ID   CP21A_PIG               Reviewed;         492 AA.
AC   P15540; A5A8W6; Q02390;
DT   01-APR-1990, integrated into UniProtKB/Swiss-Prot.
DT   26-APR-2005, sequence version 2.
DT   02-SEP-2026, entry version 168.
DE   RecName: Full=Steroid 21-hydroxylase {ECO:0000303|PubMed:2109953};
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=CYP21A1, CYP21A3;
OS   Sus scrofa (Pig).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX   NCBI_TaxID=9823;
RN   [1]
RP   PROTEIN SEQUENCE.
RC   TISSUE=Adrenal gland;
RX   PubMed=3495238; DOI=10.1016/0003-9861(87)90115-9;
RA   Haniu M., Yanagibashi K., Hall P.F., Shively J.E.;
RT   "Complete amino acid sequence of 21-hydroxylase cytochrome P-450 from
RT   porcine adrenal microsomes.";
RL   Arch. Biochem. Biophys. 254:380-384(1987).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=1482677; DOI=10.1016/0167-4781(92)90115-g;
RA   Burghelle-Mayeur C., Geffrotin C., Vaiman M.;
RT   "Sequences of the swine 21-hydroxylase gene (CYP21) and a portion of the
RT   opposite-strand overlapping gene of unknown function previously described
RT   in human.";
RL   Biochim. Biophys. Acta 1171:153-161(1992).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=Meishan;
RX   PubMed=12643481; DOI=10.2527/2003.812385x;
RA   Quintanilla R., Demeure O., Bidanel J.P., Milan D., Iannuccelli N.,
RA   Amigues Y., Gruand J., Renard C., Chevalet C., Bonneau M.;
RT   "Detection of quantitative trait loci for fat androstenone levels in
RT   pigs.";
RL   J. Anim. Sci. 81:385-394(2003).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RG   Porcine genome sequencing project;
RL   Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases.
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-99.
RX   PubMed=2109953; DOI=10.1111/j.1365-2052.1990.tb03202.x;
RA   Geffrotin C., Chardon P., de Andres-Cara D.F., Feil R., Renard C.,
RA   Vaiman M.;
RT   "The swine steroid 21-hydroxylase gene (CYP21): cloning and mapping within
RT   the swine leucocyte antigen complex.";
RL   Anim. Genet. 21:1-13(1990).
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=progesterone + reduced [NADPH--hemoprotein reductase] + O2 =
CC         21-hydroxyprogesterone + oxidized [NADPH--hemoprotein reductase] +
CC         H2O + H(+); 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 + reduced [NADPH--hemoprotein
CC         reductase] + O2 = 11-deoxycortisol + oxidized [NADPH--hemoprotein
CC         reductase] + H2O + H(+); Xref=Rhea:RHEA:50308, Rhea:RHEA-COMP:11964,
CC         Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:15379, ChEBI:CHEBI:17252, ChEBI:CHEBI:28324,
CC         ChEBI:CHEBI:57618, 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: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; M83939; AAA31080.1; -; Genomic_DNA.
DR   EMBL; AF490410; AAM11646.1; -; Genomic_DNA.
DR   EMBL; AL773560; CAN59658.1; -; Genomic_DNA.
DR   PIR; S28169; A32525.
DR   RefSeq; NP_999598.1; NM_214433.1.
DR   AlphaFoldDB; P15540; -.
DR   SMR; P15540; -.
DR   FunCoup; P15540; 43.
DR   STRING; 9823.ENSSSCP00000062899; -.
DR   PaxDb; 9823-ENSSSCP00000062899; -.
DR   Ensembl; ENSSSCT00000001571.5; ENSSSCP00000001529.2; ENSSSCG00000001428.6.
DR   Ensembl; ENSSSCT00030070209.1; ENSSSCP00030032011.1; ENSSSCG00030050353.1.
DR   Ensembl; ENSSSCT00035083801.1; ENSSSCP00035034843.1; ENSSSCG00035062342.1.
DR   Ensembl; ENSSSCT00040073731.1; ENSSSCP00040031580.1; ENSSSCG00040054409.1.
DR   Ensembl; ENSSSCT00085020983; ENSSSCP00085014455; ENSSSCG00085011229.
