ID   C11B2_RAT               Reviewed;         510 AA.
AC   P30099; Q64540;
DT   01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT   01-APR-1993, sequence version 1.
DT   13-SEP-2023, entry version 156.
DE   RecName: Full=Cytochrome P450 11B2, mitochondrial;
DE   AltName: Full=Aldosterone synthase {ECO:0000303|PubMed:2738055};
DE            Short=ALDOS;
DE   AltName: Full=Aldosterone-synthesizing enzyme;
DE   AltName: Full=CYPXIB2;
DE   AltName: Full=Corticosterone 18-monooxygenase, CYP11B2;
DE            EC=1.14.15.5 {ECO:0000250|UniProtKB:P19099};
DE   AltName: Full=Cytochrome P-450Aldo {ECO:0000303|PubMed:2738055};
DE   AltName: Full=Cytochrome P-450C18;
DE   AltName: Full=Cytochrome P450(11beta,aldo) {ECO:0000303|PubMed:1765101};
DE            Short=P450(11beta,aldo) {ECO:0000303|PubMed:1562515, ECO:0000303|PubMed:1765101};
DE   AltName: Full=Cytochrome P450-Aldo-1;
DE   AltName: Full=Steroid 11-beta-hydroxylase, CYP11B2 {ECO:0000250|UniProtKB:P19099};
DE            EC=1.14.15.4 {ECO:0000250|UniProtKB:P19099};
DE   AltName: Full=Steroid 18-hydroxylase;
DE   Flags: Precursor;
GN   Name=Cyp11b2; Synonyms=Cyp11b-2;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RC   TISSUE=Adrenal gland;
RX   PubMed=2350348; DOI=10.1016/0006-291x(90)91460-a;
RA   Matsukawa N., Nonaka Y., Ying Z., Higaki J., Ogihara T., Okamoto M.;
RT   "Molecular cloning and expression of cDNAS encoding rat aldosterone
RT   synthase: variants of cytochrome P-450(11 beta).";
RL   Biochem. Biophys. Res. Commun. 169:245-252(1990).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=1562515; DOI=10.1016/0960-0760(92)90367-r;
RA   Okamoto M., Nonaka Y.;
RT   "Molecular biology of rat steroid 11 beta-hydroxylase [P450(11 beta)] and
RT   aldosterone synthase [P450(11 beta, aldo)].";
RL   J. Steroid Biochem. Mol. Biol. 41:415-419(1992).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, AND FUNCTION.
RC   STRAIN=Sprague-Dawley; TISSUE=Adrenal gland;
RX   PubMed=8333830; DOI=10.1006/bbrc.1993.1792;
RA   Zhou M., Gomez-Sanchez C.E.;
RT   "Cloning and expression of a rat cytochrome P-450 11 beta-
RT   hydroxylase/aldosterone synthase (CYP11B2) cDNA variant.";
RL   Biochem. Biophys. Res. Commun. 194:112-117(1993).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA], INDUCTION, AND VARIANT GLY-84.
RX   PubMed=8468320; DOI=10.1093/oxfordjournals.jbchem.a124018;
RA   Nomura M., Morohashi K., Kirita S., Nonaka Y., Okamoto M., Nawata H.,
RA   Omura T.;
RT   "Three forms of rat CYP11B genes: 11 beta-hydroxylase gene, aldosterone
RT   synthase gene, and a novel gene.";
RL   J. Biochem. 113:144-152(1993).
RN   [5]
RP   PROTEIN SEQUENCE OF 35-54, FUNCTION, CATALYTIC ACTIVITY, AND TISSUE
RP   SPECIFICITY.
RC   TISSUE=Adrenal cortex;
RX   PubMed=2738055; DOI=10.1016/s0021-9258(18)60408-9;
RA   Ogishima T., Mitani F., Ishimura Y.;
RT   "Isolation of aldosterone synthase cytochrome P-450 from zona glomerulosa
RT   mitochondria of rat adrenal cortex.";
RL   J. Biol. Chem. 264:10935-10938(1989).
RN   [6]
RP   FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX   PubMed=1765101; DOI=10.1111/j.1432-1033.1991.tb16449.x;
RA   Nonaka Y., Okamoto M.;
RT   "Functional expression of the cDNAs encoding rat 11 beta-hydroxylase
RT   [cytochrome P450(11 beta)] and aldosterone synthase [cytochrome P450(11
RT   beta, aldo)].";
RL   Eur. J. Biochem. 202:897-902(1991).
