DHI2_RAT
ID DHI2_RAT Reviewed; 400 AA.
AC P50233;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=11-beta-hydroxysteroid dehydrogenase type 2;
DE Short=11-DH2;
DE Short=11-beta-HSD2;
DE EC=1.1.1.- {ECO:0000269|PubMed:7649078};
DE AltName: Full=Corticosteroid 11-beta-dehydrogenase isozyme 2;
DE AltName: Full=NAD-dependent 11-beta-hydroxysteroid dehydrogenase;
GN Name=Hsd11b2; Synonyms=Hsd11k;
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], TISSUE SPECIFICITY, FUNCTION, CATALYTIC
RP ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RC STRAIN=Sprague-Dawley; TISSUE=Kidney;
RX PubMed=7649078; DOI=10.1210/endo.136.9.7649078;
RA Zhou M.-Y., Gomez-Sanchez E.P., Cox D.L., Cosby D., Gomez-Sanchez C.E.;
RT "Cloning, expression, and tissue distribution of the rat nicotinamide
RT adenine dinucleotide-dependent 11 beta-hydroxysteroid dehydrogenase.";
RL Endocrinology 136:3729-3734(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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 [3]
RP CAUTION.
RX PubMed=1312193; DOI=10.1016/0024-3205(92)90204-3;
RA van Weerden W.M., Bierings H.G., van Steenbrugge G.J., de Jong F.H.,
RA Schroeder F.H.;
RT "Adrenal glands of mouse and rat do not synthesize androgens.";
RL Life Sci. 50:857-861(1992).
RN [4]
RP PROTEIN SEQUENCE OF 19-25, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC STRAIN=Sprague-Dawley; TISSUE=Hippocampus;
RA Lubec G., Chen W.-Q.;
RL Submitted (JAN-2009) to UniProtKB.
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=34028587; DOI=10.1007/s00424-021-02582-7;
RA Mullins L., Ivy J., Ward M., Tenstad O., Wiig H., Kitada K., Manning J.,
RA Rakova N., Muller D., Mullins J.;
RT "Abnormal neonatal sodium handling in skin precedes hypertension in the
RT SAME rat.";
RL Pflugers Arch. 473:897-910(2021).
CC -!- FUNCTION: Catalyzes the conversion of biologically active 11beta-
CC hydroxyglucocorticoids (11beta-hydroxysteroid) such as corticosterone,
CC to inactive 11-ketoglucocorticoids (11-oxosteroid) such as 11-
CC dehydrocorticosterone, in the presence of NAD(+) (PubMed:7649078).
CC Functions as a dehydrogenase (oxidase), thereby decreasing the
CC concentration of active glucocorticoids, thus protecting the
CC nonselective mineralocorticoid receptor from occupation by
CC glucocorticoids (PubMed:7649078, PubMed:34028587). Plays an important
CC role in maintaining glucocorticoids balance during preimplantation and
CC protects the fetus from excessive maternal corticosterone exposure
CC (PubMed:34028587). Catalyzes the oxidation of 11beta-
CC hydroxytestosterone (11beta,17beta-dihydroxyandrost-4-ene-3-one) to 11-
CC ketotestosterone (17beta-hydroxyandrost-4-ene-3,11-dione), a major
CC bioactive androgen (By similarity). Catalyzes the conversion of 11beta-
CC hydroxyandrostenedione (11beta-hydroxyandrost-4-ene-3,17-dione) to 11-
CC ketoandrostenedione (androst-4-ene-3,11,17-trione), which can be
CC further metabolized to 11-ketotestosterone (By similarity). Converts 7-
CC beta-25-dihydroxycholesterol to 7-oxo-25-hydroxycholesterol in vitro
CC (By similarity). 7-beta-25-dihydroxycholesterol (not 7-oxo-25-
CC hydroxycholesterol) acts as ligand for the G-protein-coupled receptor
CC (GPCR) Epstein-Barr virus-induced gene 2 (EBI2) and may thereby
CC regulate immune cell migration (By similarity).
