Full text data of AKR1C1
AKR1C1
(DDH, DDH1)
[Confidence: low (only semi-automatic identification from reviews)]
Aldo-keto reductase family 1 member C1; 1.1.1.- (20-alpha-hydroxysteroid dehydrogenase; 20-alpha-HSD; 1.1.1.149; Chlordecone reductase homolog HAKRC; Dihydrodiol dehydrogenase 1/2; DD1/DD2; High-affinity hepatic bile acid-binding protein; HBAB; Indanol dehydrogenase; 1.1.1.112; Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase; 1.3.1.20)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Aldo-keto reductase family 1 member C1; 1.1.1.- (20-alpha-hydroxysteroid dehydrogenase; 20-alpha-HSD; 1.1.1.149; Chlordecone reductase homolog HAKRC; Dihydrodiol dehydrogenase 1/2; DD1/DD2; High-affinity hepatic bile acid-binding protein; HBAB; Indanol dehydrogenase; 1.1.1.112; Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase; 1.3.1.20)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q04828
ID AK1C1_HUMAN Reviewed; 323 AA.
AC Q04828; P52896; Q5SR15; Q7M4N2; Q9UCX2;
DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1993, sequence version 1.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Aldo-keto reductase family 1 member C1;
DE EC=1.1.1.-;
DE AltName: Full=20-alpha-hydroxysteroid dehydrogenase;
DE Short=20-alpha-HSD;
DE EC=1.1.1.149;
DE AltName: Full=Chlordecone reductase homolog HAKRC;
DE AltName: Full=Dihydrodiol dehydrogenase 1/2;
DE Short=DD1/DD2;
DE AltName: Full=High-affinity hepatic bile acid-binding protein;
DE Short=HBAB;
DE AltName: Full=Indanol dehydrogenase;
DE EC=1.1.1.112;
DE AltName: Full=Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase;
DE EC=1.3.1.20;
GN Name=AKR1C1; Synonyms=DDH, DDH1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=8486699;
RA Stolz A., Hammond L., Lou H., Takikawa H., Ronk M., Shively J.E.;
RT "cDNA cloning and expression of the human hepatic bile acid-binding
RT protein. A member of the monomeric reductase gene family.";
RL J. Biol. Chem. 268:10448-10457(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=8132567;
RA Lou H., Hammond L., Sharma V., Sparkes R.S., Lusis A.J., Stolz A.;
RT "Genomic organization and chromosomal localization of a novel human
RT hepatic dihydrodiol dehydrogenase with high affinity bile acid
RT binding.";
RL J. Biol. Chem. 269:8416-8422(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Colon;
RX PubMed=7515059;
RA Ciaccio P.J., Jaiswal A.K., Tew K.D.;
RT "Regulation of human dihydrodiol dehydrogenase by Michael acceptor
RT xenobiotics.";
RL J. Biol. Chem. 269:15558-15562(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
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
RT proteins in humans.";
RL J. Steroid Biochem. Mol. Biol. 53:41-46(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=10672042; DOI=10.1046/j.1365-2443.2000.00310.x;
RA Nishizawa M., Nakajima T., Yasuda K., Kanzaki H., Sasaguri Y.,
RA Watanabe K., Ito S.;
RT "Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with
RT three aldo-keto reductase genes.";
RL Genes Cells 5:111-125(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND TISSUE SPECIFICITY.
RC TISSUE=Skin fibroblast;
RX PubMed=11013348; DOI=10.1677/jme.0.0250221;
RA Zhang Y., Dufort I., Rheault P., Luu-The V.;
RT "Characterization of a human 20alpha-hydroxysteroid dehydrogenase.";
RL J. Mol. Endocrinol. 25:221-228(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, and Testis;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-323.
RC TISSUE=Liver;
RX PubMed=8274401; DOI=10.1016/0960-0760(93)90308-J;
RA Qin K.-N., New M.I., Cheng K.-C.;
RT "Molecular cloning of multiple cDNAs encoding human enzymes
RT structurally related to 3 alpha-hydroxysteroid dehydrogenase.";
RL J. Steroid Biochem. Mol. Biol. 46:673-679(1993).