DR   GeneID; 403337; -.
DR   KEGG; ssc:403337; -.
DR   CTD; 13079; -.
DR   VGNC; VGNC:103369; CYP21A1.
DR   eggNOG; KOG0156; Eukaryota.
DR   GeneTree; ENSGT00940000158338; -.
DR   InParanoid; P15540; -.
DR   OMA; RICVHEM; -.
DR   OrthoDB; 2789670at2759; -.
DR   Reactome; R-SSC-193993; Mineralocorticoid biosynthesis.
DR   Reactome; R-SSC-194002; Glucocorticoid biosynthesis.
DR   Reactome; R-SSC-211976; Endogenous sterols.
DR   Proteomes; UP000008227; Chromosome 7.
DR   Bgee; ENSSSCG00000001428; Expressed in semimembranosus muscle and 11 other cell types or tissues.
DR   ExpressionAtlas; P15540; differential.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
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; IBA:GO_Central.
DR   GO; GO:0008395; F:steroid hydroxylase activity; ISS:UniProtKB.
DR   GO; GO:0006704; P:glucocorticoid biosynthetic process; IBA:GO_Central.
DR   GO; GO:0008202; P:steroid metabolic process; ISS:UniProtKB.
DR   CDD; cd20674; CYP21; 1.
DR   FunFam; 1.10.630.10:FF:000049; steroid 21-hydroxylase isoform X1; 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:SF17; STEROID 21-HYDROXYLASE ISOFORM X1; 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   1: Evidence at protein level;
KW   Direct protein sequencing; Endoplasmic reticulum; Heme; Iron;
KW   Lipid-binding; Membrane; Metal-binding; Microsome; Monooxygenase;
KW   Oxidoreductase; Reference proteome; Steroid-binding; Steroidogenesis.
FT   CHAIN           1..492
FT                   /note="Steroid 21-hydroxylase"
FT                   /id="PRO_0000051978"
FT   BINDING         92
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         121
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         232
FT                   /ligand="17alpha-hydroxyprogesterone"
FT                   /ligand_id="ChEBI:CHEBI:17252"
FT                   /evidence="ECO:0000250|UniProtKB:P00191"
FT   BINDING         232
FT                   /ligand="progesterone"
FT                   /ligand_id="ChEBI:CHEBI:17026"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         364
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         425
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000250|UniProtKB:P08686"
FT   BINDING         427
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        10
FT                   /note="L -> T (in Ref. 1; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        13
FT                   /note="L -> K (in Ref. 1; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        55
FT                   /note="R -> K (in Ref. 1; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        141
FT                   /note="E -> C (in Ref. 1; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        201
FT                   /note="E -> D (in Ref. 1; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        391
FT                   /note="H -> I (in Ref. 1; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        463..465
FT                   /note="HPH -> VPY (in Ref. 1; AA sequence)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   492 AA;  55620 MW;  1FD5FFBFCA5A9E02 CRC64;
     MVLVWLLLLL TLLAGARLLW GQWKLRNLHL PPLVPGFLHL LQPNLPIYLL GLTQRLGPIY
     RLRLGLQDVV VLNSKRTIEE ALVRKWVDFA GRPQIPSYKL ASQHCPDISL GDYSLFWKAH
     KKLTRSALLL GVRSSMEPRV EQLTQEFCER MRAQAGTPVT IQKEFSVLTC SIICCLTFGD
     KEDTLVHALH DCVQDLMKTW EHWSIQILDM VPFLRFFPSP GLRRLKQAIE NRDHLVEKQL
     RRHKESMVAG QWRDMLDYML QEAGRQRVEE GQGQLLEGHV HMSVVDLFIG GTETTANTLS
     WAVVYLLHHP EIQWRLQEEL DRELGPGAAG SRVPYKDRAR LPLLNATIAE VLRLRPVVPL
     ALPHRATRPS SIFGYDIPEG TVVIPNLQGA HLDETVWEQP HEFRPDRFLA PGANPSALAF
     GCGARVCLGE PLARLELFVV LVQLLQAFTL LPPEGALPSL QPHPHSGINL KVQPFQVRLQ
     PRGGRGEGPG PR
//