CC {ECO:0000250|UniProtKB:P51661, ECO:0000250|UniProtKB:P80365,
CC ECO:0000269|PubMed:7649078, ECO:0000303|PubMed:34028587,
CC ECO:0000303|PubMed:7649078}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=an 11beta-hydroxysteroid + NAD(+) = an 11-oxosteroid + H(+) +
CC NADH; Xref=Rhea:RHEA:53116, ChEBI:CHEBI:15378, ChEBI:CHEBI:35346,
CC ChEBI:CHEBI:47787, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000269|PubMed:7649078};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53117;
CC Evidence={ECO:0000269|PubMed:7649078};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=corticosterone + NAD(+) = 11-dehydrocorticosterone + H(+) +
CC NADH; Xref=Rhea:RHEA:42204, ChEBI:CHEBI:15378, ChEBI:CHEBI:16827,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:78600;
CC Evidence={ECO:0000269|PubMed:7649078};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42205;
CC Evidence={ECO:0000269|PubMed:7649078};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=11beta,17beta-dihydroxyandrost-4-ene-3-one + NAD(+) = 17beta-
CC hydroxyandrost-4-ene-3,11-dione + H(+) + NADH; Xref=Rhea:RHEA:69368,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:34133, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:81481;
CC Evidence={ECO:0000250|UniProtKB:P51661};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69369;
CC Evidence={ECO:0000250|UniProtKB:P51661};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=11beta-hydroxyandrost-4-ene-3,17-dione + NAD(+) = androst-4-
CC ene-3,11,17-trione + H(+) + NADH; Xref=Rhea:RHEA:69408,
CC ChEBI:CHEBI:2495, ChEBI:CHEBI:15378, ChEBI:CHEBI:27967,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000250|UniProtKB:P80365};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69409;
CC Evidence={ECO:0000250|UniProtKB:P80365};
CC -!- ACTIVITY REGULATION: Inhibited by glycyrrhetinic acid (By similarity).
CC Induced by progesterone, through the Ihh signaling pathway (By
CC similarity). {ECO:0000250|UniProtKB:P51661,
CC ECO:0000250|UniProtKB:P80365}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=10 nM for corticosterone {ECO:0000269|PubMed:7649078};
CC -!- PATHWAY: Steroid metabolism. {ECO:0000305}.
CC -!- SUBUNIT: Interacts with ligand-free cytoplasmic NR3C2.
CC {ECO:0000250|UniProtKB:P80365}.
CC -!- SUBCELLULAR LOCATION: Microsome {ECO:0000250|UniProtKB:P80365}.
CC Endoplasmic reticulum {ECO:0000250|UniProtKB:P80365}.
CC -!- TISSUE SPECIFICITY: Highly expressed in kidney, adrenal gland and
CC distal colon, and at much lower levels in lung, hypothalamus,
CC hippocampus, and midbrain. {ECO:0000269|PubMed:7649078}.
CC -!- DISRUPTION PHENOTYPE: Homozygous knockout pups have reduced Na(+) and
CC water content in the skin at birth, but retain higher levels of Na(+)
CC and water in the skin throughout development and into adulthood at the
CC expense of K(+), manifesting hypokalaemia by 15 days of age and
CC contributing to salt sensitive hypertension.
CC {ECO:0000269|PubMed:34028587}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
CC -!- CAUTION: Rats and mice do not produce appreciable cortisol, because
CC they do not express the 17-alpha hydroxylase (Cyp17a1) enzyme in the
CC adrenals. {ECO:0000269|PubMed:1312193}.
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DR EMBL; U22424; AAA87007.1; -; mRNA.
DR EMBL; BC087023; AAH87023.1; -; mRNA.
DR RefSeq; NP_058777.1; NM_017081.2.
DR AlphaFoldDB; P50233; -.
DR SMR; P50233; -.
DR STRING; 10116.ENSRNOP00000023130; -.
DR BindingDB; P50233; -.
DR ChEMBL; CHEMBL2908; -.
DR DrugCentral; P50233; -.
DR PhosphoSitePlus; P50233; -.
DR PaxDb; P50233; -.
DR PRIDE; P50233; -.
DR DNASU; 25117; -.