RN [11]
RP PROTEIN SEQUENCE OF 10-31; 40-61; 69-126; 137-153; 162-206; 209-230;
RP 250-267; 271-289 AND 295-323, FUNCTION, CATALYTIC ACTIVITY, ENZYME
RP REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=8573067;
RA Hara A., Matsuura K., Tamada Y., Sato K., Miyabe Y., Deyashiki Y.,
RA Ishida N.;
RT "Relationship of human liver dihydrodiol dehydrogenases to hepatic
RT bile-acid-binding protein and an oxidoreductase of human colon
RT cells.";
RL Biochem. J. 313:373-376(1996).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 18-323, AND PROTEIN SEQUENCE OF 18-31;
RP 105-131; 176-193 AND 271-294.
RC TISSUE=Liver;
RX PubMed=8172617;
RA Deyashiki Y., Ogasawara A., Nakayama T., Nakanishi M., Miyabe Y.,
RA Sato K., Hara A.;
RT "Molecular cloning of two human liver 3 alpha-
RT hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical
RT with chlordecone reductase and bile-acid binder.";
RL Biochem. J. 299:545-552(1994).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEX WITH NADP AND
RP 20ALPHA-HYDROXY-PROGESTERONE, AND MUTAGENESIS OF GLU-127; HIS-222;
RP ARG-304; TYR-305; THR-307 AND ASP-309.
RX PubMed=12899831; DOI=10.1016/S0022-2836(03)00762-9;
RA Couture J.-F., Legrand P., Cantin L., Luu-The V., Labrie F.,
RA Breton R.;
RT "Human 20alpha-hydroxysteroid dehydrogenase: crystallographic and
RT site-directed mutagenesis studies lead to the identification of an
RT alternative binding site for C21-steroids.";
RL J. Mol. Biol. 331:593-604(2003).
CC -!- FUNCTION: Converts progesterone to its inactive form, 20-alpha-
CC dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine,
CC may have a role in the transport of bile. May have a role in
CC monitoring the intrahepatic bile acid concentration. Has a low
CC bile-binding ability. May play a role in myelin formation.
CC -!- CATALYTIC ACTIVITY: 17-alpha,20-alpha-dihydroxypregn-4-en-3-one +
CC NAD(P)(+) = 17-alpha-hydroxyprogesterone + NAD(P)H.
CC -!- CATALYTIC ACTIVITY: Trans-1,2-dihydrobenzene-1,2-diol + NADP(+) =
CC catechol + NADPH.
CC -!- CATALYTIC ACTIVITY: Indan-1-ol + NAD(P)(+) = indanone + NAD(P)H.
CC -!- ENZYME REGULATION: Inhibited by hexestrol with an IC(50) of 9.5
CC uM, 1,10-phenanthroline with an IC(50) of 55 uM, 1,7-
CC phenanthroline with an IC(50) of 72 uM, flufenamic acid with an
CC IC(50) of 6.0 uM, indomethacin with an IC(50) of 140 uM, ibuprofen
CC with an IC(50) of 950 uM, lithocholic acid with an IC(50) of 25
CC uM, ursodeoxycholic acid with an IC(50) of 340 uM and
CC chenodeoxycholic acid with an IC(50) of 570 uM.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5 uM for (s)-tetralol;
CC KM=38 uM for (s)-indan-1-ol;
CC KM=580 uM for benzene dihydrodiol;
CC KM=3 uM for 5-beta-pregnane-3-alpha,20-alpha-diol;
CC KM=3 uM for 5-beta-pregnan-20-alpha-ol-3-one;
CC KM=12 uM for 4-pregnen-20-alpha-ol-3-one;
CC KM=133 uM for 9-alpha,11-beta-PGF2;
CC KM=2 uM for 5-beta-pregnan-3-alpha-ol-20-one;
CC KM=1 uM for 5-beta-androstane-3,17-dione;
CC KM=12 uM for PGD2;
CC KM=0.6 uM for 20-alpha-hydroxyprogesterone (with NADH);
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expressed in all tissues tested including
CC liver, prostate, testis, adrenal gland, brain, uterus, mammary
CC gland and keratinocytes. Highest levels found in liver, mammary
CC gland and brain.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family.
