CP4AC_RAT
ID CP4AC_RAT Reviewed; 508 AA.
AC P24464; Q642E9;
DT 01-MAR-1992, integrated into UniProtKB/Swiss-Prot.
DT 10-JAN-2006, sequence version 2.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Cytochrome P450 4A12;
DE EC=1.14.14.1 {ECO:0000269|PubMed:10620324, ECO:0000269|PubMed:10869363, ECO:0000269|PubMed:15618658};
DE AltName: Full=CYPIVA12;
DE AltName: Full=CYPIVA8;
DE AltName: Full=Cytochrome P450-KP1;
DE AltName: Full=Cytochrome P450-PP1;
GN Name=Cyp4a12; Synonyms=Cyp4a-8, Cyp4a8 {ECO:0000303|PubMed:15618658};
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 TISSUE=Prostate;
RX PubMed=1980193; DOI=10.1089/dna.1990.9.569;
RA Stroemstedt M., Hayashi S., Zaphiropoulos P.G., Gustafsson J.-A.;
RT "Cloning and characterization of a novel member of the cytochrome P450
RT subfamily IVA in rat prostate.";
RL DNA Cell Biol. 9:569-577(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=10620324; DOI=10.1006/abbi.1999.1504;
RA Hoch U., Zhang Z., Kroetz D.L., Ortiz de Montellano P.R.;
RT "Structural determination of the substrate specificities and
RT regioselectivities of the rat and human fatty acid omega-hydroxylases.";
RL Arch. Biochem. Biophys. 373:63-71(2000).
RN [4]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=10869363; DOI=10.1074/jbc.m004841200;
RA Hoch U., Falck J.R., de Montellano P.R.;
RT "Molecular basis for the omega-regiospecificity of the CYP4A2 and CYP4A3
RT fatty acid hydroxylases.";
RL J. Biol. Chem. 275:26952-26958(2000).
RN [5]
RP COVALENT HEME ATTACHMENT.
RX PubMed=11139583; DOI=10.1074/jbc.m009969200;
RA Hoch U., Ortiz de Montellano P.R.;
RT "Covalently linked heme in cytochrome P4504A fatty acid hydroxylases.";
RL J. Biol. Chem. 276:11339-11346(2001).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, PATHWAY, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=15618658; DOI=10.2133/dmpk.17.109;
RA Yamaguchi Y., Kirita S., Hasegawa H., Aoyama J., Imaoka S., Minamiyama S.,
RA Funae Y., Baba T., Matsubara T.;
RT "Contribution of CYP4A8 to the formation of 20-hydroxyeicosatetraenoic acid
RT from arachidonic acid in rat kidney.";
RL Drug Metab. Pharmacokinet. 17:109-116(2002).
CC -!- FUNCTION: A cytochrome P450 monooxygenase involved in the metabolism of
CC fatty acids. Catalyzes predominantly the oxidation of the terminal
CC carbon (omega-oxidation) of saturated and unsaturated fatty acids
CC (PubMed:10620324, PubMed:10869363, PubMed:15618658). May act as a major
CC omega-hydroxylase for dodecanoic (lauric) acid in kidney
CC (PubMed:10620324, PubMed:10869363, PubMed:15618658). At preglomerular
CC arteries, may participate in omega-hydroxylation of (5Z,8Z,11Z,14Z)-
CC eicosatetraenoic acid (arachidonate) to 20-hydroxyeicosatetraenoic acid
CC (20-HETE), a signaling molecule acting both as vasoconstrictive and
CC natriuretic with overall effect on arterial blood pressure
CC (PubMed:15618658). Can also catalyze the oxidation of the penultimate
CC carbon (omega-1 oxidation) of fatty acids with lower efficiency,
CC displaying a preference for the (R)-stereoisomer (PubMed:10869363).
