ID   CP4F1_RAT               Reviewed;         524 AA.
AC   P33274;
DT   01-FEB-1994, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1994, sequence version 1.
DT   24-JAN-2024, entry version 144.
DE   RecName: Full=Cytochrome P450 4F1 {ECO:0000303|PubMed:8424651};
DE   AltName: Full=CYPIVF1;
DE   AltName: Full=Cytochrome P450-A3;
DE   AltName: Full=Leukotriene-B4 20-monooxygenase;
DE            EC=1.14.14.94 {ECO:0000269|PubMed:10486137, ECO:0000269|PubMed:14634044};
GN   Name=Cyp4f1 {ECO:0000303|PubMed:8424651, ECO:0000312|RGD:70926};
GN   Synonyms=Cyp4f-1, Cyp4f2;
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], TISSUE SPECIFICITY, AND MISCELLANEOUS.
RC   STRAIN=Sprague-Dawley; TISSUE=Hepatoma;
RX   PubMed=8424651; DOI=10.1006/abbi.1993.1003;
RA   Chen L., Hardwick J.P.;
RT   "Identification of a new P450 subfamily, CYP4F1, expressed in rat hepatic
RT   tumors.";
RL   Arch. Biochem. Biophys. 300:18-23(1993).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=Sprague-Dawley;
RA   Donelson E.L., Wu Y., Vernell R., Chen L., Hardwick J.P.;
RT   "Structure and transcriptional activity of the CYP4F1 leukotriene omega
RT   hydroxylase gene.";
RL   Submitted (OCT-1999) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=10486137; DOI=10.1006/abbi.1999.1271;
RA   Kikuta Y., Kusunose E., Ito M., Kusunose M.;
RT   "Purification and characterization of recombinant rat hepatic CYP4F1.";
RL   Arch. Biochem. Biophys. 369:193-196(1999).
RN   [4]
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   [5]
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).
CC   -!- FUNCTION: A cytochrome P450 monooxygenase involved in the metabolism of
CC       arachidonic acid and its oxygenated derivatives (PubMed:10486137,
CC       PubMed:14634044). Mechanistically, uses molecular oxygen inserting one
CC       oxygen atom into a substrate, and reducing the second into a water
CC       molecule, with two electrons provided by NADPH via cytochrome P450
CC       reductase (CPR; NADPH-ferrihemoprotein reductase). 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). May play a role in the oxidative inactivation of
CC       eicosanoids, including both pro-inflammatory and anti-inflammatory
CC       mediators such as leukotriene B4 (LTB4), lipoxin A4 (LXA4), and several
CC       HETEs (PubMed:10486137, PubMed:14634044). {ECO:0000269|PubMed:10486137,
CC       ECO:0000269|PubMed:14634044}.
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=5-hydroxy-(6E,8Z,11Z,14Z)-eicosatetraenoate + O2 + reduced
CC         [NADPH--hemoprotein reductase] = 5,20-dihydroxy-(6E,8Z,11Z,14Z)-
CC         eicosatetraenoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:48656, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:65341,
CC         ChEBI:CHEBI:90715; Evidence={ECO:0000269|PubMed:10486137};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48657;
CC         Evidence={ECO:0000305|PubMed:10486137};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=8-hydroxy-(5Z,9E,11Z,14Z)-eicosatetraenoate + O2 + reduced
CC         [NADPH--hemoprotein reductase] = 8,20-dihydroxy-(5Z,9E,11Z,14Z)-
CC         eicosatetraenoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:48660, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:90716,
CC         ChEBI:CHEBI:90717; Evidence={ECO:0000269|PubMed:10486137};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48661;
CC         Evidence={ECO:0000305|PubMed:10486137};
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:10486137, ECO:0000269|PubMed:14634044};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22177;
CC         Evidence={ECO:0000305|PubMed:10486137, 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:10486137};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48677;
CC         Evidence={ECO:0000305|PubMed:10486137};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=lipoxin A4 + O2 + reduced [NADPH--hemoprotein reductase] = 20-
CC         hydroxy-lipoxin A4 + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:48648, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:67026,
CC         ChEBI:CHEBI:90707; Evidence={ECO:0000269|PubMed:10486137};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48649;
CC         Evidence={ECO:0000305|PubMed:10486137};
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000269|PubMed:11980497};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=18 uM for 8-hydroxy-(5Z,9E,11Z,14Z)-eicosatetraenoate
CC         {ECO:0000269|PubMed:10486137};
CC         KM=24 uM for leukotriene B4 {ECO:0000269|PubMed:14634044};
CC         KM=81 uM for lipoxin A4 {ECO:0000269|PubMed:10486137};
CC         Vmax=15 nmol/min/nmol enzyme toward
CC         8-hydroxy-(5Z,9E,11Z,14Z)-eicosatetraenoate
CC         {ECO:0000269|PubMed:10486137};
CC         Vmax=10 nmol/min/nmol enzyme toward leukotriene B4
CC         {ECO:0000269|PubMed:14634044};
CC         Vmax=9.74 nmol/min/nmol enzyme toward lipoxin A4
CC         {ECO:0000269|PubMed:10486137};
CC       pH dependence:
CC         Optimum pH is 7.5. {ECO:0000269|PubMed:10486137};
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC       membrane protein {ECO:0000255}. Microsome membrane; Peripheral membrane
CC       protein {ECO:0000255}.
