DHI2_HUMAN
ID DHI2_HUMAN Reviewed; 405 AA.
AC P80365; A7LB28; C5HTY7; Q13194; Q6P2G9; Q8N439; Q96QN8; Q99887; Q9UC50;
AC Q9UC51; Q9UCW5; Q9UCW6; Q9UCW7; Q9UCW8;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 30-APR-2003, sequence version 2.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=11-beta-hydroxysteroid dehydrogenase type 2 {ECO:0000303|PubMed:33387577};
DE Short=11-DH2;
DE Short=11-beta-HSD2 {ECO:0000303|PubMed:10497248, ECO:0000303|PubMed:30902677, ECO:0000303|PubMed:33387577};
DE EC=1.1.1.- {ECO:0000269|PubMed:10497248, ECO:0000269|PubMed:12788846, ECO:0000269|PubMed:30902677, ECO:0000269|PubMed:33387577, ECO:0000269|PubMed:7859916, ECO:0000305|PubMed:8538347};
DE AltName: Full=11-beta-hydroxysteroid dehydrogenase type II;
DE Short=11-HSD type II;
DE Short=11-beta-HSD type II;
DE AltName: Full=Corticosteroid 11-beta-dehydrogenase isozyme 2 {ECO:0000305};
DE AltName: Full=NAD-dependent 11-beta-hydroxysteroid dehydrogenase;
DE AltName: Full=Short chain dehydrogenase/reductase family 9C member 3;
GN Name=HSD11B2 {ECO:0000312|HGNC:HGNC:5209};
GN Synonyms=HSD11K {ECO:0000303|PubMed:8530071}, SDR9C3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, FUNCTION,
RP BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, AND TISSUE SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=7859916; DOI=10.1016/0303-7207(94)90176-7;
RA Albiston A.L., Obeyesekere V.R., Smith R.E., Krozowski Z.S.;
RT "Cloning and tissue distribution of the human 11 beta-hydroxysteroid
RT dehydrogenase type 2 enzyme.";
RL Mol. Cell. Endocrinol. 105:R11-R17(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY.
RC TISSUE=Kidney;
RX PubMed=8530071; DOI=10.1006/geno.1995.1231;
RA Agarwal A.K., Rogerson F.M., Mune T., White P.C.;
RT "Gene structure and chromosomal localization of the human HSD11K gene
RT encoding the kidney (type 2) isozyme of 11 beta-hydroxysteroid
RT dehydrogenase.";
RL Genomics 29:195-199(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=8611140; DOI=10.1042/bj3131007;
RA Brown R.W., Chapman K.E., Kotelevtsev Y., Yau J.L., Lindsay R.S., Brett L.,
RA Leckie C., Murad P., Lyons V., Mullins J.J., Edwards C.R.W., Seckl J.R.;
RT "Cloning and production of antisera to human placental 11 beta-
RT hydroxysteroid dehydrogenase type 2.";
RL Biochem. J. 313:1007-1017(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (JUN-2007) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary;
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 [8]
RP PROTEIN SEQUENCE OF 19-24; 77-84; 102-112; 134-154; 191-198; 214-227;
RP 229-235; 256-266; 272-278 AND 375-401.
RC TISSUE=Placenta;
RX PubMed=8611186; DOI=10.1042/bj3130997;
RA Brown R.W., Chapman K.E., Murad P., Edwards C.R., Seckl J.R.;
RT "Purification of 11 beta-hydroxysteroid dehydrogenase type 2 from human
RT placenta utilizing a novel affinity labelling technique.";
RL Biochem. J. 313:997-1005(1996).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 90-221.
RA Amin H.K., Hoeppner W.;
RT "Human hydroxysteroid dehydrogenase type 2 HSD11B2.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 182-211; 235-264 AND 325-354, AND
RP VARIANTS AME CYS-186; CYS-208; 250-PRO-SER-251 AND 337-ARG-TYR-338 DELINS
RP HIS.
RX PubMed=7593417; DOI=10.1210/jcem.80.11.7593417;
RA Wilson R.C., Harbison M.D., Krozowski Z.S., Funder J.W., Shackleton C.H.L.,
RA Hanauske-Abel H.M., Wei J.-Q., Hertecant J., Moran A., Neiberger R.E.,
RA Balfe J.W., Fattah A., Daneman D., Licholai T., New M.I.;
RT "Several homozygous mutations in the gene for 11 beta-hydroxysteroid
RT dehydrogenase type 2 in patients with apparent mineralocorticoid excess.";
RL J. Clin. Endocrinol. Metab. 80:3145-3150(1995).
RN [11] {ECO:0000312|EMBL:AAD14324.1}
RP PARTIAL NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY,
RP AND VARIANT AME 374-ARG--ARG-405 DEL.
