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   27-MAR-2024, entry version 167.
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
CC       (NADPH--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
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: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
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: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; 10116-ENSRNOP00000012448; -.
DR   Ensembl; ENSRNOT00000012448.6; ENSRNOP00000012448.4; ENSRNOG00000008842.5.
DR   GeneID; 266674; -.
DR   KEGG; rno:266674; -.
DR   UCSC; RGD:628846; rat.
DR   AGR; RGD:628846; -.
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; QMRTIMV; -.
DR   OrthoDB; 1611592at2759; -.
DR   PhylomeDB; P24464; -.
DR   TreeFam; TF105088; -.
DR   BRENDA; 1.14.14.80; 5301.
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   UniPathway; UPA00199; -.
DR   PRO; PR:P24464; -.
DR   Proteomes; UP000002494; Chromosome 5.
DR   Bgee; ENSRNOG00000008842; Expressed in adult mammalian kidney and 2 other cell types or tissues.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR   GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
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   CDD; cd20678; CYP4B-like; 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:SF39; CYTOCHROME P450 4A11-RELATED; 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; P24464; RN.
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
//