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DR EMBL; M86609; AAB02880.1; -; mRNA.
DR EMBL; U05861; AAA18115.1; -; Genomic_DNA.
DR EMBL; U05853; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05854; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05855; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05857; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05858; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05859; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05860; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05684; AAA16227.1; -; mRNA.
DR EMBL; AB031083; BAA92883.1; -; mRNA.
DR EMBL; AB032150; BAA92886.1; -; Genomic_DNA.
DR EMBL; BT007197; AAP35861.1; -; mRNA.
DR EMBL; AL713867; CAI16409.1; -; Genomic_DNA.
DR EMBL; AC091817; CAI16409.1; JOINED; Genomic_DNA.
DR EMBL; BC015490; AAH15490.1; -; mRNA.
DR EMBL; BC020216; AAH20216.1; -; mRNA.
DR EMBL; BC040210; AAH40210.1; -; mRNA.
DR EMBL; S68290; AAD14012.1; -; mRNA.
DR EMBL; D26124; BAA05121.1; -; mRNA.
DR PIR; A53436; A53436.
DR PIR; I73675; I73675.
DR PIR; S59619; S59619.
DR PIR; S61515; S61515.
DR RefSeq; NP_001344.2; NM_001353.5.
DR UniGene; Hs.460260; -.
DR PDB; 1MRQ; X-ray; 1.59 A; A=2-323.
DR PDB; 3C3U; X-ray; 1.80 A; A=1-323.
DR PDB; 3GUG; X-ray; 1.90 A; A=1-323.
DR PDB; 3NTY; X-ray; 1.87 A; A=1-323.
DR PDBsum; 1MRQ; -.
DR PDBsum; 3C3U; -.
DR PDBsum; 3GUG; -.
DR PDBsum; 3NTY; -.
DR ProteinModelPortal; Q04828; -.
DR SMR; Q04828; 2-323.
DR IntAct; Q04828; 3.
DR MINT; MINT-5001209; -.
DR STRING; 9606.ENSP00000370254; -.
DR BindingDB; Q04828; -.
DR ChEMBL; CHEMBL5905; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; Q04828; -.
DR DMDM; 416877; -.
DR PaxDb; Q04828; -.
DR PRIDE; Q04828; -.
DR DNASU; 1645; -.
DR Ensembl; ENST00000380872; ENSP00000370254; ENSG00000187134.
DR Ensembl; ENST00000434459; ENSP00000412248; ENSG00000187134.
DR Ensembl; ENST00000578362; ENSP00000462940; ENSG00000266592.
DR Ensembl; ENST00000582412; ENSP00000462966; ENSG00000266592.
DR GeneID; 1645; -.
DR KEGG; hsa:1645; -.
DR UCSC; uc001iho.3; human.
DR CTD; 1645; -.
DR GeneCards; GC10P004995; -.
DR HGNC; HGNC:384; AKR1C1.
DR HPA; CAB010874; -.
DR HPA; CAB047303; -.
DR MIM; 600449; gene.
DR neXtProt; NX_Q04828; -.
DR PharmGKB; PA24677; -.
DR eggNOG; COG0656; -.
DR HOGENOM; HOG000250272; -.
DR HOVERGEN; HBG000020; -.
DR InParanoid; Q04828; -.
DR KO; K00089; -.
DR KO; K00212; -.
DR OMA; RIASNID; -.
DR PhylomeDB; Q04828; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; Q04828; -.
DR EvolutionaryTrace; Q04828; -.
DR GeneWiki; AKR1C1; -.
DR GenomeRNAi; 1645; -.
DR NextBio; 6768; -.
DR PRO; PR:Q04828; -.
DR ArrayExpress; Q04828; -.
DR Bgee; Q04828; -.
DR CleanEx; HS_AKR1C1; -.
DR Genevestigator; Q04828; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0047006; F:17-alpha,20-alpha-dihydroxypregn-4-en-3-one dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0047042; F:androsterone dehydrogenase (B-specific) activity; IDA:UniProtKB.
DR GO; GO:0032052; F:bile acid binding; IDA:UniProtKB.
