DIDH_RAT
ID DIDH_RAT Reviewed; 322 AA.
AC P23457; Q5BKC8; Q6LDE6; Q6LDE7;
DT 01-NOV-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1991, sequence version 1.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=3-alpha-hydroxysteroid dehydrogenase;
DE Short=3-alpha-HSD;
DE EC=1.1.1.50;
DE AltName: Full=Hydroxyprostaglandin dehydrogenase;
GN Name=Akr1c9;
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], AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=1840601; DOI=10.1016/s0021-9258(18)31521-7;
RA Pawlowski J.E., Huizinga M., Penning T.M.;
RT "Cloning and sequencing of the cDNA for rat liver 3 alpha-
RT hydroxysteroid/dihydrodiol dehydrogenase.";
RL J. Biol. Chem. 266:8820-8825(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=1714456; DOI=10.1016/s0021-9258(18)98610-2;
RA Stolz A., Rahimi-Kiani M., Ameis D., Chan E., Ronk M., Shively J.E.;
RT "Molecular structure of rat hepatic 3 alpha-hydroxysteroid dehydrogenase. A
RT member of the oxidoreductase gene family.";
RL J. Biol. Chem. 266:15253-15257(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1922097; DOI=10.1210/mend-5-6-823;
RA Cheng K.-C., White P.C., Qin K.-N.;
RT "Molecular cloning and expression of rat liver 3 alpha-hydroxysteroid
RT dehydrogenase.";
RL Mol. Endocrinol. 5:823-828(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7515872; DOI=10.1093/oxfordjournals.jbchem.a124323;
RA Usui E., Okuda K., Kato Y., Noshiro M.;
RT "Rat hepatic 3 alpha-hydroxysteroid dehydrogenase: expression of cDNA and
RT physiological function in bile acid biosynthetic pathway.";
RL J. Biochem. 115:230-237(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=Sprague-Dawley;
RX PubMed=10619355; DOI=10.1016/s0960-0760(99)00122-3;
RA Lin H.K., Hung C.F., Moore M., Penning T.M.;
RT "Genomic structure of rat 3alpha-hydroxysteroid/dihydrodiol dehydrogenase
RT (3alpha-HSD/DD, AKR1C9).";
RL J. Steroid Biochem. Mol. Biol. 71:29-39(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [7]
RP PROTEIN SEQUENCE OF 2-16; 121-135; 152-166 AND 203-217.
RC TISSUE=Liver;
RX PubMed=7998972; DOI=10.1042/bj3040385;
RA Del Bello B., Maellaro E., Sugherini L., Santucci A., Comporti M.,
RA Casini A.F.;
RT "Purification of NADPH-dependent dehydroascorbate reductase from rat liver
RT and its identification with 3 alpha-hydroxysteroid dehydrogenase.";
RL Biochem. J. 304:385-390(1994).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 112-169 AND 238-322.
RX PubMed=1793046; DOI=10.1007/bf01993305;
RA Pawlowski J., Huizinga M., Penning T.M.;
RT "Isolation and partial characterization of a full-length cDNA clone for 3
RT alpha-hydroxysteroid dehydrogenase: a potential target enzyme for
RT nonsteroidal anti-inflammatory drugs.";
RL Agents Actions 34:289-293(1991).
RN [9]
RP PROTEIN SEQUENCE OF 162-171; 208-223 AND 232-246.
RX PubMed=2026597; DOI=10.1016/s0021-9258(18)31522-9;
RA Penning T.M., Abrams W.R., Pawlowski J.E.;
RT "Affinity labeling of 3 alpha-hydroxysteroid dehydrogenase with 3 alpha-
RT bromoacetoxyandrosterone and 11 alpha-bromoacetoxyprogesterone. Isolation
RT and sequence of active site peptides containing reactive cysteines;
RT sequence confirmation using nucleotide sequence from a cDNA clone.";
RL J. Biol. Chem. 266:8826-8834(1991).
