DHI2_DANRE
ID DHI2_DANRE Reviewed; 414 AA.
AC F1QLP1; Q6P0H9;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 03-MAY-2011, sequence version 1.
DT 03-AUG-2022, entry version 76.
DE RecName: Full=11-beta-hydroxysteroid dehydrogenase type 2 {ECO:0000303|PubMed:23042946};
DE Short=11-DH2;
DE Short=11-beta-HSD2 {ECO:0000303|PubMed:23042946, ECO:0000303|PubMed:33387577};
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;
GN Name=hsd11b2;
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP IDENTIFICATION.
RC STRAIN=Tuebingen;
RG Ensembl;
RL Submitted (JUL-2011) to UniProtKB.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 15-414.
RC TISSUE=Kidney;
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
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 [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND TISSUE SPECIFICITY.
RX PubMed=23042946; DOI=10.1530/joe-12-0379;
RA Alderman S.L., Vijayan M.M.;
RT "11beta-Hydroxysteroid dehydrogenase type 2 in zebrafish brain: a
RT functional role in hypothalamus-pituitary-interrenal axis regulation.";
RL J. Endocrinol. 215:393-402(2012).
RN [6]
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 [7]
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).
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:22796344, PubMed:23042946,
CC PubMed:27927697, PubMed:33387577). Cortisol is the primary
CC glucocorticoid in teleosts and is released to increase glucose
CC bioavailability in order to meet the increased energy demands in
CC response to stress (PubMed:23042946). Functions as a dehydrogenase
CC (oxidase), thereby decreasing the concentration of active
CC glucocorticoids, regulating the hypothalamus-pituitary-interrenal (HPI)
CC axis function in adult fish (PubMed:23042946). Decreasing the excess
CC glucocorticoids may be of relevance to brain function and neural
CC proliferation (PubMed:23042946). Plays a key role by catalyzing the
CC oxidation of 11beta-hydroxytestosterone (11beta,17beta-
CC dihydroxyandrost-4-ene-3-one) to 11-ketotestosterone (17beta-
CC hydroxyandrost-4-ene-3,11-dione), the major fish androgen, that
CC activates androgen receptor transcriptional activity (PubMed:22796344,
CC PubMed:27927697). 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 (PubMed:27927697). Exerts a
CC dual role in fish by inactivating glucocorticoids and activating
CC androgens (PubMed:22796344, PubMed:27927697).
CC {ECO:0000269|PubMed:22796344, ECO:0000269|PubMed:23042946,
CC ECO:0000269|PubMed:27927697, ECO:0000269|PubMed:33387577,
CC ECO:0000303|PubMed:22796344, ECO:0000303|PubMed:23042946,
CC ECO:0000303|PubMed:27927697}.
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:22796344, ECO:0000269|PubMed:23042946,
CC ECO:0000269|PubMed:27927697, ECO:0000269|PubMed:33387577};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53117;
CC Evidence={ECO:0000269|PubMed:23042946, ECO:0000305|PubMed:22796344,
CC ECO:0000305|PubMed:27927697, ECO:0000305|PubMed:33387577};
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:22796344, ECO:0000269|PubMed:23042946,
CC ECO:0000269|PubMed:33387577};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:50209;
CC Evidence={ECO:0000269|PubMed:23042946, ECO:0000305|PubMed:22796344,
CC ECO:0000305|PubMed:33387577};
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:22796344};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42205;
CC Evidence={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:0000250|UniProtKB:P80365};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69409;
CC Evidence={ECO:0000250|UniProtKB:P80365};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=72 nM for cortisol {ECO:0000269|PubMed:22796344};
CC KM=147 nM for corticosterone {ECO:0000269|PubMed:22796344};
CC KM=206 nM for 11beta,17beta-dihydroxyandrost-4-ene-3-one
CC {ECO:0000269|PubMed:22796344};
CC -!- PATHWAY: Steroid metabolism. {ECO:0000305}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane
CC protein {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Broadly expressed in peripheral (brain, gill, eye,
CC heart, liver, head kidney, posterior kidney, and gut).
