ID   CP4F4_RAT               Reviewed;         522 AA.
AC   P51869;
DT   01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 1.
DT   27-MAR-2024, entry version 149.
DE   RecName: Full=Cytochrome P450 4F4;
DE   AltName: Full=CYPIVF4;
DE   AltName: Full=Leukotriene-B4 20-monooxygenase;
DE            EC=1.14.14.94 {ECO:0000269|PubMed:14634044};
GN   Name=Cyp4f4 {ECO:0000303|PubMed:11980497, ECO:0000312|RGD:708363};
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   STRAIN=Sprague-Dawley; TISSUE=Brain;
RX   PubMed=8554568; DOI=10.1006/bbrc.1995.2887;
RA   Kawashima H., Strobel H.W.;
RT   "cDNA cloning of three new forms of rat brain cytochrome P450 belonging to
RT   the CYP4F subfamily.";
RL   Biochem. Biophys. Res. Commun. 217:1137-1144(1995).
RN   [2]
RP   FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX   PubMed=9344476; DOI=10.1006/abbi.1997.0342;
RA   Kawashima H., Kusunose E., Thompson C.M., Strobel H.W.;
RT   "Protein expression, characterization, and regulation of CYP4F4 and CYP4F5
RT   cloned from rat brain.";
RL   Arch. Biochem. Biophys. 347:148-154(1997).
RN   [3]
RP   COVALENT HEME ATTACHMENT.
RX   PubMed=11980497; DOI=10.1021/bi025527y;
RA   LeBrun L.A., Xu F., Kroetz D.L., Ortiz de Montellano P.R.;
RT   "Covalent attachment of the heme prosthetic group in the CYP4F cytochrome
RT   P450 family.";
RL   Biochemistry 41:5931-5937(2002).
RN   [4]
RP   FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=14634044; DOI=10.1124/jpet.103.059626;
RA   Xu F., Falck J.R., Ortiz de Montellano P.R., Kroetz D.L.;
RT   "Catalytic activity and isoform-specific inhibition of rat cytochrome p450
RT   4F enzymes.";
RL   J. Pharmacol. Exp. Ther. 308:887-895(2004).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, TISSUE
RP   SPECIFICITY, AND INDUCTION BY CYTOKINES.
RX   PubMed=17418803; DOI=10.1016/j.abb.2007.02.027;
RA   Kalsotra A., Anakk S., Brommer C.L., Kikuta Y., Morgan E.T., Strobel H.W.;
RT   "Catalytic characterization and cytokine mediated regulation of cytochrome
RT   P450 4Fs in rat hepatocytes.";
RL   Arch. Biochem. Biophys. 461:104-112(2007).
CC   -!- FUNCTION: A cytochrome P450 monooxygenase involved in the metabolism of
CC       arachidonic acid and its oxygenated derivatives (PubMed:14634044,
CC       PubMed:9344476, PubMed:17418803). Mechanistically, uses molecular
CC       oxygen inserting one oxygen atom into a substrate, and reducing the
CC       second into a water molecule, with two electrons provided by NADPH via
CC       cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase)
CC       (PubMed:14634044, PubMed:9344476, PubMed:17418803). Participates in the
CC       conversion of arachidonic acid to omega-hydroxyeicosatetraenoic acid
CC       (20-HETE), a signaling molecule acting both as vasoconstrictive and
CC       natriuretic with overall effect on arterial blood pressure
CC       (PubMed:14634044). Hydroxylates the terminal carbon (omega-
CC       hydroxylation) of inflammatory lipid mediators, including prostaglandin
CC       (PG) A1, PGE1 and leukotriene B4 (LTB4), and may play a role in
CC       inactivation of these oxylipins during the resolution of inflammation
CC       (PubMed:14634044, PubMed:9344476, PubMed:17418803).