DR GO; GO:0047718; F:indanol dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047086; F:ketosteroid monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0016655; F:oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor; IDA:UniProtKB.
DR GO; GO:0018636; F:phenanthrene 9,10-monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0047115; F:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0015721; P:bile acid and bile salt transport; TAS:UniProtKB.
DR GO; GO:0008206; P:bile acid metabolic process; IDA:UniProtKB.
DR GO; GO:0071395; P:cellular response to jasmonic acid stimulus; IDA:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; TAS:UniProtKB.
DR GO; GO:0044597; P:daunorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0044598; P:doxorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0030299; P:intestinal cholesterol absorption; TAS:UniProtKB.
DR GO; GO:0007603; P:phototransduction, visible light; TAS:Reactome.
DR GO; GO:0042448; P:progesterone metabolic process; IDA:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0046683; P:response to organophosphorus; IEP:UniProtKB.
DR GO; GO:0042574; P:retinal metabolic process; IDA:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; NAS:UniProtKB.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR001395; Aldo/ket_red.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR020471; Aldo/keto_reductase_subgr.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR PANTHER; PTHR11732; PTHR11732; 1.
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; Complete proteome; Cytoplasm; Direct protein sequencing;
KW NADP; Oxidoreductase; Polymorphism; Reference proteome.
FT CHAIN 1 323 Aldo-keto reductase family 1 member C1.
FT /FTId=PRO_0000124633.
FT NP_BIND 13 22 NADP (Potential).
FT NP_BIND 217 280 NADP (By similarity).
FT ACT_SITE 55 55 Proton donor (By similarity).
FT BINDING 117 117 Substrate (By similarity).
FT BINDING 304 304 Progesterone.
FT SITE 54 54 Important for substrate specificity (By
FT similarity).
FT SITE 84 84 Lowers pKa of active site Tyr (By
FT similarity).
FT SITE 222 222 May be involved in the mediating step
FT between the transformation of
FT progesterone and the release of the
FT cofactor.
FT VARIANT 170 170 R -> H (in dbSNP:rs17295755).
FT /FTId=VAR_048214.
FT VARIANT 172 172 Q -> L (in dbSNP:rs17354444).
FT /FTId=VAR_048215.
FT MUTAGEN 127 127 E->D: 30-fold decrease in k(cat)/K(m)
FT value for progesterone reduction; no
FT effect on the K(m) value.
FT MUTAGEN 222 222 H->I: Marked decrease in k(cat)/K(m)
FT value for progesterone; 24-fold decrease
FT for progesterone reduction; 18-fold
FT decrease for 20alpha-OHProg oxidation.
FT 95-fold decrease in K(m) value for NADPH.
FT MUTAGEN 222 222 H->S: Marked decrease in k(cat)/K(m)
FT value for progesterone; 10-fold decrease
FT for progesterone reduction; 3-fold
FT decrease for 20alpha-OHProg oxidation.
FT 10-fold decrease in K(m) value for NADPH.
FT MUTAGEN 304 304 R->L: 70-fold decrease in progesterone
FT reduction. No effect on DHT reduction.
FT MUTAGEN 305 305 Y->F: No effect on progesterone
FT reduction.
FT MUTAGEN 307 307 T->V: No effect on progesterone
FT reduction.
FT MUTAGEN 309 309 D->V: No effect on progesterone
FT reduction.
FT CONFLICT 3 3 S -> A (in Ref. 4; no nucleotide entry).