CC Mechanistically, uses molecular oxygen inserting one oxygen atom into a
CC substrate, and reducing the second into a water molecule, with two
CC electrons provided by NADPH via cytochrome P450 reductase (NADPH--
CC hemoprotein reductase) (PubMed:10620324, PubMed:10869363,
CC PubMed:15618658). {ECO:0000269|PubMed:10620324,
CC ECO:0000269|PubMed:10869363, ECO:0000269|PubMed:15618658}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an organic molecule + O2 + reduced [NADPH--hemoprotein
CC reductase] = an alcohol + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:17149, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:30879, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:142491; EC=1.14.14.1;
CC Evidence={ECO:0000269|PubMed:10620324, ECO:0000269|PubMed:10869363,
CC ECO:0000269|PubMed:15618658};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17150;
CC Evidence={ECO:0000305|PubMed:10620324, ECO:0000305|PubMed:10869363,
CC ECO:0000305|PubMed:15618658};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=dodecanoate + O2 + reduced [NADPH--hemoprotein reductase] =
CC 12-hydroxydodecanoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:38947, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:18262, ChEBI:CHEBI:36204, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; Evidence={ECO:0000269|PubMed:10620324,
CC ECO:0000269|PubMed:10869363, ECO:0000269|PubMed:15618658};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38948;
CC Evidence={ECO:0000305|PubMed:10620324, ECO:0000305|PubMed:10869363,
CC ECO:0000305|PubMed:15618658};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=dodecanoate + O2 + reduced [NADPH--hemoprotein reductase] =
CC (11R)-hydroxydodecanoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:41724, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:18262, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:78423; Evidence={ECO:0000269|PubMed:10869363};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:41725;
CC Evidence={ECO:0000305|PubMed:10869363};
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:15618658};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39756;
CC Evidence={ECO:0000305|PubMed:15618658};
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:15618658};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:52525;
CC Evidence={ECO:0000305|PubMed:15618658};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000269|PubMed:11139583};
CC -!- ACTIVITY REGULATION: Activated by cytochrome b5 and phosphatidylserine.
CC {ECO:0000269|PubMed:15618658}.
CC -!- PATHWAY: Lipid metabolism; fatty acid metabolism.
CC {ECO:0000305|PubMed:15618658}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:15618658}; Multi-pass membrane protein
CC {ECO:0000255}. Microsome membrane {ECO:0000269|PubMed:15618658}; Multi-
CC pass membrane protein {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Expressed at proximal straight tubules and
CC preglomerular arteries of the outer medulla as well in the cortex
CC regions of kidney (at protein level). {ECO:0000269|PubMed:15618658}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; M37828; AAA63485.1; -; mRNA.
DR EMBL; BC081771; AAH81771.1; -; mRNA.
DR PIR; A36304; A36304.
DR PIR; PC4352; PC4352.
DR RefSeq; NP_113793.2; NM_031605.2.
DR AlphaFoldDB; P24464; -.
DR SMR; P24464; -.
DR STRING; 10116.ENSRNOP00000012448; -.
DR SwissLipids; SLP:000000745; -.
DR iPTMnet; P24464; -.
DR PhosphoSitePlus; P24464; -.
DR PaxDb; P24464; -.
DR PRIDE; P24464; -.
DR Ensembl; ENSRNOT00000012448; ENSRNOP00000012448; ENSRNOG00000008842.
DR GeneID; 266674; -.
DR KEGG; rno:266674; -.
DR UCSC; RGD:628846; rat.
DR CTD; 266674; -.
DR RGD; 628846; Cyp4a8.
DR eggNOG; KOG0157; Eukaryota.
DR GeneTree; ENSGT00940000155173; -.
DR HOGENOM; CLU_001570_5_1_1; -.
DR InParanoid; P24464; -.
DR OMA; MESILHY; -.
DR OrthoDB; 1247045at2759; -.
DR PhylomeDB; P24464; -.
DR TreeFam; TF105088; -.
DR BRENDA; 1.14.14.80; 5301.
DR Reactome; R-RNO-211935; Fatty acids.
DR Reactome; R-RNO-211958; Miscellaneous substrates.
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 UniPathway; UPA00199; -.
DR PRO; PR:P24464; -.
DR Proteomes; UP000002494; Chromosome 5.
DR Bgee; ENSRNOG00000008842; Expressed in adult mammalian kidney and 2 other tissues.