CC   -!- FUNCTION: A cytochrome P450 monooxygenase that catalyzes the
CC       biosynthesis of aldosterone, the main mineralocorticoid responsible for
CC       salt and water homeostasis (PubMed:2738055, PubMed:1765101,
CC       PubMed:1562515, PubMed:2350348). Catalyzes three sequential oxidative
CC       reactions of 11-deoxycorticosterone (21-hydroxyprogesterone), namely
CC       11-beta hydroxylation, followed by two successive oxidations at C18
CC       yielding 18-hydroxy and then 18-oxo intermediates (that do not leave
CC       the enzyme active site during the consecutive hydroxylation reactions),
CC       and end with the formation of aldosterone (PubMed:2738055,
CC       PubMed:1765101, PubMed:8333830, PubMed:2350348). Can also produce 18-
CC       hydroxycortisol and 18-oxocortisol, derived from successive oxidations
CC       of cortisol at C18, normally found at very low levels, but
CC       significantly increased in primary aldosteronism, the most common form
CC       of secondary hypertension (By similarity) (PubMed:1562515).
CC       Mechanistically, uses molecular oxygen inserting one oxygen atom into a
CC       substrate and reducing the second into a water molecule. Two electrons
CC       are provided by NADPH via a two-protein mitochondrial transfer system
CC       comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and
CC       nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin).
CC       Could also be involved in the androgen metabolic pathway (By
CC       similarity). {ECO:0000250|UniProtKB:P19099, ECO:0000269|PubMed:1562515,
CC       ECO:0000269|PubMed:1765101, ECO:0000269|PubMed:2350348,
CC       ECO:0000269|PubMed:2738055, ECO:0000269|PubMed:8333830}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a steroid + 2 H(+) + O2 + 2 reduced [adrenodoxin] = an 11beta-
CC         hydroxysteroid + H2O + 2 oxidized [adrenodoxin];
CC         Xref=Rhea:RHEA:15629, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:33737, ChEBI:CHEBI:33738, ChEBI:CHEBI:35341,
CC         ChEBI:CHEBI:35346; EC=1.14.15.4;
CC         Evidence={ECO:0000269|PubMed:1562515, ECO:0000269|PubMed:1765101,
CC         ECO:0000269|PubMed:2350348, ECO:0000269|PubMed:2738055,
CC         ECO:0000269|PubMed:8333830};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:15630;
CC         Evidence={ECO:0000305|PubMed:1562515, ECO:0000305|PubMed:1765101,
CC         ECO:0000305|PubMed:2350348, ECO:0000305|PubMed:2738055,
CC         ECO:0000305|PubMed:8333830};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=21-hydroxyprogesterone + 2 H(+) + O2 + 2 reduced [adrenodoxin]
CC         = corticosterone + H2O + 2 oxidized [adrenodoxin];
CC         Xref=Rhea:RHEA:46104, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:16827, ChEBI:CHEBI:16973, ChEBI:CHEBI:33737,
CC         ChEBI:CHEBI:33738; Evidence={ECO:0000269|PubMed:1562515,
CC         ECO:0000269|PubMed:1765101, ECO:0000269|PubMed:2350348,
CC         ECO:0000269|PubMed:2738055, ECO:0000269|PubMed:8333830};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46105;
CC         Evidence={ECO:0000305|PubMed:1562515, ECO:0000305|PubMed:1765101,
CC         ECO:0000305|PubMed:2350348, ECO:0000305|PubMed:2738055,
CC         ECO:0000305|PubMed:8333830};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=corticosterone + 2 H(+) + O2 + 2 reduced [adrenodoxin] = 18-
CC         hydroxycorticosterone + H2O + 2 oxidized [adrenodoxin];
CC         Xref=Rhea:RHEA:11872, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:16485, ChEBI:CHEBI:16827, ChEBI:CHEBI:33737,
CC         ChEBI:CHEBI:33738; EC=1.14.15.5;
CC         Evidence={ECO:0000269|PubMed:1765101, ECO:0000305|PubMed:1562515,
CC         ECO:0000305|PubMed:2350348, ECO:0000305|PubMed:2738055,
CC         ECO:0000305|PubMed:8333830};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11873;
CC         Evidence={ECO:0000305|PubMed:1562515, ECO:0000305|PubMed:1765101,
CC         ECO:0000305|PubMed:2350348, ECO:0000305|PubMed:2738055,
CC         ECO:0000305|PubMed:8333830};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=18-hydroxycorticosterone + 2 H(+) + O2 + 2 reduced
CC         [adrenodoxin] = aldosterone + 2 H2O + 2 oxidized [adrenodoxin];
