ID   LCF4_YEAST              Reviewed;         694 AA.
AC   P47912; D6W073; Q05743;
DT   01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1996, sequence version 1.
DT   27-MAR-2024, entry version 188.
DE   RecName: Full=Long-chain-fatty-acid--CoA ligase 4;
DE            EC=6.2.1.3 {ECO:0000269|PubMed:11477098};
DE   AltName: Full=Fatty acid activator 4;
DE   AltName: Full=Fatty acyl-CoA synthetase;
DE            Short=FACS;
DE   AltName: Full=Long-chain acyl-CoA synthetase 4;
GN   Name=FAA4; OrderedLocusNames=YMR246W; ORFNames=YM9408.08;
OS   Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC   Saccharomycetales; Saccharomycetaceae; Saccharomyces.
OX   NCBI_TaxID=559292;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RX   PubMed=7962057; DOI=10.1083/jcb.127.3.751;
RA   Johnson D.R., Knoll L.J., Levin D.E., Gordon J.I.;
RT   "Saccharomyces cerevisiae contains four fatty acid activation (FAA) genes:
RT   an assessment of their role in regulating protein N-myristoylation and
RT   cellular lipid metabolism.";
RL   J. Cell Biol. 127:751-762(1994).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=9169872;
RA   Bowman S., Churcher C.M., Badcock K., Brown D., Chillingworth T.,
RA   Connor R., Dedman K., Devlin K., Gentles S., Hamlin N., Hunt S., Jagels K.,
RA   Lye G., Moule S., Odell C., Pearson D., Rajandream M.A., Rice P.,
RA   Skelton J., Walsh S.V., Whitehead S., Barrell B.G.;
RT   "The nucleotide sequence of Saccharomyces cerevisiae chromosome XIII.";
RL   Nature 387:90-93(1997).
RN   [3]
RP   GENOME REANNOTATION.
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=24374639; DOI=10.1534/g3.113.008995;
RA   Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R.,
RA   Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S.,
RA   Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.;
RT   "The reference genome sequence of Saccharomyces cerevisiae: Then and now.";
RL   G3 (Bethesda) 4:389-398(2014).
RN   [4]
RP   FUNCTION.
RX   PubMed=11477098; DOI=10.1074/jbc.m100884200;
RA   Faergeman N.J., Black P.N., Zhao X.D., Knudsen J., DiRusso C.C.;
RT   "The acyl-CoA synthetases encoded within FAA1 and FAA4 in Saccharomyces
RT   cerevisiae function as components of the fatty acid transport system
RT   linking import, activation, and intracellular utilization.";
RL   J. Biol. Chem. 276:37051-37059(2001).
RN   [5]
RP   FUNCTION, AND INTERACTION WITH FAT1.
RX   PubMed=12601005; DOI=10.1074/jbc.m210557200;
RA   Zou Z., Tong F., Faergeman N.J., Boersting C., Black P.N., DiRusso C.C.;
RT   "Vectorial acylation in Saccharomyces cerevisiae. Fat1p and fatty acyl-CoA
RT   synthetase are interacting components of a fatty acid import complex.";
RL   J. Biol. Chem. 278:16414-16422(2003).
RN   [6]
RP   LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS].
RX   PubMed=14562106; DOI=10.1038/nature02046;
RA   Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N.,
RA   O'Shea E.K., Weissman J.S.;
RT   "Global analysis of protein expression in yeast.";
RL   Nature 425:737-741(2003).
RN   [7]
RP   SUBCELLULAR LOCATION.
RX   PubMed=21820081; DOI=10.1016/j.bbalip.2011.07.015;
RA   Grillitsch K., Connerth M., Kofeler H., Arrey T.N., Rietschel B.,
RA   Wagner B., Karas M., Daum G.;
RT   "Lipid particles/droplets of the yeast Saccharomyces cerevisiae revisited:
RT   lipidome meets proteome.";
RL   Biochim. Biophys. Acta 1811:1165-1176(2011).