CC       {ECO:0000269|PubMed:14634044, ECO:0000269|PubMed:17418803,
CC       ECO:0000269|PubMed:9344476}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced
CC         [NADPH--hemoprotein reductase] = 20-hydroxy-(5Z,8Z,11Z,14Z)-
CC         eicosatetraenoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:39755, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:32395, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC         ChEBI:CHEBI:76624; Evidence={ECO:0000269|PubMed:14634044};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39756;
CC         Evidence={ECO:0000305|PubMed:14634044};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=leukotriene B4 + O2 + reduced [NADPH--hemoprotein reductase] =
CC         20-hydroxy-leukotriene B4 + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:22176, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:57460, ChEBI:CHEBI:57461, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210; EC=1.14.14.94;
CC         Evidence={ECO:0000269|PubMed:14634044, ECO:0000269|PubMed:17418803,
CC         ECO:0000269|PubMed:9344476};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22177;
CC         Evidence={ECO:0000305|PubMed:14634044};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=6-trans-leukotriene B4 + O2 + reduced [NADPH--hemoprotein
CC         reductase] = 20-hydroxy-6-trans-leukotriene B4 + H(+) + H2O +
CC         oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:48676,
CC         Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210, ChEBI:CHEBI:90723, ChEBI:CHEBI:90732;
CC         Evidence={ECO:0000269|PubMed:17418803, ECO:0000269|PubMed:9344476};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48677;
CC         Evidence={ECO:0000305|PubMed:9344476};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=O2 + prostaglandin A1 + reduced [NADPH--hemoprotein reductase]
CC         = 20-hydroxy prostaglandin A1 + H(+) + H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:52524, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57398,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:136663;
CC         Evidence={ECO:0000269|PubMed:9344476};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52525;
CC         Evidence={ECO:0000305|PubMed:9344476};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=O2 + prostaglandin E1 + reduced [NADPH--hemoprotein reductase]
CC         = 20-hydroxy prostaglandin E1 + H(+) + H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:52520, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57397,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:136661;
CC         Evidence={ECO:0000269|PubMed:9344476};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52521;
CC         Evidence={ECO:0000305|PubMed:9344476};
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000269|PubMed:11980497};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=31 uM for leukotriene B4 {ECO:0000269|PubMed:14634044};
CC         KM=45.5 uM for leukotriene B4 {ECO:0000269|PubMed:17418803};
CC         Vmax=40 nmol/min/nmol enzyme toward leukotriene B4
CC         {ECO:0000269|PubMed:14634044};
CC         Vmax=4.02 nmol/min/nmol enzyme toward leukotriene B4
CC         {ECO:0000269|PubMed:17418803};
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass
CC       membrane protein {ECO:0000255}. Microsome membrane; Multi-pass membrane
CC       protein {ECO:0000255}.
CC   -!- TISSUE SPECIFICITY: Expressed in hepatocytes (PubMed:17418803). High
CC       expression in liver and kidney. Lower expression in brain
CC       (PubMed:9344476). {ECO:0000269|PubMed:17418803,
CC       ECO:0000269|PubMed:9344476}.
CC   -!- INDUCTION: Up-regulated in hepatocytes by pro-inflammatory cytokine IL6
CC       and down-regulated by anti-inflammatory cytokine IL10.
CC       {ECO:0000269|PubMed:17418803}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR   EMBL; U39206; AAC52358.1; -; mRNA.
DR   PIR; JC4532; JC4532.
DR   RefSeq; NP_775146.1; NM_173123.1.
DR   AlphaFoldDB; P51869; -.
DR   SMR; P51869; -.
DR   STRING; 10116.ENSRNOP00000039545; -.
DR   ChEMBL; CHEMBL3509597; -.
DR   SwissLipids; SLP:000001704; -.
DR   PaxDb; 10116-ENSRNOP00000039545; -.
DR   GeneID; 286904; -.
DR   KEGG; rno:286904; -.
DR   UCSC; RGD:708363; rat.
DR   AGR; RGD:708363; -.
DR   CTD; 286904; -.
DR   RGD; 708363; Cyp4f4.
DR   VEuPathDB; HostDB:ENSRNOG00000032895; -.
DR   eggNOG; KOG0157; Eukaryota.
DR   HOGENOM; CLU_001570_5_1_1; -.
DR   InParanoid; P51869; -.
DR   OrthoDB; 1611592at2759; -.
DR   Reactome; R-RNO-211935; Fatty acids.
DR   Reactome; R-RNO-211979; Eicosanoids.
DR   Reactome; R-RNO-2142691; Synthesis of Leukotrienes (LT) and Eoxins (EX).
DR   Reactome; R-RNO-2142816; Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE).