FT CONFLICT 95 95 V -> D (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 158 158 G -> E (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 171 172 RQ -> ST (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 183 184 KY -> QV (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 222 222 H -> L (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 319 319 F -> I (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT STRAND 7 9
FT STRAND 15 22
FT HELIX 33 44
FT STRAND 48 50
FT HELIX 53 55
FT HELIX 58 70
FT HELIX 76 78
FT STRAND 80 85
FT HELIX 87 89
FT HELIX 92 106
FT STRAND 111 116
FT STRAND 124 126
FT HELIX 144 156
FT STRAND 159 167
FT HELIX 170 177
FT STRAND 187 192
FT STRAND 194 197
FT HELIX 200 208
FT STRAND 212 217
FT TURN 225 227
FT HELIX 235 237
FT HELIX 239 248
FT HELIX 252 262
FT STRAND 266 270
FT HELIX 274 280
FT HELIX 281 285
FT HELIX 290 297
FT HELIX 309 311
SQ SEQUENCE 323 AA; 36788 MW; 9CB215478FBD29D5 CRC64;
MDSKYQCVKL NDGHFMPVLG FGTYAPAEVP KSKALEATKL AIEAGFRHID SAHLYNNEEQ
VGLAIRSKIA DGSVKREDIF YTSKLWCNSH RPELVRPALE RSLKNLQLDY VDLYLIHFPV
SVKPGEEVIP KDENGKILFD TVDLCATWEA VEKCKDAGLA KSIGVSNFNR RQLEMILNKP
GLKYKPVCNQ VECHPYFNQR KLLDFCKSKD IVLVAYSALG SHREEPWVDP NSPVLLEDPV
LCALAKKHKR TPALIALRYQ LQRGVVVLAK SYNEQRIRQN VQVFEFQLTS EEMKAIDGLN
RNVRYLTLDI FAGPPNYPFS DEY
//
ID AK1C1_HUMAN Reviewed; 323 AA.
AC Q04828; P52896; Q5SR15; Q7M4N2; Q9UCX2;
DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1993, sequence version 1.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Aldo-keto reductase family 1 member C1;
DE EC=1.1.1.-;
DE AltName: Full=20-alpha-hydroxysteroid dehydrogenase;
DE Short=20-alpha-HSD;
DE EC=1.1.1.149;
DE AltName: Full=Chlordecone reductase homolog HAKRC;
DE AltName: Full=Dihydrodiol dehydrogenase 1/2;
DE Short=DD1/DD2;
DE AltName: Full=High-affinity hepatic bile acid-binding protein;
DE Short=HBAB;
DE AltName: Full=Indanol dehydrogenase;
DE EC=1.1.1.112;
DE AltName: Full=Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase;
DE EC=1.3.1.20;
GN Name=AKR1C1; Synonyms=DDH, DDH1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=8486699;
RA Stolz A., Hammond L., Lou H., Takikawa H., Ronk M., Shively J.E.;
RT "cDNA cloning and expression of the human hepatic bile acid-binding
RT protein. A member of the monomeric reductase gene family.";
RL J. Biol. Chem. 268:10448-10457(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=8132567;
RA Lou H., Hammond L., Sharma V., Sparkes R.S., Lusis A.J., Stolz A.;
RT "Genomic organization and chromosomal localization of a novel human
RT hepatic dihydrodiol dehydrogenase with high affinity bile acid
RT binding.";
RL J. Biol. Chem. 269:8416-8422(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Colon;
RX PubMed=7515059;
RA Ciaccio P.J., Jaiswal A.K., Tew K.D.;
RT "Regulation of human dihydrodiol dehydrogenase by Michael acceptor
RT xenobiotics.";
RL J. Biol. Chem. 269:15558-15562(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
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
RT proteins in humans.";
RL J. Steroid Biochem. Mol. Biol. 53:41-46(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=10672042; DOI=10.1046/j.1365-2443.2000.00310.x;
RA Nishizawa M., Nakajima T., Yasuda K., Kanzaki H., Sasaguri Y.,
RA Watanabe K., Ito S.;
RT "Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with
RT three aldo-keto reductase genes.";
RL Genes Cells 5:111-125(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND TISSUE SPECIFICITY.
RC TISSUE=Skin fibroblast;
RX PubMed=11013348; DOI=10.1677/jme.0.0250221;
RA Zhang Y., Dufort I., Rheault P., Luu-The V.;
RT "Characterization of a human 20alpha-hydroxysteroid dehydrogenase.";
RL J. Mol. Endocrinol. 25:221-228(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, and Testis;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 4-323.
RC TISSUE=Liver;
RX PubMed=8274401; DOI=10.1016/0960-0760(93)90308-J;
RA Qin K.-N., New M.I., Cheng K.-C.;
RT "Molecular cloning of multiple cDNAs encoding human enzymes
RT structurally related to 3 alpha-hydroxysteroid dehydrogenase.";
RL J. Steroid Biochem. Mol. Biol. 46:673-679(1993).