RX PubMed=8538347; DOI=10.1016/s0140-6736(96)90211-1;
RA Stewart P.M., Krozowski Z.S., Gupta A., Milford D.V., Howie A.J.,
RA Sheppard M.C., Whorwood C.B.;
RT "Hypertension in the syndrome of apparent mineralocorticoid excess due to
RT mutation of the 11 beta-hydroxysteroid dehydrogenase type 2 gene.";
RL Lancet 347:88-91(1996).
RN [12]
RP CHARACTERIZATION.
RX PubMed=2889032; DOI=10.1016/s0140-6736(87)91014-2;
RA Stewart P.M., Wallace A.M., Valentino R., Burt D., Shackleton C.H.L.,
RA Edwards C.R.W.;
RT "Mineralocorticoid activity of liquorice: 11-beta-hydroxysteroid
RT dehydrogenase deficiency comes of age.";
RL Lancet 2:821-824(1987).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP SUBCELLULAR LOCATION.
RX PubMed=10497248; DOI=10.1074/jbc.274.40.28762;
RA Odermatt A., Arnold P., Stauffer A., Frey B.M., Frey F.J.;
RT "The N-terminal anchor sequences of 11beta-hydroxysteroid dehydrogenases
RT determine their orientation in the endoplasmic reticulum membrane.";
RL J. Biol. Chem. 274:28762-28770(1999).
RN [14]
RP INTERACTION WITH NR3C2.
RX PubMed=11350956; DOI=10.1074/jbc.m100374200;
RA Odermatt A., Arnold P., Frey F.J.;
RT "The intracellular localization of the mineralocorticoid receptor is
RT regulated by 11beta-hydroxysteroid dehydrogenase type 2.";
RL J. Biol. Chem. 276:28484-28492(2001).
RN [15]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=22796344; DOI=10.1016/j.tox.2012.07.001;
RA Meyer A., Strajhar P., Murer C., Da Cunha T., Odermatt A.;
RT "Species-specific differences in the inhibition of human and zebrafish
RT 11beta-hydroxysteroid dehydrogenase 2 by thiram and organotins.";
RL Toxicology 301:72-78(2012).
RN [16]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=27927697; DOI=10.1530/joe-16-0495;
RA Tsachaki M., Meyer A., Weger B., Kratschmar D.V., Tokarz J., Adamski J.,
RA Belting H.G., Affolter M., Dickmeis T., Odermatt A.;
RT "Absence of 11-keto reduction of cortisone and 11-ketotestosterone in the
RT model organism zebrafish.";
RL J. Endocrinol. 232:323-335(2017).
RN [17]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=30902677; DOI=10.1016/j.jsbmb.2019.03.011;
RA Beck K.R., Kanagaratnam S., Kratschmar D.V., Birk J., Yamaguchi H.,
RA Sailer A.W., Seuwen K., Odermatt A.;
RT "Enzymatic interconversion of the oxysterols 7beta,25-dihydroxycholesterol
RT and 7-keto,25-hydroxycholesterol by 11beta-hydroxysteroid dehydrogenase
RT type 1 and 2.";
RL J. Steroid Biochem. Mol. Biol. 190:19-28(2019).
RN [18]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=33387577; DOI=10.1016/j.taap.2020.115387;
RA Inderbinen S.G., Zogg M., Kley M., Smiesko M., Odermatt A.;
RT "Species-specific differences in the inhibition of 11beta-hydroxysteroid
RT dehydrogenase 2 by itraconazole and posaconazole.";
RL Toxicol. Appl. Pharmacol. 412:115387-115387(2021).
RN [19]
RP VARIANT AME CYS-337.
RX PubMed=7608290; DOI=10.1210/jcem.80.7.7608290;
RA Wilson R.C., Krozowski Z.S., Li K., Obeyesekere V.R., Razzaghy-Azar M.,
RA Harbison M.D., Wei J.-Q., Shackleton C.H.L., Funder J.W., New M.I.;
RT "A mutation in the HSD11B2 gene in a family with apparent mineralocorticoid
RT excess.";
RL J. Clin. Endocrinol. Metab. 80:2263-2266(1995).
RN [20]
RP CHARACTERIZATION OF VARIANTS AME CYS-208; CYS-213; 250-PRO-SER-251 AND
RP 337-ARG-TYR-338 DELINS HIS.
RX PubMed=7670488; DOI=10.1038/ng0895-394;
RA Mune T., Rogerson F.M., Nikkilae H., Agarwal A.K., White P.C.;
RT "Human hypertension caused by mutations in the kidney isozyme of 11 beta-
RT hydroxysteroid dehydrogenase.";
RL Nat. Genet. 10:394-399(1995).
RN [21]
RP CHARACTERIZATION OF VARIANTS AME HIS-208 AND 337-ARG-TYR-338 DELINS HIS.
