CP2A4_MOUSE
ID CP2A4_MOUSE Reviewed; 494 AA.
AC P15392; Q91XG2;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT 03-OCT-2012, sequence version 3.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Cytochrome P450 2A4;
DE EC=1.14.14.1;
DE AltName: Full=CYPIIA4;
DE AltName: Full=Cytochrome P450-15-alpha;
DE AltName: Full=Cytochrome P450-IIA3.1;
DE AltName: Full=Testosterone 15-alpha-hydroxylase;
GN Name=Cyp2a4; Synonyms=Cyp2a-4;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=2703500; DOI=10.1016/s0021-9258(18)83371-3;
RA Lindberg R., Burkhart B., Ichikawa T., Negishi M.;
RT "The structure and characterization of type I P-450(15) alpha gene as major
RT steroid 15 alpha-hydroxylase and its comparison with type II P-450(15)
RT alpha gene.";
RL J. Biol. Chem. 264:6465-6471(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3346244; DOI=10.1016/s0021-9258(18)68904-5;
RA Squires E.J., Negishi M.;
RT "Reciprocal regulation of sex-dependent expression of testosterone 15
RT alpha-hydroxylase (P-450(15 alpha)) in liver and kidney of male mice by
RT androgen. Evidence for a single gene.";
RL J. Biol. Chem. 263:4166-4171(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; 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 [5]
RP MUTAGENESIS.
RX PubMed=2733794; DOI=10.1038/339632a0;
RA Lindberg R., Negishi M.;
RT "Alteration of mouse cytochrome P450coh substrate specificity by mutation
RT of a single amino-acid residue.";
RL Nature 339:632-634(1989).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=10490589; DOI=10.1128/mcb.19.10.6488;
RA Lavery D.J., Lopez-Molina L., Margueron R., Fleury-Olela F., Conquet F.,
RA Schibler U., Bonfils C.;
RT "Circadian expression of the steroid 15 alpha-hydroxylase (Cyp2a4) and
RT coumarin 7-hydroxylase (Cyp2a5) genes in mouse liver is regulated by the
RT PAR leucine zipper transcription factor DBP.";
RL Mol. Cell. Biol. 19:6488-6499(1999).
CC -!- FUNCTION: Highly active in the 15-alpha-hydroxylation of testosterone.
CC Also active in the 15-alpha-hydroxylation of progesterone and
CC androstenedione. Little or no activity on corticosterone, pregnenolone,
CC dehydroepiandrosterone, estradiol or estriol.
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 -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413; Evidence={ECO:0000250};
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Peripheral
CC membrane protein. Microsome membrane; Peripheral membrane protein.
CC -!- TISSUE SPECIFICITY: Kidney and lung. Expressed in liver, with a strong
CC circadian rhythmicity. Circadian expression is regulated by DBP.
CC {ECO:0000269|PubMed:10490589}.
CC -!- MISCELLANEOUS: There are only 11 differences between the sequence of
CC testosterone 15-alpha-hydroxylase and that of coumarin 7-hydroxylase.
CC By site-directed mutagenesis it has been shown that modification of
CC position 209 is sufficient to convert the specificity of the two forms
CC of the enzyme.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; M26208; AAA37797.1; -; Genomic_DNA.
DR EMBL; M25146; AAA37797.1; JOINED; Genomic_DNA.
DR EMBL; M25147; AAA37797.1; JOINED; Genomic_DNA.
DR EMBL; M26202; AAA37797.1; JOINED; Genomic_DNA.
DR EMBL; M26203; AAA37797.1; JOINED; Genomic_DNA.
DR EMBL; M26205; AAA37797.1; JOINED; Genomic_DNA.
DR EMBL; M26206; AAA37797.1; JOINED; Genomic_DNA.
DR EMBL; M26207; AAA37797.1; JOINED; Genomic_DNA.
DR EMBL; J03549; AAA40426.1; -; mRNA.
DR EMBL; M19319; AAA40429.1; -; mRNA.
DR EMBL; AC161798; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC010761; AAH10761.1; -; mRNA.
DR EMBL; BC063778; AAH63778.1; -; mRNA.
DR CCDS; CCDS21002.1; -.
DR PIR; A33531; A33531.
DR PIR; S03979; S03979.
DR PIR; S16068; S16068.
DR RefSeq; NP_034127.2; NM_009997.2.
DR AlphaFoldDB; P15392; -.
DR SMR; P15392; -.
DR STRING; 10090.ENSMUSP00000096254; -.
DR iPTMnet; P15392; -.
DR PhosphoSitePlus; P15392; -.
DR SwissPalm; P15392; -.
DR jPOST; P15392; -.
DR PaxDb; P15392; -.
DR PeptideAtlas; P15392; -.
DR PRIDE; P15392; -.
DR ProteomicsDB; 283440; -.
DR DNASU; 13086; -.
DR Ensembl; ENSMUST00000098657; ENSMUSP00000096254; ENSMUSG00000074254.