RN [11]
RP PROTEIN SEQUENCE OF 10-31; 40-61; 69-126; 137-153; 162-206; 209-230;
RP 250-267; 271-289 AND 295-323, FUNCTION, CATALYTIC ACTIVITY, ENZYME
RP REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=8573067;
RA Hara A., Matsuura K., Tamada Y., Sato K., Miyabe Y., Deyashiki Y.,
RA Ishida N.;
RT "Relationship of human liver dihydrodiol dehydrogenases to hepatic
RT bile-acid-binding protein and an oxidoreductase of human colon
RT cells.";
RL Biochem. J. 313:373-376(1996).
RN [12]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 18-323, AND PROTEIN SEQUENCE OF 18-31;
RP 105-131; 176-193 AND 271-294.
RC TISSUE=Liver;
RX PubMed=8172617;
RA Deyashiki Y., Ogasawara A., Nakayama T., Nakanishi M., Miyabe Y.,
RA Sato K., Hara A.;
RT "Molecular cloning of two human liver 3 alpha-
RT hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical
RT with chlordecone reductase and bile-acid binder.";
RL Biochem. J. 299:545-552(1994).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) IN COMPLEX WITH NADP AND
RP 20ALPHA-HYDROXY-PROGESTERONE, AND MUTAGENESIS OF GLU-127; HIS-222;
RP ARG-304; TYR-305; THR-307 AND ASP-309.
RX PubMed=12899831; DOI=10.1016/S0022-2836(03)00762-9;
RA Couture J.-F., Legrand P., Cantin L., Luu-The V., Labrie F.,
RA Breton R.;
RT "Human 20alpha-hydroxysteroid dehydrogenase: crystallographic and
RT site-directed mutagenesis studies lead to the identification of an
RT alternative binding site for C21-steroids.";
RL J. Mol. Biol. 331:593-604(2003).
CC -!- FUNCTION: Converts progesterone to its inactive form, 20-alpha-
CC dihydroxyprogesterone (20-alpha-OHP). In the liver and intestine,
CC may have a role in the transport of bile. May have a role in
CC monitoring the intrahepatic bile acid concentration. Has a low
CC bile-binding ability. May play a role in myelin formation.
CC -!- CATALYTIC ACTIVITY: 17-alpha,20-alpha-dihydroxypregn-4-en-3-one +
CC NAD(P)(+) = 17-alpha-hydroxyprogesterone + NAD(P)H.
CC -!- CATALYTIC ACTIVITY: Trans-1,2-dihydrobenzene-1,2-diol + NADP(+) =
CC catechol + NADPH.
CC -!- CATALYTIC ACTIVITY: Indan-1-ol + NAD(P)(+) = indanone + NAD(P)H.
CC -!- ENZYME REGULATION: Inhibited by hexestrol with an IC(50) of 9.5
CC uM, 1,10-phenanthroline with an IC(50) of 55 uM, 1,7-
CC phenanthroline with an IC(50) of 72 uM, flufenamic acid with an
CC IC(50) of 6.0 uM, indomethacin with an IC(50) of 140 uM, ibuprofen
CC with an IC(50) of 950 uM, lithocholic acid with an IC(50) of 25
CC uM, ursodeoxycholic acid with an IC(50) of 340 uM and
CC chenodeoxycholic acid with an IC(50) of 570 uM.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5 uM for (s)-tetralol;
CC KM=38 uM for (s)-indan-1-ol;
CC KM=580 uM for benzene dihydrodiol;
CC KM=3 uM for 5-beta-pregnane-3-alpha,20-alpha-diol;
CC KM=3 uM for 5-beta-pregnan-20-alpha-ol-3-one;
CC KM=12 uM for 4-pregnen-20-alpha-ol-3-one;
CC KM=133 uM for 9-alpha,11-beta-PGF2;
CC KM=2 uM for 5-beta-pregnan-3-alpha-ol-20-one;
CC KM=1 uM for 5-beta-androstane-3,17-dione;
CC KM=12 uM for PGD2;
CC KM=0.6 uM for 20-alpha-hydroxyprogesterone (with NADH);
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expressed in all tissues tested including
CC liver, prostate, testis, adrenal gland, brain, uterus, mammary
CC gland and keratinocytes. Highest levels found in liver, mammary
CC gland and brain.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family.