RN [10]
RP TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=7626489; DOI=10.1016/0960-0760(95)00019-v;
RA Khanna M., Qin K.-N., Cheng K.-C.;
RT "Distribution of 3 alpha-hydroxysteroid dehydrogenase in rat brain and
RT molecular cloning of multiple cDNAs encoding structurally related proteins
RT in humans.";
RL J. Steroid Biochem. Mol. Biol. 53:41-46(1995).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS).
RC TISSUE=Liver;
RX PubMed=8146147; DOI=10.1073/pnas.91.7.2517;
RA Hoog S.S., Pawlowski J.E., Alzari P.M., Penning T.M., Lewis M.;
RT "Three-dimensional structure of rat liver 3 alpha-
RT hydroxysteroid/dihydrodiol dehydrogenase: a member of the aldo-keto
RT reductase superfamily.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:2517-2521(1994).
RN [12]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS).
RX PubMed=8718859; DOI=10.1021/bi9604688;
RA Bennett M.J., Schlegel B.P., Jez J.M., Penning T.M., Lewis M.;
RT "Structure of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase complexed
RT with NADP+.";
RL Biochemistry 35:10702-10711(1996).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEX WITH NADP AND
RP TESTOSTERONE.
RX PubMed=9261071; DOI=10.1016/s0969-2126(97)00234-7;
RA Bennett M.J., Albert R.H., Jez J.M., Ma H., Penning T.M., Lewis M.;
RT "Steroid recognition and regulation of hormone action: crystal structure of
RT testosterone and NADP+ bound to 3 alpha-hydroxysteroid/dihydrodiol
RT dehydrogenase.";
RL Structure 5:799-812(1997).
CC -!- FUNCTION: Besides being a 3-alpha-hydroxysteroid dehydrogenase, the
CC enzyme can accomplish diverse functions: as quinone reductase, as an
CC aromatic alcohol dehydrogenase, as dihydrodiol dehydrogenase, and as
CC 9-, 11-, and 15-hydroxyprostaglandin dehydrogenase.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 3alpha-hydroxysteroid + NADP(+) = a 3-oxosteroid + H(+) +
CC NADPH; Xref=Rhea:RHEA:34783, ChEBI:CHEBI:15378, ChEBI:CHEBI:36835,
CC ChEBI:CHEBI:47788, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.50;
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 3alpha-hydroxysteroid + NAD(+) = a 3-oxosteroid + H(+) +
CC NADH; Xref=Rhea:RHEA:34779, ChEBI:CHEBI:15378, ChEBI:CHEBI:36835,
CC ChEBI:CHEBI:47788, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.50;
CC -!- ACTIVITY REGULATION: Potently inhibited by the nonsteroidal anti-
CC inflammatory drugs (NSAID).
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:9261071}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: In brain, highest levels found in olfactory bulb.
CC Moderate levels present in cerebellum, cerebral cortex, hypothalamus
CC and pituitary. Low levels present in amygdala, brain stem, caudate
CC putamen, cingulate cortex, hippocampus, midbrain, and thalamus.
CC {ECO:0000269|PubMed:7626489}.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
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DR EMBL; M64393; AAA40605.1; -; mRNA.
DR EMBL; M61937; AAA41077.1; -; mRNA.
DR EMBL; D17310; BAA04132.1; -; mRNA.
DR EMBL; S57790; AAB19918.1; -; mRNA.
DR EMBL; AF180334; AAF25813.1; -; Genomic_DNA.
DR EMBL; AF180326; AAF25813.1; JOINED; Genomic_DNA.
DR EMBL; AF180327; AAF25813.1; JOINED; Genomic_DNA.
DR EMBL; AF180328; AAF25813.1; JOINED; Genomic_DNA.
DR EMBL; AF180329; AAF25813.1; JOINED; Genomic_DNA.
DR EMBL; AF180330; AAF25813.1; JOINED; Genomic_DNA.