DR Genevisible; P24464; RN.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
DR GO; GO:0018685; F:alkane 1-monooxygenase activity; IBA:GO_Central.
DR GO; GO:0008391; F:arachidonic acid monooxygenase activity; IBA:GO_Central.
DR GO; GO:0070330; F:aromatase activity; IEA:UniProtKB-EC.
DR GO; GO:0120250; F:fatty acid omega-hydroxylase activity; IDA:UniProtKB.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0019369; P:arachidonic acid metabolic process; IDA:RGD.
DR GO; GO:0006631; P:fatty acid metabolic process; IDA:UniProtKB.
DR GO; GO:0046456; P:icosanoid biosynthetic process; IBA:GO_Central.
DR GO; GO:0001822; P:kidney development; IEP:RGD.
DR GO; GO:0048252; P:lauric acid metabolic process; IDA:UniProtKB.
DR GO; GO:0043651; P:linoleic acid metabolic process; IBA:GO_Central.
DR GO; GO:0033574; P:response to testosterone; IEP:RGD.
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; Lipid metabolism; Membrane;
KW Metal-binding; Microsome; Monooxygenase; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..508
FT /note="Cytochrome P450 4A12"
FT /id="PRO_0000051818"
FT TRANSMEM 10..30
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 120..140
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 319
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /note="covalent"
FT /evidence="ECO:0000269|PubMed:11139583"
FT BINDING 455
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:11139583"
FT MOD_RES 438
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P20816"
FT CONFLICT 32
FT /note="F -> L (in Ref. 1; AAA63485)"
FT /evidence="ECO:0000305"
FT CONFLICT 69
FT /note="E -> D (in Ref. 1; AAA63485)"
FT /evidence="ECO:0000305"
FT CONFLICT 101
FT /note="D -> E (in Ref. 1; AAA63485)"
FT /evidence="ECO:0000305"
FT CONFLICT 114..116
FT /note="SHH -> AHG (in Ref. 1; AAA63485)"
FT /evidence="ECO:0000305"
FT CONFLICT 226
FT /note="S -> F (in Ref. 1; AAA63485)"
FT /evidence="ECO:0000305"
FT CONFLICT 230..233
FT /note="IRNI -> VQNM (in Ref. 1; AAA63485)"
FT /evidence="ECO:0000305"
FT CONFLICT 239
FT /note="I -> F (in Ref. 1; AAA63485)"
FT /evidence="ECO:0000305"
FT CONFLICT 251..252
FT /note="RS -> HN (in Ref. 1; AAA63485)"
FT /evidence="ECO:0000305"
FT CONFLICT 259..260
FT /note="EH -> DY (in Ref. 1; AAA63485)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 508 AA; 58559 MW; 2C2218525FC65513 CRC64;
MSGSALSFTI FPGSILGFLQ IATVLTVLLL LFKTAQFYLH RRWLLRATQQ FPSPPSHWFF
GHKIPKDQEF QDILTRVKNF PSACPQWLWG SNVRIQVYDP DYMKLILGRS DPKSHHSYRF
LAPWIGYGLL LLNGQTWFQH RRMLTPAFHY DTLKPYVGIM ADSVRIMLDK WEQIVGQDST
LEIFQHITLM TLDTIMKCAF SQEGSVQLDR KYKSYIKAVE DLNNLSFFRI RNIFHQNDII
YSLSSNGRKA RSAWQLAHEH TDQVIKSRKA QLQDEEELQK VKQKRRLDFL DILLFARIEN
GSSLSDKDLR AEVDTFMFEG HDTTASGISW IFYALATNPE HQQGCRKEIQ SLLGDGASIT
WDDLDKMPYT TMCIKEALRI YPPVTAVSRM LSTPVTFPDG RSLPKGITVM LSFYGLHHNP
TVWPNPEVFD PYRFAPESSR HSHSFLPFSG GARNCIGKQF AMNELKVAVA LTLLRFELLP
DPTRIPIPIP RLVLKSKNGI YLRLKKLQ
