ID   CP21A_MOUSE             Reviewed;         487 AA.
AC   P03940; A0JP50; O88304; Q64510; Q9QX14;
DT   23-OCT-1986, integrated into UniProtKB/Swiss-Prot.
DT   26-APR-2005, sequence version 3.
DT   27-MAR-2024, entry version 173.
DE   RecName: Full=Steroid 21-hydroxylase {ECO:0000303|Ref.3};
DE            EC=1.14.14.16 {ECO:0000250|UniProtKB:P00191, ECO:0000250|UniProtKB:P08686};
DE   AltName: Full=21-OHase;
DE   AltName: Full=Cytochrome P-450c21;
DE   AltName: Full=Cytochrome P450 21;
DE   AltName: Full=Cytochrome P450 XXI;
DE   AltName: Full=Cytochrome P450-C21;
GN   Name=Cyp21; Synonyms=Cyp21a-1, Cyp21a1;
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].
RX   PubMed=3491986; DOI=10.1073/pnas.83.24.9601;
RA   Chaplin D.D., Galbraith L.J., Seidman J.G., White P.C., Parker K.L.;
RT   "Nucleotide sequence analysis of murine 21-hydroxylase genes: mutations
RT   affecting gene expression.";
RL   Proc. Natl. Acad. Sci. U.S.A. 83:9601-9605(1986).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=B10.WR;
RX   PubMed=1918990;
RA   Zepf N.E., Ogata R.T.;
RT   "The murine Slp gene: additional evidence that sex-limited protein has no
RT   biological function.";
RL   J. Immunol. 147:2756-2763(1991).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=C57BL/6 X CBA;
RA   Matsumoto K., Ikuta T.;
RT   "Mus musculus 5' truncated pseudogene of tenascin-X, steroid 21-hydroxylase
RT   (Cyp21), and sex-limited protein (Slp) genes, partial cds and complete
RT   sequences.";
RL   Submitted (JUN-1998) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=129;
RX   PubMed=14656967; DOI=10.1101/gr.1736803;
RA   Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., Campbell R.D.,
RA   Hood L.;
RT   "Analysis of the gene-dense major histocompatibility complex class III
RT   region and its comparison to mouse.";
RL   Genome Res. 13:2621-2636(2003).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 399-487.
RX   PubMed=3874401; DOI=10.1073/pnas.82.13.4453;
RA   Amor M., Tosi M., Duponchel C., Steinmetz M., Meo T.;
RT   "Liver mRNA probes disclose two cytochrome P-450 genes duplicated in tandem
RT   with the complement C4 loci of the mouse H-2S region.";
RL   Proc. Natl. Acad. Sci. U.S.A. 82:4453-4457(1985).
CC   -!- FUNCTION: A cytochrome P450 monooxygenase that plays a major role in
CC       adrenal steroidogenesis. Catalyzes the hydroxylation at C-21 of
CC       progesterone and 17alpha-hydroxyprogesterone to respectively form 11-
CC       deoxycorticosterone and 11-deoxycortisol, intermediate metabolites in
CC       the biosynthetic pathway of mineralocorticoids and glucocorticoids.
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 (CPR; NADPH-
CC       ferrihemoprotein reductase). {ECO:0000250|UniProtKB:P00191,
CC       ECO:0000250|UniProtKB:P08686}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=O2 + progesterone + reduced [NADPH--hemoprotein reductase] =
CC         21-hydroxyprogesterone + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:50304, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:16973, ChEBI:CHEBI:17026, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210; EC=1.14.14.16;
CC         Evidence={ECO:0000250|UniProtKB:P00191,
CC         ECO:0000250|UniProtKB:P08686};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50305;
CC         Evidence={ECO:0000250|UniProtKB:P00191,
CC         ECO:0000250|UniProtKB:P08686};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=17alpha-hydroxyprogesterone + O2 + reduced [NADPH--hemoprotein
CC         reductase] = 11-deoxycortisol + H(+) + H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:50308, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17252,
CC         ChEBI:CHEBI:28324, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210;
CC         EC=1.14.14.16; Evidence={ECO:0000250|UniProtKB:P00191,
CC         ECO:0000250|UniProtKB:P08686};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50309;
CC         Evidence={ECO:0000250|UniProtKB:P00191,
CC         ECO:0000250|UniProtKB:P08686};
CC   -!- COFACTOR:
CC       Name=heme b; Xref=ChEBI:CHEBI:60344;
CC         Evidence={ECO:0000250|UniProtKB:P00191,
CC         ECO:0000250|UniProtKB:P08686};
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000250|UniProtKB:P08686}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:P08686}. Microsome membrane
CC       {ECO:0000250|UniProtKB:P08686}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:P08686}.
CC   -!- DOMAIN: The leucine-rich hydrophobic amino acid N-terminal region
CC       probably helps to anchor the protein to the microsomal membrane.
CC       {ECO:0000250|UniProtKB:P08686}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR   EMBL; M15009; AAA37114.1; -; Genomic_DNA.
DR   EMBL; M64933; AAA40118.1; -; Genomic_DNA.
DR   EMBL; AB015623; BAA31153.1; -; Genomic_DNA.
DR   EMBL; AF049850; AAC05278.1; -; Genomic_DNA.
DR   EMBL; BC127167; AAI27168.1; -; mRNA.
DR   CCDS; CCDS28658.1; -.
DR   PIR; A26660; A26660.
DR   PIR; S54785; S54785.
DR   RefSeq; NP_034125.2; NM_009995.2.
