ID   LTC4S_MOUSE             Reviewed;         150 AA.
AC   Q60860; Q5SVR7; Q9QVS1;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   24-JAN-2024, entry version 152.
DE   RecName: Full=Leukotriene C4 synthase;
DE            Short=LTC4 synthase;
DE            EC=4.4.1.20 {ECO:0000269|PubMed:11319240, ECO:0000269|PubMed:8706658};
DE   AltName: Full=Glutathione S-transferase LTC4;
DE            EC=2.5.1.- {ECO:0000250|UniProtKB:Q16873};
DE   AltName: Full=Leukotriene-C(4) synthase;
GN   Name=Ltc4s;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=9342232; DOI=10.1111/j.1432-1033.1997.00807.x;
RA   Penrose J.F., Baldasaro M.H., Webster M., Xu K., Austen K.F., Lam B.K.;
RT   "Molecular cloning of the gene for mouse leukotriene-C4 synthase.";
RL   Eur. J. Biochem. 248:807-813(1997).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=C57BL/6J;
RX   PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA   Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA   Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA   Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA   Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA   Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA   Eichler E.E., Ponting C.P.;
RT   "Lineage-specific biology revealed by a finished genome assembly of the
RT   mouse.";
RL   PLoS Biol. 7:E1000112-E1000112(2009).
RN   [3]
RP   PROTEIN SEQUENCE OF 1-27.
RC   TISSUE=Mast cell;
RX   PubMed=7766706; DOI=10.1016/0005-2760(95)00031-7;
RA   Goppelt-Struebe M.;
RT   "Two step purification of human and murine leukotriene C4 synthase.";
RL   Biochim. Biophys. Acta 1256:257-261(1995).
RN   [4]
RP   IDENTIFICATION, TISSUE SPECIFICITY, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP   PROPERTIES, AND FUNCTION.
RX   PubMed=8706658; DOI=10.1111/j.1432-1033.1996.0606w.x;
RA   Lam B.K., Penrose J.F., Rokach J., Xu K., Baldasaro M.H., Austen K.F.;
RT   "Molecular cloning, expression and characterization of mouse leukotriene C4
RT   synthase.";
RL   Eur. J. Biochem. 238:606-612(1996).
RN   [5]
RP   DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, AND FUNCTION.
RX   PubMed=11319240; DOI=10.1074/jbc.m103562200;
RA   Kanaoka Y., Maekawa A., Penrose J.F., Austen K.F., Lam B.K.;
RT   "Attenuated zymosan-induced peritoneal vascular permeability and IgE-
RT   dependent passive cutaneous anaphylaxis in mice lacking leukotriene C4
RT   synthase.";
RL   J. Biol. Chem. 276:22608-22613(2001).
CC   -!- FUNCTION: Catalyzes the conjugation of leukotriene A4 with reduced
CC       glutathione (GSH) to form leukotriene C4 with high specificity
CC       (PubMed:8706658, PubMed:11319240). Can also catalyze the transfer of a
CC       glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-
CC       docosahexaenoic acid to form maresin conjugate in tissue regeneration 1
CC       (MCTR1), a bioactive lipid mediator that possess potent anti-
CC       inflammatory and proresolving actions (By similarity).
CC       {ECO:0000250|UniProtKB:Q16873, ECO:0000269|PubMed:11319240,
CC       ECO:0000269|PubMed:8706658}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=leukotriene C4 = glutathione + leukotriene A4;
CC         Xref=Rhea:RHEA:17617, ChEBI:CHEBI:57463, ChEBI:CHEBI:57925,
CC         ChEBI:CHEBI:57973; EC=4.4.1.20;
CC         Evidence={ECO:0000269|PubMed:11319240, ECO:0000269|PubMed:8706658};
CC       PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:17619;
CC         Evidence={ECO:0000250|UniProtKB:Q16873};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(13S,14S)-epoxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate +
CC         glutathione = (13R)-S-glutathionyl-(14S)-hydroxy-
CC         (4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate; Xref=Rhea:RHEA:53508,
CC         ChEBI:CHEBI:57925, ChEBI:CHEBI:131958, ChEBI:CHEBI:137407;
CC         Evidence={ECO:0000250|UniProtKB:Q16873};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53509;
CC         Evidence={ECO:0000250|UniProtKB:Q16873};
CC   -!- ACTIVITY REGULATION: Inhibited by MK886.
CC       {ECO:0000250|UniProtKB:Q16873}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=10.3 uM for leukotriene A4 {ECO:0000269|PubMed:8706658};
CC         KM=1.9 uM for glutathione {ECO:0000269|PubMed:8706658};
CC         Vmax=2.3 umol/min/mg enzyme with leukotriene A4 as substrate
CC         {ECO:0000269|PubMed:8706658};
CC         Vmax=2.2 umol/min/mg enzyme with glutathione as substrate
CC         {ECO:0000269|PubMed:8706658};
CC   -!- PATHWAY: Lipid metabolism; leukotriene C4 biosynthesis.