RX PubMed=9398712; DOI=10.1210/jcem.82.12.4455;
RA Kitanaka S., Katsumata N., Tanae A., Hibi I., Takeyama K., Fuse H.,
RA Kato S., Tanaka T.;
RT "A new compound heterozygous mutation in the 11 beta-hydroxysteroid
RT dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess.";
RL J. Clin. Endocrinol. Metab. 82:4054-4058(1997).
RN [22]
RP CHARACTERIZATION OF VARIANT AME CYS-279.
RX PubMed=9683587; DOI=10.1086/301955;
RA Li A., Tedde R., Krozowski Z.S., Pala A., Li K.X.Z., Shackleton C.H.L.,
RA Mantero F., Palermo M., Stewart P.M.;
RT "Molecular basis for hypertension in the 'type II variant' of apparent
RT mineralocorticoid excess.";
RL Am. J. Hum. Genet. 63:370-379(1998).
RN [23]
RP VARIANTS AME CYS-186; CYS-208; ASN-244; ARG-250; 250-PRO-SER-251; CYS-337
RP AND 337-ARG-TYR-338 DELINS HIS.
RX PubMed=9661590; DOI=10.1210/jcem.83.7.4986;
RA Dave-Sharma S., Wilson R.C., Harbison M.D., Newfield R., Azar M.R.,
RA Krozowski Z.S., Funder J.W., Shackleton C.H.L., Bradlow H.L., Wei J.-Q.,
RA Hertecant J., Moran A., Neiberger R.E., Balfe J.W., Fattah A., Daneman D.,
RA Akkurt H.I., De Santis C., New M.I.;
RT "Examination of genotype and phenotype relationships in 14 patients with
RT apparent mineralocorticoid excess.";
RL J. Clin. Endocrinol. Metab. 83:2244-2254(1998).
RN [24]
RP CHARACTERIZATION OF VARIANT AME CYS-213.
RX PubMed=9851783; DOI=10.1210/jcem.83.12.5329;
RA Rogoff D., Smolenicka Z., Bergada I., Vallejo G., Barontini M.,
RA Heinrich J.J., Ferrari P.;
RT "The codon 213 of the 11beta-hydroxysteroid dehydrogenase type 2 gene is a
RT hot spot for mutations in apparent mineralocorticoid excess.";
RL J. Clin. Endocrinol. Metab. 83:4391-4393(1998).
RN [25]
RP CHARACTERIZATION OF VARIANT HYPERTENSION LEU-227.
RX PubMed=9707624; DOI=10.1073/pnas.95.17.10200;
RA Wilson R.C., Dave-Sharma S., Wei J.-Q., Obeyesekere V.R., Li K.,
RA Ferrari P., Krozowski Z.S., Shackleton C.H.L., Bradlow L., Wiens T.,
RA New M.I.;
RT "A genetic defect resulting in mild low-renin hypertension.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:10200-10205(1998).
RN [26]
RP CHARACTERIZATION OF VARIANTS AME CYS-213 AND VAL-328.
RX PubMed=10489390; DOI=10.1161/01.hyp.34.3.435;
RA Morineau G., Marc J.-M., Boudi A., Galons H., Gourmelen M., Corvol P.,
RA Pascoe L., Fiet J.;
RT "Genetic, biochemical, and clinical studies of patients with A328V or R213C
RT mutations in 11betaHSD2 causing apparent mineralocorticoid excess.";
RL Hypertension 34:435-441(1999).
RN [27]
RP CHARACTERIZATION OF VARIANTS AME ARG-179; PHE-180; HIS-208; VAL-237 AND
RP VAL-328.
RX PubMed=10523339; DOI=10.1161/01.hyp.34.4.638;
RA Nunez B.S., Rogerson F.M., Mune T., Igarashi Y., Nakagawa Y., Phillipov G.,
RA Moudgil A., Travis L.B., Palermo M., Shackleton C.H.L., White P.C.;
RT "Mutants of 11beta-hydroxysteroid dehydrogenase (11-HSD2) with partial
RT activity: improved correlations between genotype and biochemical phenotype
RT in apparent mineralocorticoid excess.";
RL Hypertension 34:638-642(1999).
RN [28]
RP CHARACTERIZATION OF VARIANT AME 114-LEU-GLU-115 DEL, AND MUTAGENESIS OF
RP GLU-115.
RX PubMed=11238516; DOI=10.1210/jcem.86.3.7334;
RA Odermatt A., Dick B., Arnold P., Zaehner T., Plueschke V., Deregibus M.N.,
RA Repetto H., Frey B.M., Frey F.J., Ferrari P.;
RT "A mutation in the cofactor-binding domain of 11beta-hydroxysteroid
RT dehydrogenase type 2 associated with mineralocorticoid hypertension.";
RL J. Clin. Endocrinol. Metab. 86:1247-1252(2001).
RN [29]
RP VARIANT AME ASN-223, BIOPHYSICOCHEMICAL PROPERTIES, FUNCTION, AND CATALYTIC
RP ACTIVITY.
