CP21A_BOVIN
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 03-AUG-2022, entry version 148.
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:25855791, PubMed:22262854). 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:25855791, PubMed:22262854). {ECO:0000269|PubMed:22262854,
CC ECO:0000269|PubMed:25855791}.
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: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 + O2 + reduced [NADPH--hemoprotein
CC reductase] = 11-deoxycortisol + H(+) + H2O + oxidized [NADPH--
CC hemoprotein reductase]; 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}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
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 RefSeq; NP_777064.1; NM_174639.1.
DR PDB; 3QZ1; X-ray; 3.00 A; A/B/C/D=1-496.
DR PDBsum; 3QZ1; -.
DR AlphaFoldDB; P00191; -.
DR SMR; P00191; -.
DR STRING; 9913.ENSBTAP00000054564; -.
DR SwissLipids; SLP:000001620; -.
DR PaxDb; P00191; -.
DR Ensembl; ENSBTAT00000063123; ENSBTAP00000054564; ENSBTAG00000047039.
DR GeneID; 281741; -.
DR GeneID; 282425; -.
DR KEGG; bta:281741; -.
DR CTD; 1589; -.
DR CTD; 281741; -.
DR VEuPathDB; HostDB:ENSBTAG00000047039; -.
DR eggNOG; KOG0156; Eukaryota.
DR GeneTree; ENSGT00940000158338; -.
DR InParanoid; P00191; -.
DR OMA; ICPAWTL; -.
DR OrthoDB; 702827at2759; -.
DR BRENDA; 1.14.14.16; 908.
DR Proteomes; UP000009136; Chromosome 23.
DR Bgee; ENSBTAG00000047039; Expressed in ureter and 91 other tissues.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
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:0005496; F:steroid binding; IEA:UniProtKB-KW.
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 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 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 77..80
FT /evidence="ECO:0007829|PDB:3QZ1"
FT TURN 81..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 137..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 STRAND 423..426
FT /evidence="ECO:0007829|PDB:3QZ1"
FT HELIX 430..447
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
