CP4A2_RAT
ID CP4A2_RAT Reviewed; 504 AA.
AC P20816; Q4G071;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1991, sequence version 2.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=Cytochrome P450 4A2;
DE AltName: Full=CYPIVA2;
DE AltName: Full=Cytochrome P-450 K-2;
DE AltName: Full=Cytochrome P450 K-5;
DE AltName: Full=Cytochrome P450-LA-omega 2;
DE AltName: Full=Lauric acid omega-hydroxylase;
DE AltName: Full=Long-chain fatty acid omega-monooxygenase;
DE EC=1.14.14.80 {ECO:0000269|PubMed:1739747};
DE Flags: Precursor;
GN Name=Cyp4a2 {ECO:0000303|PubMed:10620324, ECO:0000312|RGD:2479};
GN Synonyms=Cyp4a-2, Cyp4a11;
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 [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=2766932; DOI=10.1089/dna.1.1989.8.503;
RA Kimura S., Hanioka N., Matsunaga E., Gonzalez F.J.;
RT "The rat clofibrate-inducible CYP4A gene subfamily. I. Complete intron and
RT exon sequence of the CYP4A1 and CYP4A2 genes, unique exon organization, and
RT identification of a conserved 19-bp upstream element.";
RL DNA 8:503-516(1989).
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 PROTEIN SEQUENCE OF 5-34.
RC TISSUE=Kidney;
RX PubMed=1739747; DOI=10.1016/0005-2760(92)90106-6;
RA Kawashima H., Kusunose E., Kubota I., Maekawa M., Kusunose M.;
RT "Purification and NH2-terminal amino acid sequences of human and rat kidney
RT fatty acid omega-hydroxylases.";
RL Biochim. Biophys. Acta 1123:156-162(1992).
RN [4]
RP PROTEIN SEQUENCE OF 5-19.
RC STRAIN=Sprague-Dawley; TISSUE=Kidney;
RX PubMed=2306108; DOI=10.1016/0003-9861(90)90747-m;
RA Imaoka S., Nagashima K., Funae Y.;
RT "Characterization of three cytochrome P450s purified from renal microsomes
RT of untreated male rats and comparison with human renal cytochrome P450.";
RL Arch. Biochem. Biophys. 276:473-480(1990).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
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 [6]
RP FUNCTION, CATALYTIC ACTIVITY, MUTAGENESIS OF SER-116, AND PATHWAY.
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 [7]
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 [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-434, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
CC -!- FUNCTION: A cytochrome P450 monooxygenase that catalyzes omega and
CC omega-1 hydroxylation of saturated fatty acids. Exhibits preferential
CC omega versus omega-1 regioselectivity and (R) versus (S)
CC stereoselectivity for hydroxylation of lauric and myristic acids
CC (PubMed:10869363, PubMed:10620324). Has low activity toward palmitic
CC acid (PubMed:10620324). Mechanistically, uses molecular oxygen
CC inserting one oxygen atom into a substrate, and reducing the second
CC into a water molecule, with two electrons provided by NADPH via
CC cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase)
CC (PubMed:10869363, PubMed:10620324). {ECO:0000269|PubMed:10620324,
CC ECO:0000269|PubMed:10869363}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an omega-methyl-long-chain fatty acid + O2 + reduced [NADPH--
CC hemoprotein reductase] = an omega-hydroxy-long-chain fatty acid +
CC H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:56748, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:140991,
CC ChEBI:CHEBI:140992; EC=1.14.14.80;
CC Evidence={ECO:0000269|PubMed:1739747};
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=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};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:38948;
CC Evidence={ECO:0000305|PubMed:10620324, ECO:0000305|PubMed:10869363};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=O2 + reduced [NADPH--hemoprotein reductase] + tetradecanoate =
CC 14-hydroxytetradecanoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:40203, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:30807, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:77033; Evidence={ECO:0000269|PubMed:10620324,
CC ECO:0000269|PubMed:10869363};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40204;
CC Evidence={ECO:0000305|PubMed:10620324, ECO:0000305|PubMed:10869363};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=hexadecanoate + O2 + reduced [NADPH--hemoprotein reductase] =
CC 16-hydroxyhexadecanoate + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:40199, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:7896, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:55329, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; EC=1.14.14.80;
CC Evidence={ECO:0000269|PubMed:10620324};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:40200;
CC Evidence={ECO:0000305|PubMed:10620324};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P20817};
CC -!- PATHWAY: Lipid metabolism; fatty acid metabolism.
CC {ECO:0000305|PubMed:10620324, ECO:0000305|PubMed:10869363}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral
CC membrane protein. Microsome membrane; Peripheral membrane protein.
CC -!- INDUCTION: By clofibrate.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; M57719; AAA41039.1; -; Genomic_DNA.
DR EMBL; BC078684; AAH78684.1; -; mRNA.