DR   AlphaFoldDB; P03940; -.
DR   SMR; P03940; -.
DR   BioGRID; 199004; 14.
DR   STRING; 10090.ENSMUSP00000025223; -.
DR   iPTMnet; P03940; -.
DR   PhosphoSitePlus; P03940; -.
DR   MaxQB; P03940; -.
DR   PaxDb; 10090-ENSMUSP00000025223; -.
DR   ProteomicsDB; 283808; -.
DR   GeneID; 13079; -.
DR   KEGG; mmu:13079; -.
DR   UCSC; uc008cdo.2; mouse.
DR   AGR; MGI:88591; -.
DR   CTD; 13079; -.
DR   MGI; MGI:88591; Cyp21a1.
DR   eggNOG; KOG0156; Eukaryota.
DR   InParanoid; P03940; -.
DR   OrthoDB; 2900138at2759; -.
DR   PhylomeDB; P03940; -.
DR   TreeFam; TF105095; -.
DR   Reactome; R-MMU-193993; Mineralocorticoid biosynthesis.
DR   Reactome; R-MMU-194002; Glucocorticoid biosynthesis.
DR   Reactome; R-MMU-211976; Endogenous sterols.
DR   BioGRID-ORCS; 13079; 1 hit in 81 CRISPR screens.
DR   PRO; PR:P03940; -.
DR   Proteomes; UP000000589; Unplaced.
DR   RNAct; P03940; Protein.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0103069; F:17-hydroxyprogesterone 21-hydroxylase activity; ISS:UniProtKB.
DR   GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0106309; F:progesterone 21-hydroxylase activity; ISS:UniProtKB.
DR   GO; GO:0004509; F:steroid 21-monooxygenase activity; ISO:MGI.
DR   GO; GO:0005496; F:steroid binding; IEA:UniProtKB-KW.
DR   GO; GO:0008395; F:steroid hydroxylase activity; ISS:UniProtKB.
DR   GO; GO:0006700; P:C21-steroid hormone biosynthetic process; ISO:MGI.
DR   GO; GO:0006704; P:glucocorticoid biosynthetic process; IBA:GO_Central.
DR   GO; GO:0006705; P:mineralocorticoid biosynthetic process; ISO:MGI.
DR   GO; GO:0042448; P:progesterone metabolic process; ISO:MGI.
DR   GO; GO:0008202; P:steroid metabolic process; ISS:UniProtKB.
DR   CDD; cd20674; CYP21; 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; PTHR24289; STEROID 17-ALPHA-HYDROXYLASE/17,20 LYASE; 1.
DR   PANTHER; PTHR24289:SF14; STEROID 21-HYDROXYLASE-LIKE; 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.
PE   2: Evidence at transcript level;
KW   Endoplasmic reticulum; Heme; Iron; Lipid-binding; Membrane; Metal-binding;
KW   Microsome; Monooxygenase; Oxidoreductase; Reference proteome;
KW   Steroid-binding; Steroidogenesis.
FT   CHAIN           1..487
FT                   /note="Steroid 21-hydroxylase"
FT                   /id="PRO_0000051977"
FT   BINDING         92
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         117
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         228
FT                   /ligand="17alpha-hydroxyprogesterone"
FT                   /ligand_id="ChEBI:CHEBI:17252"
FT                   /evidence="ECO:0000250|UniProtKB:P00191"
FT   BINDING         228
FT                   /ligand="progesterone"
FT                   /ligand_id="ChEBI:CHEBI:17026"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         357
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         418
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         420
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /ligand_part="Fe"
FT                   /ligand_part_id="ChEBI:CHEBI:18248"
FT                   /note="axial binding residue"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   CONFLICT        31..32
FT                   /note="PP -> LR (in Ref. 1; AAA37114)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        66
FT                   /note="M -> L (in Ref. 1; AAA37114)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        218
FT                   /note="L -> F (in Ref. 3; BAA31153)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        238
FT                   /note="Q -> R (in Ref. 3; BAA31153 and 4; AAC05278)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        241
FT                   /note="D -> E (in Ref. 1; AAA37114)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        314
FT                   /note="E -> A (in Ref. 1; AAA37114)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   487 AA;  55328 MW;  CAD32B606004449F CRC64;
     MLLPGLLLLL LLLAGTRWLW GQWKLRKLHL PPLAPGFLHF LQPNLPIYLL GLTQKLGPIY
     RIRLGMQDVV VLNSNRTIEE ALIQKWVDFA GRPHMLNGKM DLDLSLGDYS LMWKAHKKLS
     RSALMLGMRD SMEPLIEQLT QEFCERMRAQ AGTPVAIHKE FSFLTCSIIS CLTFGDKDST
     LVQTLHDCVQ DLLQAWNHWS IQILTIIPLL RFLPNPGLQK LKQIQESRDH IVKQQLKQHK
     DSLVAGQWKD MIDYMLQGVE KQRDGKDEER LHEGHVHMSV VDLFIGGTET TATTLSWAVA
     FLLHHPEIQK RLQEELDLKL GPGSQLLYRN RMQLPLLMAT IAEVLRLRPV VPLALPHRAT
     RASSISGYDI PKDMVIIPNI QGANLDEMVW ELPSKFWPDR FLEPGKNPRT PSFGCGARVC
     LGEPLARLEL FVVLARLLQA FTLLPPPDGT LPSLQPQPYA GINLPIPPFQ VRLQPRNLAP
     QDQGERP
//