ID   CP21A_BOVIN             Reviewed;         496 AA.
AC   P00191;
DT   21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1990, sequence version 2.
DT   02-SEP-2026, entry version 164.
DE   RecName: Full=Steroid 21-hydroxylase {ECO:0000303|PubMed:25855791};
DE            EC=1.14.14.16 {ECO:0000269|PubMed:22262854, ECO:0000269|PubMed:25855791};
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, CYP21A2;
OS   Bos taurus (Bovine).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC   Bovinae; Bos.
OX   NCBI_TaxID=9913;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=3487086; DOI=10.1073/pnas.83.12.4243;
RA   Chung B., Matteson K.J., Miller W.L.;
RT   "Structure of a bovine gene for P-450c21 (steroid 21-hydroxylase) defines a
RT   novel cytochrome P-450 gene family.";
RL   Proc. Natl. Acad. Sci. U.S.A. 83:4243-4247(1986).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=3005319; DOI=10.1016/s0021-9258(17)35630-2;
RA   Yoshioka H., Morohashi K., Sogawa K., Yamane M., Kominami S., Takemori S.,
RA   Okada Y., Omura T., Fujii-Kuriyama Y.;
RT   "Structural analysis of cloned cDNA for mRNA of microsomal cytochrome P-
RT   450(C21) which catalyzes steroid 21-hydroxylation in bovine adrenal
RT   cortex.";
RL   J. Biol. Chem. 261:4106-4109(1986).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 121-496.
RX   PubMed=2424492; DOI=10.1021/bi00358a016;
RA   John M.E., Okamura T., Dee A., Adler B., John M.C., White P.C.,
RA   Simpson E.R., Waterman M.R.;
RT   "Bovine steroid 21-hydroxylase: regulation of biosynthesis.";
RL   Biochemistry 25:2846-2853(1986).
RN   [4]
RP   PROTEIN SEQUENCE OF 1-15.
RX   PubMed=6654880;
RA   Ogishima T., Okada Y., Kominami S., Takemori S., Omura T.;
RT   "Partial amino acid sequences of two mitochondrial and two microsomal
RT   cytochrome P-450's from adrenal cortex.";
RL   J. Biochem. 94:1711-1714(1983).
RN   [5]
RP   FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=25855791; DOI=10.1074/jbc.m115.646307;
RA   Pallan P.S., Wang C., Lei L., Yoshimoto F.K., Auchus R.J., Waterman M.R.,
RA   Guengerich F.P., Egli M.;
RT   "Human Cytochrome P450 21A2, the major steroid 21-hydroxylase: structure of
RT   the enzyme-progesterone substrate complex and rate-limiting c-h bond
RT   cleavage.";
RL   J. Biol. Chem. 290:13128-13143(2015).
RN   [6] {ECO:0007744|PDB:3QZ1}
RP   X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) IN COMPLEX WITH HEME AND
RP   17-HYDROXYPROGESTERONE, FUNCTION, COFACTOR, AND CATALYTIC ACTIVITY.
RX   PubMed=22262854; DOI=10.1074/jbc.m111.323501;
RA   Zhao B., Lei L., Kagawa N., Sundaramoorthy M., Banerjee S., Nagy L.D.,
RA   Guengerich F.P., Waterman M.R.;
RT   "Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450
RT   21A2) with two substrates reveals locations of disease-associated
RT   variants.";
RL   J. Biol. Chem. 287:10613-10622(2012).
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       (PubMed:22262854, PubMed:25855791). Mechanistically, uses molecular
CC       oxygen inserting one oxygen atom into a substrate, and reducing the
CC       second into a water molecule, with two electrons provided by NADPH via
CC       cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase)
CC       (PubMed:22262854, PubMed:25855791). {ECO:0000269|PubMed:22262854,
CC       ECO:0000269|PubMed:25855791}.
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:0000269|PubMed:22262854, ECO:0000269|PubMed:25855791};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50305;
CC         Evidence={ECO:0000305|PubMed:22262854, ECO:0000305|PubMed:25855791};
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:0000269|PubMed:22262854, ECO:0000269|PubMed:25855791};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50309;
CC         Evidence={ECO:0000305|PubMed:22262854, ECO:0000305|PubMed:25855791};
CC   -!- COFACTOR:
CC       Name=heme b; Xref=ChEBI:CHEBI:60344;
CC         Evidence={ECO:0000269|PubMed:22262854};
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.5 uM for progesterone {ECO:0000269|PubMed:25855791};
CC         KM=0.44 uM for 17alpha-hydroxyprogesterone
CC         {ECO:0000269|PubMed:25855791};
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; M11267; AAA83247.1; -; Genomic_DNA.
DR   EMBL; M12918; AAA30487.1; -; mRNA.
DR   EMBL; K01333; AAA30486.1; -; mRNA.
DR   PIR; A27555; O4BOC2.
DR   RefSeq; NP_001013614.1; NM_001013596.1.
DR   PDB; 3QZ1; X-ray; 3.00 A; A/B/C/D=1-496.
DR   AlphaFoldDB; P00191; -.
DR   SMR; P00191; -.
DR   FunCoup; P00191; 2.
DR   STRING; 9913.ENSBTAP00000054564; -.
DR   SwissLipids; SLP:000001620; -.
DR   PaxDb; 9913-ENSBTAP00000054564; -.
DR   Ensembl; ENSBTAT00000063123.2; ENSBTAP00000054564.2; ENSBTAG00000047039.3.