CC         Xref=Rhea:RHEA:50792, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:16485, ChEBI:CHEBI:27584, ChEBI:CHEBI:33737,
CC         ChEBI:CHEBI:33738; Evidence={ECO:0000269|PubMed:1765101,
CC         ECO:0000305|PubMed:1562515, ECO:0000305|PubMed:2350348,
CC         ECO:0000305|PubMed:2738055, ECO:0000305|PubMed:8333830};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50793;
CC         Evidence={ECO:0000305|PubMed:1562515, ECO:0000305|PubMed:1765101,
CC         ECO:0000305|PubMed:2350348, ECO:0000305|PubMed:2738055,
CC         ECO:0000305|PubMed:8333830};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=11-deoxycortisol + 2 H(+) + O2 + 2 reduced [adrenodoxin] =
CC         cortisol + H2O + 2 oxidized [adrenodoxin]; Xref=Rhea:RHEA:46100,
CC         Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:17650,
CC         ChEBI:CHEBI:28324, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738;
CC         Evidence={ECO:0000269|PubMed:1562515};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46101;
CC         Evidence={ECO:0000305|PubMed:1562515};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=cortisol + 2 H(+) + O2 + 2 reduced [adrenodoxin] = 18-
CC         hydroxycortisol + H2O + 2 oxidized [adrenodoxin];
CC         Xref=Rhea:RHEA:76019, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:17650, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC         ChEBI:CHEBI:89455; Evidence={ECO:0000305|PubMed:1562515};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76020;
CC         Evidence={ECO:0000305|PubMed:1562515};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=21-hydroxyprogesterone + 2 H(+) + O2 + 2 reduced [adrenodoxin]
CC         = 18-hydroxy-11-deoxycorticosterone + H2O + 2 oxidized [adrenodoxin];
CC         Xref=Rhea:RHEA:76151, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:16973, ChEBI:CHEBI:33737, ChEBI:CHEBI:33738,
CC         ChEBI:CHEBI:195166; Evidence={ECO:0000269|PubMed:2738055};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76152;
CC         Evidence={ECO:0000305|PubMed:2738055};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=18-hydroxycortisol + 2 H(+) + O2 + 2 reduced [adrenodoxin] =
CC         18-oxocortisol + 2 H2O + 2 oxidized [adrenodoxin];
CC         Xref=Rhea:RHEA:76023, Rhea:RHEA-COMP:9998, Rhea:RHEA-COMP:9999,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:33737, ChEBI:CHEBI:33738, ChEBI:CHEBI:89213,
CC         ChEBI:CHEBI:89455; Evidence={ECO:0000250|UniProtKB:P19099};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:76024;
CC         Evidence={ECO:0000250|UniProtKB:P19099};
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000250|UniProtKB:P19099};
CC   -!- PATHWAY: Steroid biosynthesis. {ECO:0000305|PubMed:1765101}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC       {ECO:0000250|UniProtKB:P14137}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:P14137}.
CC   -!- TISSUE SPECIFICITY: Adrenal cortex. {ECO:0000269|PubMed:2738055}.
CC   -!- INDUCTION: A 12-fold increase was seen in the presence of a low sodium-
CC       high potassium diet. {ECO:0000269|PubMed:8468320}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR   EMBL; D00567; BAA00444.1; -; mRNA.
DR   EMBL; U14908; AAB60457.1; -; mRNA.
DR   PIR; A35342; A35342.
DR   PIR; JN0615; JN0615.
DR   AlphaFoldDB; P30099; -.
DR   SMR; P30099; -.
DR   BindingDB; P30099; -.
DR   ChEMBL; CHEMBL3237; -.
DR   iPTMnet; P30099; -.
DR   PhosphoSitePlus; P30099; -.
DR   UCSC; RGD:2454; rat.
DR   AGR; RGD:2454; -.
DR   RGD; 2454; Cyp11b2.
DR   InParanoid; P30099; -.
DR   PhylomeDB; P30099; -.
DR   Reactome; R-RNO-194002; Glucocorticoid biosynthesis.
DR   Reactome; R-RNO-211976; Endogenous sterols.
DR   PRO; PR:P30099; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0030425; C:dendrite; IDA:RGD.
DR   GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central.
DR   GO; GO:0005739; C:mitochondrion; ISO:RGD.
DR   GO; GO:0047783; F:corticosterone 18-monooxygenase activity; IDA:RGD.
DR   GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0004507; F:steroid 11-beta-monooxygenase activity; IDA:RGD.
DR   GO; GO:0032342; P:aldosterone biosynthetic process; IDA:RGD.