RN   [8]
RP   FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=22633490; DOI=10.1016/j.molcel.2012.04.033;
RA   Nakahara K., Ohkuni A., Kitamura T., Abe K., Naganuma T., Ohno Y.,
RA   Zoeller R.A., Kihara A.;
RT   "The Sjogren-Larsson syndrome gene encodes a hexadecenal dehydrogenase of
RT   the sphingosine 1-phosphate degradation pathway.";
RL   Mol. Cell 46:461-471(2012).
RN   [9]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA   Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA   Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA   Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT   "N-terminal acetylome analyses and functional insights of the N-terminal
RT   acetyltransferase NatB.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN   [10]
RP   CATALYTIC ACTIVITY.
RX   PubMed=24269233; DOI=10.1016/j.bbrc.2013.11.036;
RA   Ohkuni A., Ohno Y., Kihara A.;
RT   "Identification of acyl-CoA synthetases involved in the mammalian
RT   sphingosine 1-phosphate metabolic pathway.";
RL   Biochem. Biophys. Res. Commun. 442:195-201(2013).
RN   [11]
RP   SUBCELLULAR LOCATION.
RX   PubMed=24868093; DOI=10.1194/jlr.m050229;
RA   Currie E., Guo X., Christiano R., Chitraju C., Kory N., Harrison K.,
RA   Haas J., Walther T.C., Farese R.V. Jr.;
RT   "High-confidence proteomic analysis of yeast lipid droplets identifies
RT   additional droplet proteins and reveals connections to dolichol synthesis
RT   and sterol acetylation.";
RL   J. Lipid Res. 55:1465-1477(2014).
RN   [12]
RP   FUNCTION.
RX   PubMed=27136724; DOI=10.1038/srep25469;
RA   Narita T., Naganuma T., Sase Y., Kihara A.;
RT   "Long-chain bases of sphingolipids are transported into cells via the acyl-
RT   CoA synthetases.";
RL   Sci. Rep. 6:25469-25469(2016).
CC   -!- FUNCTION: Activates long-chain fatty acids (LCFA) by esterification of
CC       the fatty acids into metabolically active CoA-thioesters for subsequent
CC       degradation or incorporation into phospholipids. Also facilitates the
CC       transport of LCFAs into the cell, either by active transport or by
CC       decreasing the intracellular LCFA concentration (PubMed:7962057,
CC       PubMed:11477098, PubMed:12601005). Contributes, with FAA1, to the
CC       activation of imported myristate (PubMed:7962057). Also involved in
CC       long-chain base (LCB) uptake. In contrast ot LCFA uptake, LCB uptake
CC       does not require ATP, suggesting that the enzyme is directly involved
CC       in LCB uptake (PubMed:27136724). Involved in the sphingolipid-to-
CC       glycerolipid metabolic pathway, converting the sphingolipid metabolite
CC       hexadecenoic acid to hexadecenoyl-CoA, which is then further converted
CC       to glycerolipids (PubMed:22633490). {ECO:0000269|PubMed:11477098,
CC       ECO:0000269|PubMed:12601005, ECO:0000269|PubMed:22633490,
CC       ECO:0000269|PubMed:27136724, ECO:0000269|PubMed:7962057}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a long-chain fatty acid + ATP + CoA = a long-chain fatty acyl-
CC         CoA + AMP + diphosphate; Xref=Rhea:RHEA:15421, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:33019, ChEBI:CHEBI:57287, ChEBI:CHEBI:57560,
CC         ChEBI:CHEBI:83139, ChEBI:CHEBI:456215; EC=6.2.1.3;
CC         Evidence={ECO:0000269|PubMed:11477098};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(9Z)-hexadecenoate + ATP + CoA = (9Z)-hexadecenoyl-CoA + AMP +
CC         diphosphate; Xref=Rhea:RHEA:33647, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:32372, ChEBI:CHEBI:33019, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:61540, ChEBI:CHEBI:456215;
CC         Evidence={ECO:0000269|PubMed:11477098};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33648;
CC         Evidence={ECO:0000305|PubMed:11477098};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(9Z)-octadecenoate + ATP + CoA = (9Z)-octadecenoyl-CoA + AMP +
CC         diphosphate; Xref=Rhea:RHEA:33607, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:30823, ChEBI:CHEBI:33019, ChEBI:CHEBI:57287,
CC         ChEBI:CHEBI:57387, ChEBI:CHEBI:456215;
CC         Evidence={ECO:0000269|PubMed:11477098};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33608;
CC         Evidence={ECO:0000305|PubMed:11477098};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=ATP + CoA + hexadecanoate = AMP + diphosphate + hexadecanoyl-
CC         CoA; Xref=Rhea:RHEA:30751, ChEBI:CHEBI:7896, ChEBI:CHEBI:30616,
CC         ChEBI:CHEBI:33019, ChEBI:CHEBI:57287, ChEBI:CHEBI:57379,
CC         ChEBI:CHEBI:456215; Evidence={ECO:0000269|PubMed:22633490,
CC         ECO:0000269|PubMed:24269233};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:30752;
CC         Evidence={ECO:0000305|PubMed:22633490, ECO:0000305|PubMed:24269233};
CC   -!- COFACTOR:
CC       Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000250};
CC   -!- SUBUNIT: Interacts with FAT1. {ECO:0000269|PubMed:12601005}.