CC       {ECO:0000250|UniProtKB:Q16873}.
CC   -!- SUBUNIT: Homotrimer. Interacts with ALOX5AP and ALOX5.
CC       {ECO:0000250|UniProtKB:Q16873}.
CC   -!- SUBCELLULAR LOCATION: Nucleus outer membrane
CC       {ECO:0000250|UniProtKB:Q16873}; Multi-pass membrane protein
CC       {ECO:0000250|UniProtKB:Q16873}. Endoplasmic reticulum membrane
CC       {ECO:0000250|UniProtKB:Q16873}; Multi-pass membrane protein
CC       {ECO:0000250|UniProtKB:Q16873}. Nucleus membrane
CC       {ECO:0000250|UniProtKB:Q16873}; Multi-pass membrane protein
CC       {ECO:0000250|UniProtKB:Q16873}.
CC   -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:8706658}.
CC   -!- PTM: Phosphorylation at Ser-36 by RPS6KB1 inhibits the leukotriene-C4
CC       synthase activity. {ECO:0000250|UniProtKB:Q16873}.
CC   -!- DISRUPTION PHENOTYPE: Deficient mice developed normally and are
CC       fertile. However mice display abnormal inflammatory and
CC       hypersensitivity reactions. {ECO:0000269|PubMed:11319240}.
CC   -!- SIMILARITY: Belongs to the MAPEG family. {ECO:0000305}.
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DR   EMBL; U27195; AAA75042.1; -; mRNA.
DR   EMBL; AL627187; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   CCDS; CCDS24631.1; -.
DR   PIR; S68961; S68961.
DR   RefSeq; NP_032547.1; NM_008521.2.
DR   PDB; 4NTA; X-ray; 2.70 A; A=2-150.
DR   PDB; 4NTB; X-ray; 2.70 A; A=2-150.
DR   PDB; 4NTF; X-ray; 2.65 A; A=2-150.
DR   PDBsum; 4NTA; -.
DR   PDBsum; 4NTB; -.
DR   PDBsum; 4NTF; -.
DR   AlphaFoldDB; Q60860; -.
DR   SMR; Q60860; -.
DR   STRING; 10090.ENSMUSP00000099833; -.
DR   SwissLipids; SLP:000001453; -.
DR   iPTMnet; Q60860; -.
DR   PhosphoSitePlus; Q60860; -.
DR   MaxQB; Q60860; -.
DR   PaxDb; 10090-ENSMUSP00000099833; -.
DR   PeptideAtlas; Q60860; -.
DR   ProteomicsDB; 252682; -.
DR   DNASU; 17001; -.
DR   Ensembl; ENSMUST00000102772.4; ENSMUSP00000099833.4; ENSMUSG00000020377.16.
DR   GeneID; 17001; -.
DR   KEGG; mmu:17001; -.
DR   UCSC; uc007isa.1; mouse.
DR   AGR; MGI:107498; -.
DR   CTD; 4056; -.
DR   MGI; MGI:107498; Ltc4s.
DR   VEuPathDB; HostDB:ENSMUSG00000020377; -.
DR   eggNOG; ENOG502RZYY; Eukaryota.
DR   GeneTree; ENSGT00900000143680; -.
DR   HOGENOM; CLU_110291_3_0_1; -.
DR   InParanoid; Q60860; -.
DR   OMA; AGIYFHE; -.
DR   OrthoDB; 5396066at2759; -.
DR   TreeFam; TF105328; -.
DR   BRENDA; 4.4.1.20; 3474.
DR   Reactome; R-MMU-2142688; Synthesis of 5-eicosatetraenoic acids.
DR   Reactome; R-MMU-2142691; Synthesis of Leukotrienes (LT) and Eoxins (EX).
DR   Reactome; R-MMU-2142700; Synthesis of Lipoxins (LX).
DR   Reactome; R-MMU-9026762; Biosynthesis of maresin conjugates in tissue regeneration (MCTR).
DR   Reactome; R-MMU-9026766; Biosynthesis of protectin and resolvin conjugates in tissue regeneration (PCTR and RCTR).
DR   UniPathway; UPA00879; -.
DR   BioGRID-ORCS; 17001; 3 hits in 79 CRISPR screens.
DR   ChiTaRS; Ltc4s; mouse.
DR   PRO; PR:Q60860; -.
DR   Proteomes; UP000000589; Chromosome 11.
DR   RNAct; Q60860; Protein.
DR   Bgee; ENSMUSG00000020377; Expressed in choroid plexus of fourth ventricle and 87 other cell types or tissues.