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DR EMBL; M86609; AAB02880.1; -; mRNA.
DR EMBL; U05861; AAA18115.1; -; Genomic_DNA.
DR EMBL; U05853; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05854; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05855; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05857; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05858; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05859; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05860; AAA18115.1; JOINED; Genomic_DNA.
DR EMBL; U05684; AAA16227.1; -; mRNA.
DR EMBL; AB031083; BAA92883.1; -; mRNA.
DR EMBL; AB032150; BAA92886.1; -; Genomic_DNA.
DR EMBL; BT007197; AAP35861.1; -; mRNA.
DR EMBL; AL713867; CAI16409.1; -; Genomic_DNA.
DR EMBL; AC091817; CAI16409.1; JOINED; Genomic_DNA.
DR EMBL; BC015490; AAH15490.1; -; mRNA.
DR EMBL; BC020216; AAH20216.1; -; mRNA.
DR EMBL; BC040210; AAH40210.1; -; mRNA.
DR EMBL; S68290; AAD14012.1; -; mRNA.
DR EMBL; D26124; BAA05121.1; -; mRNA.
DR PIR; A53436; A53436.
DR PIR; I73675; I73675.
DR PIR; S59619; S59619.
DR PIR; S61515; S61515.
DR RefSeq; NP_001344.2; NM_001353.5.
DR UniGene; Hs.460260; -.
DR PDB; 1MRQ; X-ray; 1.59 A; A=2-323.
DR PDB; 3C3U; X-ray; 1.80 A; A=1-323.
DR PDB; 3GUG; X-ray; 1.90 A; A=1-323.
DR PDB; 3NTY; X-ray; 1.87 A; A=1-323.
DR PDBsum; 1MRQ; -.
DR PDBsum; 3C3U; -.
DR PDBsum; 3GUG; -.
DR PDBsum; 3NTY; -.
DR ProteinModelPortal; Q04828; -.
DR SMR; Q04828; 2-323.
DR IntAct; Q04828; 3.
DR MINT; MINT-5001209; -.
DR STRING; 9606.ENSP00000370254; -.
DR BindingDB; Q04828; -.
DR ChEMBL; CHEMBL5905; -.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; Q04828; -.
DR DMDM; 416877; -.
DR PaxDb; Q04828; -.
DR PRIDE; Q04828; -.
DR DNASU; 1645; -.
DR Ensembl; ENST00000380872; ENSP00000370254; ENSG00000187134.
DR Ensembl; ENST00000434459; ENSP00000412248; ENSG00000187134.
DR Ensembl; ENST00000578362; ENSP00000462940; ENSG00000266592.
DR Ensembl; ENST00000582412; ENSP00000462966; ENSG00000266592.
DR GeneID; 1645; -.
DR KEGG; hsa:1645; -.
DR UCSC; uc001iho.3; human.
DR CTD; 1645; -.
DR GeneCards; GC10P004995; -.
DR HGNC; HGNC:384; AKR1C1.
DR HPA; CAB010874; -.
DR HPA; CAB047303; -.
DR MIM; 600449; gene.
DR neXtProt; NX_Q04828; -.
DR PharmGKB; PA24677; -.
DR eggNOG; COG0656; -.
DR HOGENOM; HOG000250272; -.
DR HOVERGEN; HBG000020; -.
DR InParanoid; Q04828; -.
DR KO; K00089; -.
DR KO; K00212; -.
DR OMA; RIASNID; -.
DR PhylomeDB; Q04828; -.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_116125; Disease.
DR SABIO-RK; Q04828; -.
DR EvolutionaryTrace; Q04828; -.
DR GeneWiki; AKR1C1; -.
DR GenomeRNAi; 1645; -.
DR NextBio; 6768; -.
DR PRO; PR:Q04828; -.
DR ArrayExpress; Q04828; -.
DR Bgee; Q04828; -.