RX PubMed=12788846; DOI=10.1210/jc.2002-021909;
RA Carvajal C.A., Gonzalez A.A., Romero D.G., Gonzalez A., Mosso L.M.,
RA Lagos E.T., Hevia Mdel P., Rosati M.P., Perez-Acle T.O.,
RA Gomez-Sanchez C.E., Montero J.A., Fardella C.E.;
RT "Two homozygous mutations in the 11 beta-hydroxysteroid dehydrogenase type
RT 2 gene in a case of apparent mineralocorticoid excess.";
RL J. Clin. Endocrinol. Metab. 88:2501-2507(2003).
RN [30]
RP VARIANTS AME CYS-337 AND HIS-338, FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR
RP LOCATION, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF ARG-335;
RP ARG-336; ARG-337; TYR-338 AND TYR-339.
RX PubMed=17314322; DOI=10.1681/asn.2006111235;
RA Atanasov A.G., Ignatova I.D., Nashev L.G., Dick B., Ferrari P., Frey F.J.,
RA Odermatt A.;
RT "Impaired protein stability of 11beta-hydroxysteroid dehydrogenase type 2:
RT a novel mechanism of apparent mineralocorticoid excess.";
RL J. Am. Soc. Nephrol. 18:1262-1270(2007).
CC -!- FUNCTION: Catalyzes the conversion of biologically active 11beta-
CC hydroxyglucocorticoids (11beta-hydroxysteroid) such as cortisol, to
CC inactive 11-ketoglucocorticoids (11-oxosteroid) such as cortisone, in
CC the presence of NAD(+) (PubMed:7859916, PubMed:8538347,
CC PubMed:10497248, PubMed:22796344, PubMed:27927697, PubMed:30902677,
CC PubMed:33387577, PubMed:12788846, PubMed:17314322). Functions as a
CC dehydrogenase (oxidase), thereby decreasing the concentration of active
CC glucocorticoids, thus protecting the nonselective mineralocorticoid
CC receptor from occupation by glucocorticoids (PubMed:7859916,
CC PubMed:10497248, PubMed:33387577, PubMed:12788846, PubMed:17314322).
CC Plays an important role in maintaining glucocorticoids balance during
CC preimplantation and protects the fetus from excessive maternal
CC corticosterone exposure (By similarity). Catalyzes the oxidation of
CC 11beta-hydroxytestosterone (11beta,17beta-dihydroxyandrost-4-ene-3-one)
CC to 11-ketotestosterone (17beta-hydroxyandrost-4-ene-3,11-dione), a
CC major bioactive androgen (PubMed:22796344, PubMed:27927697). Catalyzes
CC the conversion of 11beta-hydroxyandrostenedione (11beta-hydroxyandrost-
CC 4-ene-3,17-dione) to 11-ketoandrostenedione (androst-4-ene-3,11,17-
CC trione), which can be further metabolized to 11-ketotestosterone
CC (PubMed:27927697). Converts 7-beta-25-dihydroxycholesterol to 7-oxo-25-
CC hydroxycholesterol in vitro (PubMed:30902677). 7-beta-25-
CC dihydroxycholesterol (not 7-oxo-25-hydroxycholesterol) acts as ligand
CC for the G-protein-coupled receptor (GPCR) Epstein-Barr virus-induced
CC gene 2 (EBI2) and may thereby regulate immune cell migration
CC (PubMed:30902677). May protect ovulating oocytes and fertilizing
CC spermatozoa from the adverse effects of cortisol (By similarity).
CC {ECO:0000250|UniProtKB:O77667, ECO:0000250|UniProtKB:P51661,
CC ECO:0000269|PubMed:10497248, ECO:0000269|PubMed:12788846,
CC ECO:0000269|PubMed:17314322, ECO:0000269|PubMed:22796344,
CC ECO:0000269|PubMed:27927697, ECO:0000269|PubMed:30902677,
CC ECO:0000269|PubMed:33387577, ECO:0000269|PubMed:7859916,
CC ECO:0000269|PubMed:8538347, ECO:0000303|PubMed:30902677}.