CC   -!- SUBCELLULAR LOCATION: Lipid droplet {ECO:0000269|PubMed:21820081,
CC       ECO:0000269|PubMed:24868093}.
CC   -!- DOMAIN: The FACS motif is required for catalytic activity and substrate
CC       specificity. {ECO:0000250|UniProtKB:P30624}.
CC   -!- MISCELLANEOUS: Present with 31200 molecules/cell in log phase SD
CC       medium. {ECO:0000269|PubMed:14562106}.
CC   -!- SIMILARITY: Belongs to the ATP-dependent AMP-binding enzyme family.
CC       {ECO:0000305}.
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DR   EMBL; Z48744; CAA88635.1; -; Genomic_DNA.
DR   EMBL; Z48756; CAA88656.1; -; Genomic_DNA.
DR   EMBL; BK006946; DAA10147.1; -; Genomic_DNA.
DR   PIR; S56060; S56060.
DR   RefSeq; NP_013974.1; NM_001182754.1.
DR   AlphaFoldDB; P47912; -.
DR   SMR; P47912; -.
DR   BioGRID; 35425; 163.
DR   DIP; DIP-4361N; -.
DR   IntAct; P47912; 44.
DR   MINT; P47912; -.
DR   STRING; 4932.YMR246W; -.
DR   SwissLipids; SLP:000000130; -.
DR   iPTMnet; P47912; -.
DR   MaxQB; P47912; -.
DR   PaxDb; 4932-YMR246W; -.
DR   PeptideAtlas; P47912; -.
DR   EnsemblFungi; YMR246W_mRNA; YMR246W; YMR246W.
DR   GeneID; 855288; -.
DR   KEGG; sce:YMR246W; -.
DR   AGR; SGD:S000004860; -.
DR   SGD; S000004860; FAA4.
DR   VEuPathDB; FungiDB:YMR246W; -.
DR   eggNOG; KOG1180; Eukaryota.
DR   GeneTree; ENSGT00940000171609; -.
DR   HOGENOM; CLU_000022_45_2_1; -.
DR   InParanoid; P47912; -.
DR   OMA; HTDKPHP; -.
DR   OrthoDB; 443463at2759; -.
DR   BioCyc; YEAST:YMR246W-MONOMER; -.
DR   Reactome; R-SCE-434313; Intracellular metabolism of fatty acids regulates insulin secretion.
DR   Reactome; R-SCE-75876; Synthesis of very long-chain fatty acyl-CoAs.
DR   BioGRID-ORCS; 855288; 0 hits in 10 CRISPR screens.
DR   PRO; PR:P47912; -.
DR   Proteomes; UP000002311; Chromosome XIII.
DR   RNAct; P47912; Protein.
DR   GO; GO:0005737; C:cytoplasm; HDA:SGD.
DR   GO; GO:0010494; C:cytoplasmic stress granule; HDA:SGD.