DR   ExpressionAtlas; Q60860; baseline and differential.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
DR   GO; GO:0005635; C:nuclear envelope; ISS:UniProtKB.
DR   GO; GO:0031965; C:nuclear membrane; ISS:UniProtKB.
DR   GO; GO:0005640; C:nuclear outer membrane; ISS:UniProtKB.
DR   GO; GO:0008047; F:enzyme activator activity; IEA:InterPro.
DR   GO; GO:0043295; F:glutathione binding; ISO:MGI.
DR   GO; GO:0004602; F:glutathione peroxidase activity; IBA:GO_Central.
DR   GO; GO:0004364; F:glutathione transferase activity; IBA:GO_Central.
DR   GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR   GO; GO:0004464; F:leukotriene-C4 synthase activity; IDA:UniProtKB.
DR   GO; GO:0008289; F:lipid binding; IDA:MGI.
DR   GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR   GO; GO:0019370; P:leukotriene biosynthetic process; ISO:MGI.
DR   GO; GO:0006691; P:leukotriene metabolic process; IDA:MGI.
DR   GO; GO:0042759; P:long-chain fatty acid biosynthetic process; ISO:MGI.
DR   Gene3D; 1.20.120.550; Membrane associated eicosanoid/glutathione metabolism-like domain; 1.
DR   InterPro; IPR001446; 5_LipOase_AP.
DR   InterPro; IPR018295; FLAP/GST2/LTC4S_CS.
DR   InterPro; IPR023352; MAPEG-like_dom_sf.
DR   InterPro; IPR001129; Membr-assoc_MAPEG.
DR   PANTHER; PTHR10250:SF4; LEUKOTRIENE C4 SYNTHASE; 1.
DR   PANTHER; PTHR10250; MICROSOMAL GLUTATHIONE S-TRANSFERASE; 1.
DR   Pfam; PF01124; MAPEG; 1.
DR   PRINTS; PR00488; 5LPOXGNASEAP.
DR   SUPFAM; SSF161084; MAPEG domain-like; 1.
DR   PROSITE; PS01297; FLAP_GST2_LTC4S; 1.
DR   Genevisible; Q60860; MM.
PE   1: Evidence at protein level;
KW   3D-structure; Direct protein sequencing; Endoplasmic reticulum;
KW   Leukotriene biosynthesis; Lipid metabolism; Lyase; Membrane; Nucleus;
KW   Phosphoprotein; Reference proteome; Transferase; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..150
FT                   /note="Leukotriene C4 synthase"
FT                   /id="PRO_0000217749"
FT   TOPO_DOM        1..6
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   TRANSMEM        7..27
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   TOPO_DOM        28..48
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   TRANSMEM        49..69
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   TOPO_DOM        70..73
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   TRANSMEM        74..94
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   TOPO_DOM        95..104
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   TRANSMEM        105..124
FT                   /note="Helical"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   TOPO_DOM        125..150
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   ACT_SITE        31
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   ACT_SITE        104
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   BINDING         30
FT                   /ligand="glutathione"
FT                   /ligand_id="ChEBI:CHEBI:57925"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   BINDING         51..55
FT                   /ligand="glutathione"
FT                   /ligand_id="ChEBI:CHEBI:57925"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   BINDING         53
FT                   /ligand="glutathione"
FT                   /ligand_id="ChEBI:CHEBI:57925"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   BINDING         58..59
FT                   /ligand="glutathione"
FT                   /ligand_id="ChEBI:CHEBI:57925"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   BINDING         93..97
FT                   /ligand="glutathione"
FT                   /ligand_id="ChEBI:CHEBI:57925"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   MOD_RES         36
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q16873"
FT   HELIX           2..5
FT                   /evidence="ECO:0007829|PDB:4NTF"
FT   HELIX           6..32
FT                   /evidence="ECO:0007829|PDB:4NTF"
FT   HELIX           44..73
FT                   /evidence="ECO:0007829|PDB:4NTF"
FT   HELIX           76..99
FT                   /evidence="ECO:0007829|PDB:4NTF"
FT   HELIX           102..104
FT                   /evidence="ECO:0007829|PDB:4NTF"
FT   HELIX           105..141
FT                   /evidence="ECO:0007829|PDB:4NTF"
SQ   SEQUENCE   150 AA;  16814 MW;  120ABC53892189C0 CRC64;
     MKDEVALLAT VTLVGVLLQA YFSLQVISAR RAFHVSPPLT SGPPEFERVF RAQVNCSEYF
     PLFLATLWVA GIFFHEGAAA LCGLFYLFAR LRYFQGYARS AQLRLTPLYA SARALWLLVA
     MAALGLLVHF LPGTLRTALF RWLQMLLPMA
//