CC {ECO:0000269|PubMed:23042946}.
CC -!- MISCELLANEOUS: As zebrafish lack the enzyme catalyzing the reverse
CC reaction (HSD11B1), cortisone cannot be recycled, it is metabolized and
CC excreted (PubMed:27927697). To maintain glucocorticoid signaling a new
CC cortisol molecule must be synthesized (PubMed:27927697).
CC {ECO:0000303|PubMed:27927697}.
CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR)
CC family. {ECO:0000305}.
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DR EMBL; CR381641; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC065613; AAH65613.1; -; mRNA.
DR RefSeq; NP_997885.2; NM_212720.2.
DR AlphaFoldDB; F1QLP1; -.
DR SMR; F1QLP1; -.
DR STRING; 7955.ENSDARP00000118501; -.
DR PaxDb; F1QLP1; -.
DR Ensembl; ENSDART00000141211; ENSDARP00000118501; ENSDARG00000001975.
DR GeneID; 334098; -.
DR KEGG; dre:334098; -.
DR CTD; 3291; -.
DR ZFIN; ZDB-GENE-030131-6030; hsd11b2.
DR eggNOG; KOG1610; Eukaryota.
DR GeneTree; ENSGT00940000159716; -.
DR HOGENOM; CLU_010194_2_0_1; -.
DR InParanoid; F1QLP1; -.
DR OMA; ATFRNCM; -.
DR OrthoDB; 1313182at2759; -.
DR PhylomeDB; F1QLP1; -.
DR TreeFam; TF325617; -.
DR BRENDA; 1.1.1.146; 928.
DR Reactome; R-DRE-194002; Glucocorticoid biosynthesis.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 7.
DR Bgee; ENSDARG00000001975; Expressed in pharyngeal gill and 44 other tissues.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IBA:GO_Central.
DR GO; GO:0070523; F:11-beta-hydroxysteroid dehydrogenase (NAD+) activity; IBA:GO_Central.
DR GO; GO:0003845; F:11-beta-hydroxysteroid dehydrogenase [NAD(P)] activity; ISS:ZFIN.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0016229; F:steroid dehydrogenase activity; IBA:GO_Central.
DR GO; GO:0034650; P:cortisol metabolic process; IDA:ZFIN.
DR GO; GO:0008211; P:glucocorticoid metabolic process; IBA:GO_Central.
DR GO; GO:0033555; P:multicellular organismal response to stress; IDA:ZFIN.
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 Lipid metabolism; Membrane; Oxidoreductase; Reference proteome;
KW Steroid metabolism; Transmembrane; Transmembrane helix.
FT CHAIN 1..414
FT /note="11-beta-hydroxysteroid dehydrogenase type 2"
FT /id="PRO_0000455007"
FT TRANSMEM 3..23
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 26..46
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 52..72
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 341..361
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 382..414
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 384..414
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ SEQUENCE 414 AA; 45902 MW; F4B224E913C0480A CRC64;
MEDFAVSFWI YIGVMSIFVG GAVKKFLAFN IGAMPSVVVW LGATLLVERL CALCMPAVLA
RLVLCVCCWL YFTWATPKPS LPVEDKAVFI TGCDSGFGNA TAKKLDAMGF EVFATVLNLE
GEGAKHLRKV CSSRLTLLQV DITQPQQVQQ ALLDTKAKLG IRDLWGLVNN AGWCVNIGDA
ELSLMSNYRG CMEVNFFGTV TVTRTFLPLL RQSKGRIVTI SSPSGEHPFP CLASYGASKA
ALNLFINTLR HELDPWGVKV STILPSAYKT GQSSNAEYWE KQYKSLLQGL SPNLLEEYGE
EYLLETKELF QNYAKTANED LSPVIDTIVE ALLSPQPQVR YYAGPGLILM YFICSYLPLS
ISDRFLQKLF VQKKVMPRAL IKQQGLSPND NNNSIKENMN DSSSNNSNFT KCID
