379-2381, 2000.
10. Maier, T.; Leibundgut, M.; Ban, N.: The crystal structure of
a mammalian fatty acid synthase. Science 321: 1315-1322, 2008.
11. Menendez, J. A.; Vellon, L.; Mehmi, I.; Oza, B. P.; Ropero, S.;
Colomer, R.; Lupu, R.: Inhibition of fatty acid synthase (FAS) suppresses
HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc.
Nat. Acad. Sci. 101: 10715-10720, 2004.
12. Wakil, S. J.: Fatty acid synthase, a proficient multifunctional
enzyme. Biochemistry 28: 4523-4530, 1989.
13. Ye, Q.; Chung, L. W. K.; Li, S.; Zhau, H. E.: Identification
of a novel FAS/ER-alpha fusion transcript expressed in human cancer
cells. Biochim. Biophys. Acta 1493: 373-377, 2000.
*FIELD* CN
Ada Hamosh - updated: 05/16/2013
Ada Hamosh - updated: 2/7/2013
Paul J. Converse - updated: 6/14/2012
Ada Hamosh - updated: 10/1/2008
Victor A. McKusick - updated: 9/23/2004
Patricia A. Hartz - updated: 5/7/2004
Jane Kelly - updated: 10/22/2003
Victor A. McKusick - updated: 6/25/2003
Ada Hamosh - updated: 5/29/2001
Paul J. Converse - updated: 2/6/2001
*FIELD* CD
Victor A. McKusick: 12/1/1994
*FIELD* ED
alopez: 05/16/2013
alopez: 3/5/2013
terry: 2/7/2013
mgross: 6/19/2012
terry: 6/14/2012
alopez: 10/2/2008
terry: 10/1/2008
tkritzer: 9/23/2004
mgross: 5/7/2004
cwells: 10/22/2003
tkritzer: 6/26/2003
tkritzer: 6/25/2003
alopez: 10/31/2001
cwells: 6/4/2001
cwells: 5/29/2001
terry: 5/29/2001
cwells: 2/6/2001
carol: 2/5/2001
alopez: 6/13/1997
mark: 9/28/1995
carol: 1/10/1995
carol: 12/1/1994