CP4F4_RAT
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 03-AUG-2022, entry version 141.
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 [NADPH--
CC hemoprotein reductase] = 20-hydroxy-(5Z,8Z,11Z,14Z)-eicosatetraenoate
CC + H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:39755, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC 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 [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:52524, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57398, ChEBI:CHEBI:57618,
CC 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 [NADPH--
CC hemoprotein reductase]; Xref=Rhea:RHEA:52520, Rhea:RHEA-COMP:11964,
CC Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57397, ChEBI:CHEBI:57618,
CC 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; P51869; -.
DR PRIDE; P51869; -.
DR GeneID; 286904; -.
DR KEGG; rno:286904; -.
DR UCSC; RGD:708363; rat.
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 OMA; WVFPNQK; -.
DR OrthoDB; 1247045at2759; -.
DR Reactome; R-RNO-211935; Fatty acids.
DR Reactome; R-RNO-211979; Eicosanoids.
DR PRO; PR:P51869; -.
DR Proteomes; UP000002494; Chromosome 7.
DR Bgee; ENSRNOG00000032895; Expressed in liver and 11 other tissues.
DR Genevisible; P51869; RN.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
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:0042361; P:menaquinone catabolic process; IBA:GO_Central.
DR GO; GO:0097267; P:omega-hydroxylase P450 pathway; IDA:UniProtKB.
DR GO; GO:0042376; P:phylloquinone catabolic process; IBA:GO_Central.
DR GO; GO:1905344; P:prostaglandin catabolic process; IDA:UniProtKB.
DR Gene3D; 1.10.630.10; -; 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 Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 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..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