DR EMBL; AF180331; AAF25813.1; JOINED; Genomic_DNA.
DR EMBL; AF180332; AAF25813.1; JOINED; Genomic_DNA.
DR EMBL; AF180333; AAF25813.1; JOINED; Genomic_DNA.
DR EMBL; BC091123; AAH91123.1; -; mRNA.
DR EMBL; S35751; AAB21512.1; -; mRNA.
DR EMBL; S35752; AAB21513.1; -; mRNA.
DR PIR; A39350; A39350.
DR PIR; PC2175; PC2175.
DR RefSeq; NP_612556.1; NM_138547.3.
DR PDB; 1AFS; X-ray; 2.50 A; A/B=1-322.
DR PDB; 1LWI; X-ray; 2.70 A; A/B=1-322.
DR PDB; 1RAL; X-ray; 3.00 A; A=1-308.
DR PDBsum; 1AFS; -.
DR PDBsum; 1LWI; -.
DR PDBsum; 1RAL; -.
DR AlphaFoldDB; P23457; -.
DR SMR; P23457; -.
DR STRING; 10116.ENSRNOP00000023835; -.
DR ChEMBL; CHEMBL1075221; -.
DR iPTMnet; P23457; -.
DR PhosphoSitePlus; P23457; -.
DR jPOST; P23457; -.
DR PaxDb; P23457; -.
DR PRIDE; P23457; -.
DR Ensembl; ENSRNOT00000023835; ENSRNOP00000023835; ENSRNOG00000017672.
DR GeneID; 191574; -.
DR KEGG; rno:191574; -.
DR UCSC; RGD:708361; rat.
DR CTD; 105387; -.
DR RGD; 708361; LOC191574.
DR eggNOG; KOG1577; Eukaryota.
DR GeneTree; ENSGT00940000153677; -.
DR HOGENOM; CLU_023205_0_0_1; -.
DR InParanoid; P23457; -.
DR OMA; IEIHPYN; -.
DR OrthoDB; 1016440at2759; -.
DR PhylomeDB; P23457; -.
DR TreeFam; TF106492; -.
DR BioCyc; MetaCyc:MON-14305; -.
DR BRENDA; 1.1.1.213; 5301.
DR BRENDA; 1.1.1.50; 5301.
DR BRENDA; 1.6.5.10; 5301.
DR SABIO-RK; P23457; -.
DR EvolutionaryTrace; P23457; -.
DR PRO; PR:P23457; -.
DR Proteomes; UP000002494; Chromosome 17.
DR Bgee; ENSRNOG00000017672; Expressed in liver and 19 other tissues.
DR Genevisible; P23457; RN.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0047042; F:androsterone dehydrogenase (B-specific) activity; IEA:UniProtKB-EC.
DR GO; GO:0047023; F:androsterone dehydrogenase activity; IBA:GO_Central.
DR GO; GO:0032052; F:bile acid binding; IBA:GO_Central.
DR GO; GO:0047086; F:ketosteroid monooxygenase activity; IBA:GO_Central.
DR GO; GO:0016229; F:steroid dehydrogenase activity; IDA:RGD.
DR GO; GO:0044597; P:daunorubicin metabolic process; IBA:GO_Central.
DR GO; GO:0044598; P:doxorubicin metabolic process; IBA:GO_Central.
DR GO; GO:0021766; P:hippocampus development; IEP:RGD.
DR GO; GO:0042448; P:progesterone metabolic process; IBA:GO_Central.
DR GO; GO:0006693; P:prostaglandin metabolic process; IBA:GO_Central.
DR GO; GO:0008202; P:steroid metabolic process; IBA:GO_Central.
DR CDD; cd19108; AKR_AKR1C1-35; 1.
DR DisProt; DP02646; -.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR020471; AKR.
DR InterPro; IPR044482; AKR1C.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR InterPro; IPR036812; NADP_OxRdtase_dom_sf.