DR   PRO; PR:P51869; -.
DR   Proteomes; UP000002494; Chromosome 7.
DR   Bgee; ENSRNOG00000032895; Expressed in liver and 11 other cell types or tissues.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0008391; F:arachidonic acid monooxygenase activity; IDA:UniProtKB.
DR   GO; GO:0020037; F:heme binding; IDA:RGD.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0050051; F:leukotriene-B4 20-monooxygenase activity; IDA:UniProtKB.
DR   GO; GO:0019369; P:arachidonic acid metabolic process; IBA:GO_Central.
DR   GO; GO:0036101; P:leukotriene B4 catabolic process; IDA:UniProtKB.
DR   GO; GO:0097267; P:omega-hydroxylase P450 pathway; IDA:UniProtKB.
DR   GO; GO:1905344; P:prostaglandin catabolic process; IDA:UniProtKB.
DR   GO; GO:1904681; P:response to 3-methylcholanthrene; IEP:RGD.
DR   CDD; cd20679; CYP4F; 1.
DR   Gene3D; 1.10.630.10; Cytochrome P450; 1.
DR   InterPro; IPR001128; Cyt_P450.
DR   InterPro; IPR017972; Cyt_P450_CS.
DR   InterPro; IPR002401; Cyt_P450_E_grp-I.
DR   InterPro; IPR036396; Cyt_P450_sf.
DR   PANTHER; PTHR24291:SF112; CYTOCHROME P450 4F2; 1.
DR   PANTHER; PTHR24291; CYTOCHROME P450 FAMILY 4; 1.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00463; EP450I.
DR   PRINTS; PR00385; P450.
DR   SUPFAM; SSF48264; Cytochrome P450; 1.
DR   PROSITE; PS00086; CYTOCHROME_P450; 1.
DR   Genevisible; P51869; RN.
PE   1: Evidence at protein level;
KW   Endoplasmic reticulum; Heme; Iron; Membrane; Metal-binding; Microsome;
KW   Monooxygenase; Oxidoreductase; Reference proteome; Transmembrane;
KW   Transmembrane helix.
FT   CHAIN           1..522
FT                   /note="Cytochrome P450 4F4"
FT                   /id="PRO_0000051852"
FT   TRANSMEM        15..35
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        87..107
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   BINDING         328
FT                   /ligand="heme"
FT                   /ligand_id="ChEBI:CHEBI:30413"
FT                   /note="covalent"
FT                   /evidence="ECO:0000269|PubMed:11980497"
FT   BINDING         468
FT                   /ligand="heme"
FT                   /ligand_id="ChEBI:CHEBI:30413"
FT                   /ligand_part="Fe"
FT                   /ligand_part_id="ChEBI:CHEBI:18248"
FT                   /note="axial binding residue"
FT                   /evidence="ECO:0000269|PubMed:11980497"
SQ   SEQUENCE   522 AA;  60050 MW;  193EA8E7CE8864D6 CRC64;
     MPQLDLSWLG LRLETSLPWL LLLLIGASWL LVRVLTQTYI FYRTYQHLCD FPQPPKWNWF
     LGHLGMITPT EQGLKQVTKL VATYPQGFMT WLGPILPIIT LCHPDVIRSV LSASASVALK
     EVIFYSFLKP WLGDGLLLSD GDKWSCHRRM LTPAFHFNIL KPYVKIFNDS TNIMHAKWQD
     LASGGSARLD MFKNISLMTL DSLQKCVFSF DSNCQEKPSE YISAILELSA LVAKRYQQLL
     LHTDSLYQLT HNGRRFHKAC KLVHNFTDAV IQGRRRALPS QHEDDILKAK ARSKTLDFID
     VLLLTKDEDG KELSDEDIRA EADTFMFEGH DTTASGLSWI LYNLARHPEY QERCRQEVRE
     LLRDRESTEI EWDDLAQLPF LTMCIKESLR LHPPVTVISR RCTQDIVLPD GRVIPKGVIC
     IINIFATHHN PTVWPDPEVY DPFRFDPENI KDRSPLAFIP FSAGPRNCIG QTFAMNEMKV
     ALALTLLRFR VLPDDKEPRR KPELILRAEG GLWLRVEPLS TQ
//