DR   GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
DR   GO; GO:0005811; C:lipid droplet; IDA:SGD.
DR   GO; GO:0005886; C:plasma membrane; IDA:SGD.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004467; F:long-chain fatty acid-CoA ligase activity; IDA:SGD.
DR   GO; GO:0044539; P:long-chain fatty acid import into cell; IGI:SGD.
DR   GO; GO:0001676; P:long-chain fatty acid metabolic process; IBA:GO_Central.
DR   GO; GO:0035336; P:long-chain fatty-acyl-CoA metabolic process; IMP:SGD.
DR   GO; GO:1905329; P:sphingoid long-chain base transport; IGI:SGD.
DR   CDD; cd17639; LC_FACS_euk1; 1.
DR   Gene3D; 3.40.50.12780; N-terminal domain of ligase-like; 1.
DR   InterPro; IPR020845; AMP-binding_CS.
DR   InterPro; IPR000873; AMP-dep_Synth/Lig_com.
DR   InterPro; IPR042099; ANL_N_sf.
DR   PANTHER; PTHR43272:SF83; ACYL-COA SYNTHETASE LONG-CHAIN, ISOFORM J; 1.
DR   PANTHER; PTHR43272; LONG-CHAIN-FATTY-ACID--COA LIGASE; 1.
DR   Pfam; PF00501; AMP-binding; 1.
DR   SUPFAM; SSF56801; Acetyl-CoA synthetase-like; 1.
DR   PROSITE; PS00455; AMP_BINDING; 1.
PE   1: Evidence at protein level;
KW   ATP-binding; Fatty acid metabolism; Ligase; Lipid droplet;
KW   Lipid metabolism; Magnesium; Nucleotide-binding; Reference proteome.
FT   CHAIN           1..694
FT                   /note="Long-chain-fatty-acid--CoA ligase 4"
FT                   /id="PRO_0000193122"
FT   REGION          1..21
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           527..576
FT                   /note="FACS"
FT                   /evidence="ECO:0000250|UniProtKB:P30624"
FT   BINDING         269..280
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P69451"
FT   CONFLICT        552
FT                   /note="N -> G (in Ref. 1; CAA88635)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        631
FT                   /note="V -> G (in Ref. 1; CAA88635)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   694 AA;  77267 MW;  CF6524949C96D24D CRC64;
     MTEQYSVAVG EAANEHETAP RRNIRVKDQP LIRPINSSAS TLYEFALECF TKGGKRDGMA
     WRDIIDIHET KKTIVKRVDG KDKPIEKTWL YYELTPYITM TYEEMICVMH DIGRGLIKIG
     VKPNGENKFH IFASTSHKWM KTFLGCMSQG IPVVTAYDTL GESGLIHSMV ETDSVAIFTD
     NQLLSKLAVP LKTAKNVKFV IHNEPIDPSD KRQNGKLYKA AKDAVDKIKE VRPDIKIYSF
     DEIIEIGKKA KDEVELHFPK PEDPACIMYT SGSTGTPKGV VLTHYNIVAG IGGVGHNVIG
     WIGPTDRIIA FLPLAHIFEL TFEFEAFYWN GILGYANVKT LTPTSTRNCQ GDLMEFKPTV
     MVGVAAVWET VRKGILAKIN ELPGWSQTLF WTVYALKERN IPCSGLLSGL IFKRIREATG
     GNLRFILNGG SAISIDAQKF LSNLLCPMLI GYGLTEGVAN ACVLEPEHFD YGIAGDLVGT
     ITAKLVDVED LGYFAKNNQG ELLFKGAPIC SEYYKNPEET AAAFTDDGWF RTGDIAEWTP
     KGQVKIIDRK KNLVKTLNGE YIALEKLESI YRSNPYVQNI CVYADENKVK PVGIVVPNLG
     HLSKLAIELG IMVPGEDVES YIHEKKLQDA VCKDMLSTAK SQGLNGIELL CGIVFFEEEW
     TPENGLVTSA QKLKRRDILA AVKPDVERVY KENT
//