DR Pfam; PF00248; Aldo_ket_red; 1.
DR PIRSF; PIRSF000097; AKR; 1.
DR PRINTS; PR00069; ALDKETRDTASE.
DR SUPFAM; SSF51430; SSF51430; 1.
DR PROSITE; PS00798; ALDOKETO_REDUCTASE_1; 1.
DR PROSITE; PS00062; ALDOKETO_REDUCTASE_2; 1.
DR PROSITE; PS00063; ALDOKETO_REDUCTASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Direct protein sequencing; NAD; NADP;
KW Oxidoreductase; Reference proteome.
FT CHAIN 1..322
FT /note="3-alpha-hydroxysteroid dehydrogenase"
FT /id="PRO_0000124654"
FT ACT_SITE 55
FT /note="Proton donor"
FT BINDING 20..24
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:9261071"
FT BINDING 50
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:9261071"
FT BINDING 117
FT /ligand="substrate"
FT BINDING 166..167
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:9261071"
FT BINDING 190
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:9261071"
FT BINDING 216..221
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:9261071"
FT BINDING 227
FT /ligand="substrate"
FT BINDING 270..280
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:9261071"
FT SITE 84
FT /note="Lowers pKa of active site Tyr"
FT /evidence="ECO:0000250"
FT MOD_RES 1
FT /note="Blocked amino end (Met)"
FT CONFLICT 108
FT /note="L -> Q (in Ref. 3; AAB19918)"
FT /evidence="ECO:0000305"
FT CONFLICT 273..274
FT /note="NA -> KP (in Ref. 3; AAB19918)"
FT /evidence="ECO:0000305"
FT CONFLICT 280
FT /note="L -> P (in Ref. 3; AAB19918)"
FT /evidence="ECO:0000305"
FT HELIX 3..5
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 7..9
FT /evidence="ECO:0007829|PDB:1AFS"
FT TURN 11..13
FT /evidence="ECO:0007829|PDB:1RAL"
FT STRAND 15..22
FT /evidence="ECO:0007829|PDB:1AFS"
FT TURN 28..30
FT /evidence="ECO:0007829|PDB:1RAL"
FT HELIX 33..43
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:1AFS"
FT TURN 53..56
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 58..70
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 76..78
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 80..85
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 87..89
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 92..94
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 95..106
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 109..117
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 124..129
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 131..137
FT /evidence="ECO:0007829|PDB:1RAL"
FT HELIX 144..156
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 159..167
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 170..177
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 187..192
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 200..209
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 212..217
FT /evidence="ECO:0007829|PDB:1AFS"
FT TURN 225..227
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 235..237
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 239..247
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 252..262
FT /evidence="ECO:0007829|PDB:1AFS"
FT STRAND 266..269
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 274..280
FT /evidence="ECO:0007829|PDB:1AFS"
FT TURN 281..284
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 290..297
FT /evidence="ECO:0007829|PDB:1AFS"
FT HELIX 309..311
FT /evidence="ECO:0007829|PDB:1AFS"
SQ SEQUENCE 322 AA; 37028 MW; 592EFC584726A4F6 CRC64;
MDSISLRVAL NDGNFIPVLG FGTTVPEKVA KDEVIKATKI AIDNGFRHFD SAYLYEVEEE
VGQAIRSKIE DGTVKREDIF YTSKLWSTFH RPELVRTCLE KTLKSTQLDY VDLYIIHFPM
ALQPGDIFFP RDEHGKLLFE TVDICDTWEA MEKCKDAGLA KSIGVSNFNC RQLERILNKP
GLKYKPVCNQ VECHLYLNQS KMLDYCKSKD IILVSYCTLG SSRDKTWVDQ KSPVLLDDPV
LCAIAKKYKQ TPALVALRYQ LQRGVVPLIR SFNAKRIKEL TQVFEFQLAS EDMKALDGLN
RNFRYNNAKY FDDHPNHPFT DE