DR GeneID; 13086; -.
DR KEGG; mmu:13086; -.
DR UCSC; uc009fui.1; mouse.
DR CTD; 13086; -.
DR MGI; MGI:88596; Cyp2a4.
DR VEuPathDB; HostDB:ENSMUSG00000074254; -.
DR eggNOG; KOG0156; Eukaryota.
DR GeneTree; ENSGT00940000154117; -.
DR HOGENOM; CLU_001570_22_3_1; -.
DR InParanoid; P15392; -.
DR OMA; EHIAYIG; -.
DR OrthoDB; 702827at2759; -.
DR PhylomeDB; P15392; -.
DR TreeFam; TF352043; -.
DR Reactome; R-MMU-211935; Fatty acids.
DR Reactome; R-MMU-211981; Xenobiotics.
DR Reactome; R-MMU-211999; CYP2E1 reactions.
DR BioGRID-ORCS; 13086; 2 hits in 41 CRISPR screens.
DR ChiTaRS; Cyp2a4; mouse.
DR PRO; PR:P15392; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; P15392; protein.
DR Bgee; ENSMUSG00000074254; Expressed in proximal tubule and 26 other tissues.
DR Genevisible; P15392; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005881; C:cytoplasmic microtubule; ISO:MGI.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0008392; F:arachidonic acid epoxygenase activity; IBA:GO_Central.
DR GO; GO:0070330; F:aromatase activity; IEA:UniProtKB-EC.
DR GO; GO:0008389; F:coumarin 7-hydroxylase activity; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0020037; F:heme binding; ISO:MGI.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0016712; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen; IBA:GO_Central.
DR GO; GO:0008395; F:steroid hydroxylase activity; IBA:GO_Central.
DR GO; GO:0009804; P:coumarin metabolic process; IBA:GO_Central.
DR GO; GO:0019373; P:epoxygenase P450 pathway; IBA:GO_Central.
DR GO; GO:0006082; P:organic acid metabolic process; IBA:GO_Central.
DR GO; GO:0035634; P:response to stilbenoid; IEP:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; IBA:GO_Central.
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; IPR008067; Cyt_P450_E_grp-I_CYP2A-like.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00463; EP450I.
DR PRINTS; PR01684; EP450ICYP2A.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 2: Evidence at transcript level;
KW Acetylation; Endoplasmic reticulum; Heme; Iron; Membrane; Metal-binding;
KW Microsome; Monooxygenase; Oxidoreductase; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..494
FT /note="Cytochrome P450 2A4"
FT /id="PRO_0000051666"
FT BINDING 439
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 MOD_RES 131
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P00176"
FT MOD_RES 379
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q64458"
FT CONFLICT 86
FT /note="T -> A (in Ref. 1; AAA37797 and 2; AAA40426/
FT AAA40429)"
FT /evidence="ECO:0000305"
FT CONFLICT 129
FT /note="R -> S (in Ref. 1; AAA37797 and 2; AAA40426/
FT AAA40429)"
FT /evidence="ECO:0000305"
FT CONFLICT 133
FT /note="T -> A (in Ref. 1; AAA37797 and 2; AAA40426/
FT AAA40429)"
FT /evidence="ECO:0000305"
FT CONFLICT 296
FT /note="L -> Q (in Ref. 2; AAA40426/AAA40429)"
FT /evidence="ECO:0000305"
FT CONFLICT 306
FT /note="V -> G (in Ref. 2; AAA40426/AAA40429)"
FT /evidence="ECO:0000305"
FT CONFLICT 467
FT /note="E -> A (in Ref. 1; AAA37797 and 2; AAA40426/
FT AAA40429)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 494 AA; 56782 MW; B75D17F6EAF4A8EC CRC64;
MLTSGLLLVA AVAFLSVLVL MSVWKQRKLS GKLPPGPTPL PFVGNFLQLN TEQMYNSLMK
ISQRYGPVFT IYLGSRRIVV LCGQETVKEA LVDQAEEFSG RGEQATFDWL FKGYGIAFSS
GERAKQLRRF SITTLRDFGV GKRGIEERIQ EEAGFLIDSF RKTNGAFIDP TFYLSRTVSN
VISSIVFGDR FDYEDKEFLS LLRMMLGSLQ FTATSMGQVY EMFSSVMKHL PGPQQQAFKE
LQGLEDFITK KVEHNQRTLD PNSPRDFIDS FLIRMLEEKK NPNTEFYMKN LVLTTLNLFF
AGTETVSTTL RYGFLLLMKY PDIEAKVHEE IDRVIGRNRQ PKYEDRMKMP YTEAVIHEIQ
RFADLIPMGL ARRVTKDTKF RDFLLPKGTE VFPMLGSVLK DPKFFSNPKD FNPKHFLDDK
GQFKKSDAFV PFSIGKRYCF GEGLARMELF LFLTNIMQNF HFKSTQEPQD IDVSPRLVGF
VTIPPTYTMS FLSR