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:10497248, ECO:0000269|PubMed:12788846,
CC ECO:0000269|PubMed:17314322, ECO:0000269|PubMed:22796344,
CC ECO:0000269|PubMed:27927697, ECO:0000269|PubMed:30902677,
CC ECO:0000269|PubMed:33387577, ECO:0000269|PubMed:7859916,
CC ECO:0000305|PubMed:8538347};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53117;
CC Evidence={ECO:0000269|PubMed:12788846, ECO:0000269|PubMed:17314322,
CC ECO:0000269|PubMed:30902677, ECO:0000269|PubMed:33387577,
CC ECO:0000269|PubMed:7859916, ECO:0000305|PubMed:10497248,
CC ECO:0000305|PubMed:22796344, ECO:0000305|PubMed:27927697,
CC ECO:0000305|PubMed:8538347};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cortisol + NAD(+) = cortisone + H(+) + NADH;
CC Xref=Rhea:RHEA:50208, ChEBI:CHEBI:15378, ChEBI:CHEBI:16962,
CC ChEBI:CHEBI:17650, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000269|PubMed:12788846, ECO:0000269|PubMed:17314322,
CC ECO:0000269|PubMed:22796344, ECO:0000269|PubMed:27927697,
CC ECO:0000269|PubMed:30902677, ECO:0000269|PubMed:33387577,
CC ECO:0000269|PubMed:7859916, ECO:0000305|PubMed:8538347};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50209;
CC Evidence={ECO:0000269|PubMed:12788846, ECO:0000269|PubMed:17314322,
CC ECO:0000269|PubMed:30902677, ECO:0000269|PubMed:33387577,
CC ECO:0000269|PubMed:7859916, ECO:0000305|PubMed:22796344,
CC ECO:0000305|PubMed:27927697, ECO:0000305|PubMed:8538347};
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:10497248, ECO:0000269|PubMed:17314322,
CC ECO:0000269|PubMed:22796344, ECO:0000269|PubMed:7859916};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42205;
CC Evidence={ECO:0000269|PubMed:17314322, ECO:0000269|PubMed:7859916,
CC ECO:0000305|PubMed:10497248, ECO:0000305|PubMed:22796344};
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:0000269|PubMed:22796344, ECO:0000269|PubMed:27927697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69369;
CC Evidence={ECO:0000305|PubMed:22796344, ECO:0000305|PubMed:27927697};
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:0000269|PubMed:27927697};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69409;
CC Evidence={ECO:0000305|PubMed:27927697};
CC -!- ACTIVITY REGULATION: Inhibited by glycyrrhetinic acid (derived from
CC liquorice). {ECO:0000269|PubMed:7859916}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=47 nM for cortisol {ECO:0000269|PubMed:7859916};
CC KM=84 nM for cortisol {ECO:0000269|PubMed:22796344};
CC KM=26.1 nM for cortisol {ECO:0000269|PubMed:12788846};
CC KM=785 nM for cortisol {ECO:0000269|PubMed:17314322};
CC KM=5.1 nM for corticosterone {ECO:0000269|PubMed:7859916};
CC KM=5.5 nM for corticosterone {ECO:0000269|PubMed:10497248};
CC KM=5.7 nM for corticosterone {ECO:0000269|PubMed:22796344};
CC KM=77 nM for corticosterone {ECO:0000269|PubMed:17314322};
CC KM=37 nM for 11beta,17beta-dihydroxyandrost-4-ene-3-one
CC {ECO:0000269|PubMed:22796344};
CC Vmax=1.5 nmol/h/mg enzyme toward corticosterone
CC {ECO:0000269|PubMed:10497248};
CC Vmax=64.1 nmol/h/mg enzyme toward corticosterone
CC {ECO:0000269|PubMed:17314322};
CC Vmax=66 nmol/h/mg enzyme toward cortisol
CC {ECO:0000269|PubMed:17314322};
CC -!- PATHWAY: Steroid metabolism. {ECO:0000305}.
CC -!- SUBUNIT: Interacts with ligand-free cytoplasmic NR3C2.
CC {ECO:0000269|PubMed:11350956}.
CC -!- SUBCELLULAR LOCATION: Microsome {ECO:0000269|PubMed:17314322}.
CC Endoplasmic reticulum {ECO:0000269|PubMed:10497248,
CC ECO:0000269|PubMed:17314322}.
CC -!- TISSUE SPECIFICITY: Expressed in kidney, placenta, pancreas, prostate,
CC ovary, small intestine and colon, and in lower levels in the spleen and
CC testis (PubMed:7859916). At midgestation, expressed at high levels in
CC placenta and in fetal kidney and, at much lower levels, in fetal lung
CC and testis (PubMed:8530071). {ECO:0000269|PubMed:7859916,
CC ECO:0000269|PubMed:8530071}.
CC -!- DISEASE: Apparent mineralocorticoid excess (AME) [MIM:218030]: An
CC autosomal recessive form of low-renin hypertension. It is usually
CC diagnosed within the first years of life and is characterized by
CC polyuria and polydipsia, failure to thrive, hypernatremia, severe
CC hypertension with low renin and aldosterone levels, profound
CC hypokalemia with metabolic alkalosis, and most often nephrocalcinosis.
CC {ECO:0000269|PubMed:10489390, ECO:0000269|PubMed:10523339,
CC ECO:0000269|PubMed:11238516, ECO:0000269|PubMed:12788846,
CC ECO:0000269|PubMed:17314322, ECO:0000269|PubMed:7593417,
CC ECO:0000269|PubMed:7608290, ECO:0000269|PubMed:7670488,
CC ECO:0000269|PubMed:8538347, ECO:0000269|PubMed:9398712,
CC ECO:0000269|PubMed:9661590, ECO:0000269|PubMed:9683587,
CC ECO:0000269|PubMed:9851783}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: Consumption of large amounts of liquorice can lead to
CC apparent mineralocorticoid excess and hypertension.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; U14631; AAA91969.1; -; mRNA.