DR EMBL; BC098705; AAH98705.1; -; mRNA.
DR PIR; A32965; A32965.
DR PIR; PC4350; PC4350.
DR RefSeq; NP_001038235.1; NM_001044770.2.
DR RefSeq; XP_017448632.1; XM_017593143.1.
DR AlphaFoldDB; P20816; -.
DR SMR; P20816; -.
DR STRING; 10116.ENSRNOP00000042072; -.
DR SwissLipids; SLP:000000743; -.
DR iPTMnet; P20816; -.
DR PaxDb; P20816; -.
DR PRIDE; P20816; -.
DR Ensembl; ENSRNOT00000111375; ENSRNOP00000082696; ENSRNOG00000066487.
DR Ensembl; ENSRNOT00000115710; ENSRNOP00000088666; ENSRNOG00000064139.
DR GeneID; 24306; -.
DR KEGG; rno:24306; -.
DR CTD; 24306; -.
DR RGD; 2479; Cyp4a2.
DR eggNOG; KOG0157; Eukaryota.
DR GeneTree; ENSGT00940000155173; -.
DR HOGENOM; CLU_001570_5_1_1; -.
DR InParanoid; P20816; -.
DR OMA; NWAGRFA; -.
DR OrthoDB; 1247045at2759; -.
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 UniPathway; UPA00199; -.
DR PRO; PR:P20816; -.
DR Proteomes; UP000002494; Chromosome 5.
DR Bgee; ENSRNOG00000030154; Expressed in adult mammalian kidney and 14 other tissues.
DR Genevisible; P20816; RN.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
DR GO; GO:0018685; F:alkane 1-monooxygenase activity; IMP:RGD.
DR GO; GO:0008405; F:arachidonic acid 11,12-epoxygenase activity; TAS:RGD.
DR GO; GO:0050544; F:arachidonic acid binding; IDA:RGD.
DR GO; GO:0008391; F:arachidonic acid monooxygenase activity; IMP:RGD.
DR GO; GO:0005504; F:fatty acid binding; IDA:RGD.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0102033; F:long-chain fatty acid omega-hydroxylase activity; IEA:UniProtKB-EC.
DR GO; GO:0019369; P:arachidonic acid metabolic process; IMP:RGD.
DR GO; GO:0046456; P:icosanoid biosynthetic process; IMP:RGD.
DR GO; GO:0001822; P:kidney development; IEP:RGD.
DR GO; GO:0048252; P:lauric acid metabolic process; IDA:RGD.
DR GO; GO:0043651; P:linoleic acid metabolic process; IDA:RGD.
DR GO; GO:0009725; P:response to hormone; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; 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 Direct protein sequencing; Endoplasmic reticulum; Heme; Iron; Membrane;
KW Metal-binding; Microsome; Monooxygenase; NADP; Oxidoreductase;
KW Phosphoprotein; Reference proteome.
FT PROPEP 1..4
FT /evidence="ECO:0000269|PubMed:1739747,
FT ECO:0000269|PubMed:2306108"
FT /id="PRO_0000003567"
FT CHAIN 5..504
FT /note="Cytochrome P450 4A2"
FT /id="PRO_0000003568"
FT BINDING 315
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /note="covalent"
FT /evidence="ECO:0000269|PubMed:11139583"
FT BINDING 451
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 434
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MUTAGEN 116
FT /note="S->F: 2-fold decrease of omega/omega-1 hydroxylation
FT ratio for lauric acid."
FT /evidence="ECO:0000269|PubMed:10869363"
SQ SEQUENCE 504 AA; 57969 MW; 8A795DD454125287 CRC64;
MGFSVFSPTR SLDGVSGFFQ GAFLLSLFLV LFKAVQFYLR RQWLLKALEK FPSTPSHWLW
GHNLKDREFQ QVLTWVEKFP GACLQWLSGS TARVLLYDPD YVKVVLGRSD PKPYQSLAPW
IGYGLLLLNG KKWFQHRRML TPAFHYDILK PYVKIMADSV SIMLDKWEKL DDQDHPLEIF
HYVSLMTLDT VMKCAFSHQG SVQLDVNSRS YTKAVEDLNN LIFFRVRSAF YGNSIIYNMS
SDGRLSRRAC QIAHEHTDGV IKTRKAQLQN EEELQKARKK RHLDFLDILL FAKMEDGKSL
SDEDLRAEVD TFMFEGHDTT ASGISWVFYA LATHPEHQER CREEVQSILG DGTSVTWDHL
DQMPYTTMCI KEALRLYSPV PSVSRELSSP VTFPDGRSIP KGIRVTILIY GLHHNPSYWP
NPKVFDPSRF SPDSPRHSHA YLPFSGGARN CIGKQFAMNE LKVAVALTLL RFELLPDPTR
IPVPMPRLVL KSKNGIHLRL KKLR