DR   Ensembl; ENSBTAT00085077966; ENSBTAP00085021425; ENSBTAG00085014754.
DR   Ensembl; ENSBTAT00090060090; ENSBTAP00090032358; ENSBTAG00090028470.
DR   GeneID; 281741; -.
DR   KEGG; bta:281741; -.
DR   CTD; 1589; -.
DR   VEuPathDB; HostDB:ENSBTAG00000047039; -.
DR   eggNOG; KOG0156; Eukaryota.
DR   GeneTree; ENSGT00940000158338; -.
DR   InParanoid; P00191; -.
DR   OMA; RICVHEM; -.
DR   OrthoDB; 2789670at2759; -.
DR   BRENDA; 1.14.14.16; 908.
DR   Reactome; R-BTA-193993; Mineralocorticoid biosynthesis.
DR   Reactome; R-BTA-194002; Glucocorticoid biosynthesis.
DR   Reactome; R-BTA-211976; Endogenous sterols.
DR   SABIO-RK; P00191; -.
DR   EvolutionaryTrace; P00191; -.
DR   Proteomes; UP000009136; Chromosome 23.
DR   Bgee; ENSBTAG00000047039; Expressed in ureter and 91 other cell types or tissues.
DR   ExpressionAtlas; P00191; baseline.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
DR   GO; GO:0103069; F:17-hydroxyprogesterone 21-hydroxylase activity; IDA: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; IDA: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:0006694; P:steroid biosynthetic process; IDA:UniProtKB.
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.
DR   PDBsum; 3QZ1; -.
PE   1: Evidence at protein level;
KW   3D-structure; Direct protein sequencing; Endoplasmic reticulum; Heme; Iron;
KW   Lipid metabolism; Lipid-binding; Membrane; Metal-binding; Microsome;
KW   Monooxygenase; Oxidoreductase; Reference proteome; Steroid-binding;
KW   Steroidogenesis.
FT   CHAIN           1..496
FT                   /note="Steroid 21-hydroxylase"
FT                   /id="PRO_0000051974"
FT   BINDING         109
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000269|PubMed:22262854,
FT                   ECO:0007744|PDB:3QZ1"
FT   BINDING         232
FT                   /ligand="17alpha-hydroxyprogesterone"
FT                   /ligand_id="ChEBI:CHEBI:17252"
FT                   /evidence="ECO:0000269|PubMed:22262854,
FT                   ECO:0007744|PDB:3QZ1"
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:0000269|PubMed:22262854,
FT                   ECO:0007744|PDB:3QZ1"
FT   BINDING         425
FT                   /ligand="heme b"
FT                   /ligand_id="ChEBI:CHEBI:60344"
FT                   /evidence="ECO:0000269|PubMed:22262854,
FT                   ECO:0007744|PDB:3QZ1"
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:0000269|PubMed:22262854,
FT                   ECO:0007744|PDB:3QZ1"
FT   CONFLICT        13
FT                   /note="L -> K (in Ref. 4; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        14
FT                   /note="A -> S (in Ref. 2; AAA30487)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        401
FT                   /note="H -> Y (in Ref. 2; AAA30487)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        431
FT                   /note="S -> C (in Ref. 3; AAA30486)"
FT                   /evidence="ECO:0000305"
FT   STRAND          41..43
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           45..51
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           52..54
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          58..62
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          64..67
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          69..72
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           80..84
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   TURN            96..100
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          108..111
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           115..129
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           136..152
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           160..165
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           167..172
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   TURN            173..176
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           183..194
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   TURN            195..200
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           203..210
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           212..214
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           220..245
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          253..255
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           256..259
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           278..308
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           310..324
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          326..331
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           337..339
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           342..354
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          357..360
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          373..377
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          382..385
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           387..390
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   TURN            394..396
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          397..399
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          410..412
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           414..416
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   STRAND          423..426
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           430..447
FT                   /evidence="ECO:0007829|PDB:3QZ1"
FT   HELIX           457..459
FT                   /evidence="ECO:0007829|PDB:3QZ1"
SQ   SEQUENCE   496 AA;  56077 MW;  2E87C829A7E66B31 CRC64;
     MVLAGLLLLL TLLAGAHLLW GRWKLRNLHL PPLVPGFLHL LQPNLPIHLL SLTQKLGPVY
     RLRLGLQEVV VLNSKRTIEE AMIRKWVDFA GRPQIPSYKL VSQRCQDISL GDYSLLWKAH
     KKLTRSALLL GTRSSMEPWV DQLTQEFCER MRVQAGAPVT IQKEFSLLTC SIICYLTFGN
     KEDTLVHAFH DCVQDLMKTW DHWSIQILDM VPFLRFFPNP GLWRLKQAIE NRDHMVEKQL
     TRHKESMVAG QWRDMTDYML QGVGRQRVEE GPGQLLEGHV HMSVVDLFIG GTETTASTLS
     WAVAFLLHHP EIQRRLQEEL DRELGPGASC SRVTYKDRAR LPLLNATIAE VLRLRPVVPL
     ALPHRTTRPS SIFGYDIPEG MVVIPNLQGA HLDETVWEQP HEFRPDRFLE PGANPSALAF
     GCGARVCLGE SLARLELFVV LLRLLQAFTL LPPPVGALPS LQPDPYCGVN LKVQPFQVRL
     QPRGVEAGAW ESASAQ
//