DR EMBL; U27317; AAB48544.1; -; Genomic_DNA.
DR EMBL; U26726; AAC50356.1; -; mRNA.
DR EMBL; S80133; AAD14324.1; -; Genomic_DNA.
DR EMBL; EF694683; ABS29267.1; -; Genomic_DNA.
DR EMBL; FJ515828; ACS13714.1; -; Genomic_DNA.
DR EMBL; CH471092; EAW83134.1; -; Genomic_DNA.
DR EMBL; BC036780; AAH36780.1; -; mRNA.
DR EMBL; BC064536; AAH64536.1; -; mRNA.
DR EMBL; AY046280; AAK91586.1; -; Genomic_DNA.
DR CCDS; CCDS10837.1; -.
DR PIR; S62789; S62789.
DR RefSeq; NP_000187.3; NM_000196.3.
DR AlphaFoldDB; P80365; -.
DR SMR; P80365; -.
DR BioGRID; 109524; 7.
DR STRING; 9606.ENSP00000316786; -.
DR BindingDB; P80365; -.
DR ChEMBL; CHEMBL3746; -.
DR DrugBank; DB01234; Dexamethasone.
DR DrugBank; DB14649; Dexamethasone acetate.
DR DrugBank; DB00687; Fludrocortisone.
DR DrugBank; DB01185; Fluoxymesterone.
DR DrugBank; DB01569; Formebolone.
DR DrugBank; DB00741; Hydrocortisone.
DR DrugBank; DB14538; Hydrocortisone aceponate.
DR DrugBank; DB14539; Hydrocortisone acetate.
DR DrugBank; DB14540; Hydrocortisone butyrate.
DR DrugBank; DB14541; Hydrocortisone cypionate.
DR DrugBank; DB14542; Hydrocortisone phosphate.
DR DrugBank; DB14543; Hydrocortisone probutate.
DR DrugBank; DB14544; Hydrocortisone valerate.
DR DrugBank; DB00959; Methylprednisolone.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB14631; Prednisolone phosphate.
DR DrugCentral; P80365; -.
DR GuidetoPHARMACOLOGY; 3143; -.
DR SwissLipids; SLP:000000810; -.
DR iPTMnet; P80365; -.
DR PhosphoSitePlus; P80365; -.
DR BioMuta; HSD11B2; -.
DR DMDM; 30316367; -.
DR EPD; P80365; -.
DR jPOST; P80365; -.
DR MassIVE; P80365; -.
DR MaxQB; P80365; -.
DR PaxDb; P80365; -.
DR PeptideAtlas; P80365; -.
DR PRIDE; P80365; -.
DR ProteomicsDB; 57680; -.
DR Antibodypedia; 29548; 323 antibodies from 32 providers.
DR DNASU; 3291; -.
DR Ensembl; ENST00000326152.6; ENSP00000316786.5; ENSG00000176387.7.
DR GeneID; 3291; -.
DR KEGG; hsa:3291; -.
DR MANE-Select; ENST00000326152.6; ENSP00000316786.5; NM_000196.4; NP_000187.3.
DR UCSC; uc002etd.4; human.
DR CTD; 3291; -.
DR DisGeNET; 3291; -.
DR GeneCards; HSD11B2; -.
DR HGNC; HGNC:5209; HSD11B2.
DR HPA; ENSG00000176387; Group enriched (intestine, kidney, salivary gland).
DR MalaCards; HSD11B2; -.
DR MIM; 218030; phenotype.
DR MIM; 614232; gene.
DR neXtProt; NX_P80365; -.
DR OpenTargets; ENSG00000176387; -.
DR Orphanet; 320; Apparent mineralocorticoid excess.
DR PharmGKB; PA29477; -.
DR VEuPathDB; HostDB:ENSG00000176387; -.
DR eggNOG; KOG1610; Eukaryota.
DR GeneTree; ENSGT00940000159716; -.
DR HOGENOM; CLU_010194_2_0_1; -.
DR InParanoid; P80365; -.
DR OMA; ATFRNCM; -.
DR OrthoDB; 1313182at2759; -.
DR PhylomeDB; P80365; -.
DR TreeFam; TF325617; -.
DR BioCyc; MetaCyc:ENSG00000176387-MON; -.
DR BRENDA; 1.1.1.146; 2681.
DR BRENDA; 1.1.1.B40; 2681.
DR PathwayCommons; P80365; -.
DR Reactome; R-HSA-194002; Glucocorticoid biosynthesis.