CC   -!- TISSUE SPECIFICITY: Expressed in liver. {ECO:0000269|PubMed:8424651}.
CC   -!- MISCELLANEOUS: Highly expressed in aflatoxin B1-induced hepatic tumors.
CC       {ECO:0000269|PubMed:8424651}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR   EMBL; M94548; AAA41040.1; -; mRNA.
DR   EMBL; AF200361; AAF20822.1; -; Genomic_DNA.
DR   PIR; S29723; S29723.
DR   AlphaFoldDB; P33274; -.
DR   SMR; P33274; -.
DR   IntAct; P33274; 1.
DR   STRING; 10116.ENSRNOP00000006533; -.
DR   ChEMBL; CHEMBL3509587; -.
DR   SwissLipids; SLP:000001703; -.
DR   PhosphoSitePlus; P33274; -.
DR   PaxDb; 10116-ENSRNOP00000006533; -.
DR   UCSC; RGD:70926; rat.
DR   AGR; RGD:70926; -.
DR   RGD; 70926; Cyp4f1.
DR   eggNOG; KOG0157; Eukaryota.
DR   InParanoid; P33274; -.
DR   PhylomeDB; P33274; -.
DR   Reactome; R-RNO-211979; Eicosanoids.
DR   Reactome; R-RNO-2142691; Synthesis of Leukotrienes (LT) and Eoxins (EX).
DR   PRO; PR:P33274; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0050544; F:arachidonic acid binding; IDA:RGD.
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; IDA:RGD.
DR   GO; GO:0006690; P:icosanoid metabolic process; IDA:RGD.
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:0009636; P:response to toxic substance; 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; CYTOCHROME P450 FAMILY 4; 1.
DR   PANTHER; PTHR24291:SF190; LEUKOTRIENE-B4 OMEGA-HYDROXYLASE 3; 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.
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..524
FT                   /note="Cytochrome P450 4F1"
FT                   /id="PRO_0000051849"
FT   TRANSMEM        15..35
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   524 AA;  59868 MW;  572CEA2617CE632D CRC64;
     MSQLSLSWLG LGPEVAFPWQ TLLLFGASWI LAQILTQIYA AYRNFRRLRG FPQPPKRNWL
     MGHVGMVTPT EQGLKELTRL VGTYPQGFLM WIGPMVPVIT LCHSDIVRSI LNASAAVALK
     DVIFYTILKP WLGDGLLVSA GDKWSRHRRM LTPAFHFNIL KPYVKIFNDS TNIMHAKWKR
     LISEGSSRLD MFEHVSLMTL DSLQKCVFSF DSNCQEKSSE YIAAILELSA LVAKRHQQPL
     LFMDLLYNLT PDGMRFHKAC NLVHEFTDAV IRERRRTLPD QGLDEFLKSK AKSKTLDFID
     VLLLTKDEDG KELSDEDIRA EADTFMFEGH DTTASGLSWI LYNLANDPEY QERCRQEVQE
     LLRDRDPEEI EWDDLAQLPF LTMCIKESLR LHPPVTVISR CCTQDILLPD GRTIPKGIIC
     LISIFGIHHN PSVWPDPEVY NPFRFDPENI KDSSPLAFIP FSAGPRNCIG QTFAMSEMKV
     ALALTLLRFR LLPDDKEPRR QPELILRAEG GLWLRVEPLT AGAQ
//