DR Ensembl; ENSRNOT00000023130; ENSRNOP00000023130; ENSRNOG00000017084.
DR GeneID; 25117; -.
DR KEGG; rno:25117; -.
DR UCSC; RGD:2835; rat.
DR CTD; 3291; -.
DR RGD; 2835; Hsd11b2.
DR eggNOG; KOG1610; Eukaryota.
DR GeneTree; ENSGT00940000159716; -.
DR HOGENOM; CLU_010194_2_0_1; -.
DR InParanoid; P50233; -.
DR OMA; ATFRNCM; -.
DR OrthoDB; 1313182at2759; -.
DR PhylomeDB; P50233; -.
DR TreeFam; TF325617; -.
DR BRENDA; 1.1.1.146; 5301.
DR Reactome; R-RNO-194002; Glucocorticoid biosynthesis.
DR PRO; PR:P50233; -.
DR Proteomes; UP000002494; Chromosome 19.
DR Bgee; ENSRNOG00000017084; Expressed in kidney and 17 other tissues.
DR ExpressionAtlas; P50233; baseline and differential.
DR Genevisible; P50233; RN.
DR GO; GO:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:RGD.
DR GO; GO:0005811; C:lipid droplet; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0070523; F:11-beta-hydroxysteroid dehydrogenase (NAD+) activity; ISO:RGD.
DR GO; GO:0051287; F:NAD binding; IDA:RGD.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0005496; F:steroid binding; IPI:RGD.
DR GO; GO:0016229; F:steroid dehydrogenase activity; IBA:GO_Central.
DR GO; GO:0034650; P:cortisol metabolic process; ISO:RGD.
DR GO; GO:0007565; P:female pregnancy; IEP:RGD.
DR GO; GO:0008211; P:glucocorticoid metabolic process; IDA:RGD.
DR GO; GO:0002017; P:regulation of blood volume by renal aldosterone; IMP:RGD.
DR GO; GO:0032094; P:response to food; IEP:RGD.
DR GO; GO:0051384; P:response to glucocorticoid; IEP:RGD.
DR GO; GO:0001666; P:response to hypoxia; IEP:RGD.
DR GO; GO:0032868; P:response to insulin; IEP:RGD.
DR GO; GO:0048545; P:response to steroid hormone; IEP:RGD.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR GO; GO:0008202; P:steroid metabolic process; IBA:GO_Central.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR InterPro; IPR002347; SDR_fam.
DR Pfam; PF00106; adh_short; 1.
DR PRINTS; PR00081; GDHRDH.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Endoplasmic reticulum; Lipid metabolism;
KW Microsome; NAD; Oxidoreductase; Reference proteome; Steroid metabolism.
FT CHAIN 1..400
FT /note="11-beta-hydroxysteroid dehydrogenase type 2"
FT /id="PRO_0000054630"
FT REGION 378..400
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 385..400
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 232
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001"
FT BINDING 82..111
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250"
FT BINDING 219
FT /ligand="substrate"
FT /evidence="ECO:0000250"
SQ SEQUENCE 400 AA; 43726 MW; A1BAAA328E2F189D CRC64;
MERWPWPSGG AWLLVAARAL LQLLRSDLRL GRPLLAALAL LAALDWLCQR LLPPPAALVV
LAGAGWIALS RLARPPRLPV ATRAVLITGC DTGFGKETAK KLDAMGFTVL ATVLDLNGPG
ALELRARCSP RLKLLQMDLT KPEDISRVLE ITKAHTASTG LWGLVNNAGL NMVVADVELS
PVVTFRECME VNFFGALELT KGLLPLLRHS RGRIVTVGSP AGDMPYPCLA AYGTSKAAIA
LLMDTFSCEL LPWGIKVSII QPGCFKTEAV TNVNLWEKRK QLLLANLPRE LLQAYGEDYI
EHLHGQFLNS LRMALPDLSP VVDAIIDALL AAQPRSRYYT GRGLGLMYFI HHYLPGGLRR
RFLQNFFISH LLPRALRPGQ PGPVHDTTQD PNPSPTVSAL