DR SABIO-RK; P80365; -.
DR SignaLink; P80365; -.
DR SIGNOR; P80365; -.
DR BioGRID-ORCS; 3291; 18 hits in 1073 CRISPR screens.
DR ChiTaRS; HSD11B2; human.
DR GeneWiki; Corticosteroid_11-beta-dehydrogenase_isozyme_2; -.
DR GenomeRNAi; 3291; -.
DR Pharos; P80365; Tchem.
DR PRO; PR:P80365; -.
DR Proteomes; UP000005640; Chromosome 16.
DR RNAct; P80365; protein.
DR Bgee; ENSG00000176387; Expressed in mucosa of transverse colon and 102 other tissues.
DR ExpressionAtlas; P80365; baseline and differential.
DR Genevisible; P80365; HS.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0005811; C:lipid droplet; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0070523; F:11-beta-hydroxysteroid dehydrogenase (NAD+) activity; IMP:UniProtKB.
DR GO; GO:0051287; F:NAD binding; IEA:Ensembl.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0005496; F:steroid binding; IEA:Ensembl.
DR GO; GO:0016229; F:steroid dehydrogenase activity; IBA:GO_Central.
DR GO; GO:0034650; P:cortisol metabolic process; IMP:UniProtKB.
DR GO; GO:0007565; P:female pregnancy; IEA:Ensembl.
DR GO; GO:0008211; P:glucocorticoid metabolic process; IBA:GO_Central.
DR GO; GO:0002017; P:regulation of blood volume by renal aldosterone; IEA:Ensembl.
DR GO; GO:0032094; P:response to food; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0032868; P:response to insulin; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
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; Disease variant; Endoplasmic reticulum;
KW Lipid metabolism; Microsome; NAD; Oxidoreductase; Reference proteome;
KW Steroid metabolism.
FT CHAIN 1..405
FT /note="11-beta-hydroxysteroid dehydrogenase type 2"
FT /id="PRO_0000054627"
FT REGION 335..339
FT /note="Essential for protein stability"
FT REGION 377..405
FT /note="Disordered"
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"
FT VARIANT 114..115
FT /note="Missing (in AME; reduces enzyme activity by at least
FT 95%)"
FT /evidence="ECO:0000269|PubMed:11238516"
FT /id="VAR_015634"
FT VARIANT 147
FT /note="R -> H (in dbSNP:rs13306425)"
FT /id="VAR_052317"
FT VARIANT 179
FT /note="L -> R (in AME; abolishes enzyme activity)"
FT /evidence="ECO:0000269|PubMed:10523339"
FT /id="VAR_015635"
FT VARIANT 180
FT /note="S -> F (in AME; reduces enzyme activity)"
FT /evidence="ECO:0000269|PubMed:10523339"
FT /id="VAR_015636"
FT VARIANT 186
FT /note="R -> C (in AME; dbSNP:rs768507002)"
FT /evidence="ECO:0000269|PubMed:7593417,
FT ECO:0000269|PubMed:9661590"
FT /id="VAR_015637"
FT VARIANT 208
FT /note="R -> C (in AME; reduces enzyme activity by at least
FT 95%; dbSNP:rs121917780)"
FT /evidence="ECO:0000269|PubMed:7593417,
FT ECO:0000269|PubMed:7670488, ECO:0000269|PubMed:9661590"
FT /id="VAR_006958"
FT VARIANT 208
FT /note="R -> H (in AME; abolishes enzyme activity;
FT dbSNP:rs28934592)"
FT /evidence="ECO:0000269|PubMed:10523339,
FT ECO:0000269|PubMed:9398712"
FT /id="VAR_015638"
FT VARIANT 213
FT /note="R -> C (in AME; reduces enzyme activity by 90%;
FT dbSNP:rs28934591)"
FT /evidence="ECO:0000269|PubMed:10489390,
FT ECO:0000269|PubMed:7670488, ECO:0000269|PubMed:9851783"
FT /id="VAR_006959"
FT VARIANT 223
FT /note="D -> N (in AME; reduces enzyme activity to about 6%
FT of wild type; dbSNP:rs121917833)"
FT /evidence="ECO:0000269|PubMed:12788846"
FT /id="VAR_066514"
FT VARIANT 227
FT /note="P -> L (in hypertension; decreases affinity for
FT cortisol; dbSNP:rs121917782)"
FT /evidence="ECO:0000269|PubMed:9707624"
FT /id="VAR_015639"
FT VARIANT 237
FT /note="A -> V (in AME; reduces enzyme activity;