DR   GO; GO:0006700; P:C21-steroid hormone biosynthetic process; IDA:RGD.
DR   GO; GO:0032870; P:cellular response to hormone stimulus; ISO:RGD.
DR   GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:RGD.
DR   GO; GO:0031670; P:cellular response to nutrient; IEP:RGD.
DR   GO; GO:0071375; P:cellular response to peptide hormone stimulus; IEP:RGD.
DR   GO; GO:0035865; P:cellular response to potassium ion; ISO:RGD.
DR   GO; GO:0051365; P:cellular response to potassium ion starvation; IEP:RGD.
DR   GO; GO:0008203; P:cholesterol metabolic process; IBA:GO_Central.
DR   GO; GO:0034651; P:cortisol biosynthetic process; ISO:RGD.
DR   GO; GO:0034650; P:cortisol metabolic process; IBA:GO_Central.
DR   GO; GO:0006704; P:glucocorticoid biosynthetic process; IDA:RGD.
DR   GO; GO:0045777; P:positive regulation of blood pressure; IMP:RGD.
DR   GO; GO:0008217; P:regulation of blood pressure; ISO:RGD.
DR   GO; GO:0032868; P:response to insulin; IEP:RGD.
DR   GO; GO:0007584; P:response to nutrient; IEP:RGD.
DR   GO; GO:0043434; P:response to peptide hormone; IEP:RGD.
DR   GO; GO:0009651; P:response to salt stress; IEP:RGD.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR   Gene3D; 1.10.630.10; Cytochrome P450; 1.
DR   InterPro; IPR001128; Cyt_P450.
DR   InterPro; IPR017972; Cyt_P450_CS.
DR   InterPro; IPR002399; Cyt_P450_mitochondrial.
DR   InterPro; IPR036396; Cyt_P450_sf.
DR   PANTHER; PTHR24279; -; 1.
DR   PANTHER; PTHR24279:SF1; CYTOCHROME P450 11B2, MITOCHONDRIAL; 1.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00408; MITP450.
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; Heme; Iron; Membrane; Metal-binding;
KW   Mitochondrion; Mitochondrion inner membrane; Monooxygenase; Oxidoreductase;
KW   Reference proteome; Steroidogenesis; Transit peptide.
FT   TRANSIT         1..34
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000269|PubMed:2738055"
FT   CHAIN           35..510
FT                   /note="Cytochrome P450 11B2, mitochondrial"
FT                   /id="PRO_0000003604"
FT   BINDING         391
FT                   /ligand="21-hydroxyprogesterone"
FT                   /ligand_id="ChEBI:CHEBI:16973"
FT                   /evidence="ECO:0000250|UniProtKB:P19099"
FT   BINDING         457
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                   /evidence="ECO:0000250|UniProtKB:P19099"
FT   VARIANT         84
FT                   /note="E -> G"
FT                   /evidence="ECO:0000269|PubMed:8468320"
FT   VARIANT         146
FT                   /note="E -> D"
FT   VARIANT         261
FT                   /note="Q -> R"
FT   VARIANT         509
FT                   /note="I -> V"
FT   CONFLICT        1..13
FT                   /note="MGACDNDFIELHS -> MNKAPAKAL (in Ref. 3; AAB60457)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   510 AA;  58241 MW;  2E5129EE513DEA9E CRC64;
     MGACDNDFIE LHSRVTADVW LARPWQCLHR TRALGTTATL APKTLKPFEA IPQYSRNKWL
     KMIQILREQG QENLHLEMHQ AFQELGPIFR HSAGGAQIVS VMLPEDAEKL HQVESILPRR
     MHLEPWVAHR ELRGLRRGVF LLNGAEWRFN RLKLNPNVLS PKAVQNFVPM VDEVARDFLE
     ALKKKVRQNA RGSLTMDVQQ SLFNYTIEAS NFALFGERLG LLGHDLNPGS LKFIHALHSM
     FKSTTQLLFL PRSLTRWTST QVWKEHFDAW DVISEYANRC IWKVHQELRL GSSQTYSGIV
     AALITQGALP LDAIKANSME LTAGSVDTTA IPLVMTLFEL ARNPDVQQAL RQETLAAEAS
     IAANPQKAMS DLPLLRAALK ETLRLYPVGG FLERILNSDL VLQNYHVPAG TLVLLYLYSM
     GRNPAVFPRP ERYMPQRWLE RKRSFQHLAF GFGVRQCLGR RLAEVEMLLL LHHMLKTFQV
     ETLRQEDVQM AYRFVLMPSS SPVLTFRPIS
//