FT dbSNP:rs1309642469)"
FT /evidence="ECO:0000269|PubMed:10523339"
FT /id="VAR_015640"
FT VARIANT 244
FT /note="D -> N (in AME; associated with R-250)"
FT /evidence="ECO:0000269|PubMed:9661590"
FT /id="VAR_015641"
FT VARIANT 250..251
FT /note="LL -> PS (in AME; abolishes enzyme activity)"
FT /id="VAR_015643"
FT VARIANT 250
FT /note="L -> R (in AME; associated with N-244)"
FT /evidence="ECO:0000269|PubMed:9661590"
FT /id="VAR_015642"
FT VARIANT 279
FT /note="R -> C (in AME; decreases enzyme activity by 33%;
FT dbSNP:rs28934594)"
FT /evidence="ECO:0000269|PubMed:9683587"
FT /id="VAR_015644"
FT VARIANT 328
FT /note="A -> V (in AME; abolishes enzyme activity;
FT dbSNP:rs1453036708)"
FT /evidence="ECO:0000269|PubMed:10489390,
FT ECO:0000269|PubMed:10523339"
FT /id="VAR_015645"
FT VARIANT 337..338
FT /note="RY -> H (in AME; abolishes enzyme activity)"
FT /evidence="ECO:0000269|PubMed:7593417,
FT ECO:0000269|PubMed:7670488, ECO:0000269|PubMed:9398712,
FT ECO:0000269|PubMed:9661590"
FT /id="VAR_015647"
FT VARIANT 337
FT /note="R -> C (in AME; decreased half-life from 21 to 4
FT hours compared to wild-type, probably due to degradation
FT via the proteasomal pathway; dbSNP:rs121917781)"
FT /evidence="ECO:0000269|PubMed:17314322,
FT ECO:0000269|PubMed:7608290, ECO:0000269|PubMed:9661590"
FT /id="VAR_066515"
FT VARIANT 338
FT /note="Y -> H (in AME; abolishes enzyme activity; decreased
FT half-life from 21 to 3 hours compared to wild-type,
FT probably due to degradation via the proteasomal pathway;
FT dbSNP:rs387907117)"
FT /evidence="ECO:0000269|PubMed:17314322"
FT /id="VAR_015646"
FT VARIANT 374..405
FT /note="Missing (in AME; decreases enzyme activity)"
FT /evidence="ECO:0000269|PubMed:8538347"
FT /id="VAR_085553"
FT MUTAGEN 115
FT /note="E->K,Q: Abolishes cofactor specificity."
FT /evidence="ECO:0000269|PubMed:11238516"
FT MUTAGEN 335
FT /note="R->A,Q: Reduced enzyme activity."
FT /evidence="ECO:0000269|PubMed:17314322"
FT MUTAGEN 335
FT /note="R->K: No effect on enzyme activity."
FT /evidence="ECO:0000269|PubMed:17314322"
FT MUTAGEN 336
FT /note="R->A,Q: Almost complete loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:17314322"
FT MUTAGEN 336
FT /note="R->K: Reduced enzyme activity."
FT /evidence="ECO:0000269|PubMed:17314322"
FT MUTAGEN 337
FT /note="R->A,Q: Almost complete loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:17314322"
FT MUTAGEN 337
FT /note="R->K: Reduced enzyme activity."
FT /evidence="ECO:0000269|PubMed:17314322"
FT MUTAGEN 338
FT /note="Y->F,A: Complete loss of enzyme activity."
FT /evidence="ECO:0000269|PubMed:17314322"
FT MUTAGEN 339
FT /note="Y->A,F,H: Reduced enzyme activity."
FT /evidence="ECO:0000269|PubMed:17314322"
FT CONFLICT 148
FT /note="V -> F (in Ref. 2; AAB48544)"
FT /evidence="ECO:0000305"
FT CONFLICT 148
FT /note="V -> L (in Ref. 1; AAA91969)"
FT /evidence="ECO:0000305"
FT CONFLICT 350
FT /note="I -> T (in Ref. 7; AAH64536)"
FT /evidence="ECO:0000305"
FT CONFLICT 392
FT /note="D -> G (in Ref. 7; AAH36780)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 405 AA; 44127 MW; 4AB269E269982D24 CRC64;
MERWPWPSGG AWLLVAARAL LQLLRSDLRL GRPLLAALAL LAALDWLCQR LLPPPAALAV
LAAAGWIALS RLARPQRLPV ATRAVLITGC DSGFGKETAK KLDSMGFTVL ATVLELNSPG
AIELRTCCSP RLRLLQMDLT KPGDISRVLE FTKAHTTSTG LWGLVNNAGH NEVVADAELS
PVATFRSCME VNFFGALELT KGLLPLLRSS RGRIVTVGSP AGDMPYPCLG AYGTSKAAVA
LLMDTFSCEL LPWGVKVSII QPGCFKTESV RNVGQWEKRK QLLLANLPQE LLQAYGKDYI
EHLHGQFLHS LRLAMSDLTP VVDAITDALL AARPRRRYYP GQGLGLMYFI HYYLPEGLRR
RFLQAFFISH CLPRALQPGQ PGTTPPQDAA QDPNLSPGPS PAVAR