DR CleanEx; HS_AKR1C1; -.
DR Genevestigator; Q04828; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0047006; F:17-alpha,20-alpha-dihydroxypregn-4-en-3-one dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0047042; F:androsterone dehydrogenase (B-specific) activity; IDA:UniProtKB.
DR GO; GO:0032052; F:bile acid binding; IDA:UniProtKB.
DR GO; GO:0047718; F:indanol dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047086; F:ketosteroid monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0016655; F:oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor; IDA:UniProtKB.
DR GO; GO:0018636; F:phenanthrene 9,10-monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0047115; F:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0015721; P:bile acid and bile salt transport; TAS:UniProtKB.
DR GO; GO:0008206; P:bile acid metabolic process; IDA:UniProtKB.
DR GO; GO:0071395; P:cellular response to jasmonic acid stimulus; IDA:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; TAS:UniProtKB.
DR GO; GO:0044597; P:daunorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0044598; P:doxorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0030299; P:intestinal cholesterol absorption; TAS:UniProtKB.
DR GO; GO:0007603; P:phototransduction, visible light; TAS:Reactome.
DR GO; GO:0042448; P:progesterone metabolic process; IDA:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0046683; P:response to organophosphorus; IEP:UniProtKB.
DR GO; GO:0042574; P:retinal metabolic process; IDA:UniProtKB.
DR GO; GO:0006805; P:xenobiotic metabolic process; NAS:UniProtKB.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR001395; Aldo/ket_red.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR020471; Aldo/keto_reductase_subgr.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR PANTHER; PTHR11732; PTHR11732; 1.
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; Complete proteome; Cytoplasm; Direct protein sequencing;
KW NADP; Oxidoreductase; Polymorphism; Reference proteome.
FT CHAIN 1 323 Aldo-keto reductase family 1 member C1.
FT /FTId=PRO_0000124633.
FT NP_BIND 13 22 NADP (Potential).
FT NP_BIND 217 280 NADP (By similarity).
FT ACT_SITE 55 55 Proton donor (By similarity).
FT BINDING 117 117 Substrate (By similarity).
FT BINDING 304 304 Progesterone.
FT SITE 54 54 Important for substrate specificity (By
FT similarity).
FT SITE 84 84 Lowers pKa of active site Tyr (By
FT similarity).
FT SITE 222 222 May be involved in the mediating step
FT between the transformation of
FT progesterone and the release of the
FT cofactor.
FT VARIANT 170 170 R -> H (in dbSNP:rs17295755).
FT /FTId=VAR_048214.
FT VARIANT 172 172 Q -> L (in dbSNP:rs17354444).
FT /FTId=VAR_048215.
FT MUTAGEN 127 127 E->D: 30-fold decrease in k(cat)/K(m)
FT value for progesterone reduction; no
FT effect on the K(m) value.
FT MUTAGEN 222 222 H->I: Marked decrease in k(cat)/K(m)
FT value for progesterone; 24-fold decrease
FT for progesterone reduction; 18-fold
FT decrease for 20alpha-OHProg oxidation.
FT 95-fold decrease in K(m) value for NADPH.
FT MUTAGEN 222 222 H->S: Marked decrease in k(cat)/K(m)
FT value for progesterone; 10-fold decrease
FT for progesterone reduction; 3-fold
FT decrease for 20alpha-OHProg oxidation.
FT 10-fold decrease in K(m) value for NADPH.
FT MUTAGEN 304 304 R->L: 70-fold decrease in progesterone
FT reduction. No effect on DHT reduction.
FT MUTAGEN 305 305 Y->F: No effect on progesterone
FT reduction.
FT MUTAGEN 307 307 T->V: No effect on progesterone
FT reduction.
FT MUTAGEN 309 309 D->V: No effect on progesterone
FT reduction.
FT CONFLICT 3 3 S -> A (in Ref. 4; no nucleotide entry).
FT CONFLICT 95 95 V -> D (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 158 158 G -> E (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 171 172 RQ -> ST (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 183 184 KY -> QV (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 222 222 H -> L (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT CONFLICT 319 319 F -> I (in Ref. 4; no nucleotide entry
FT and 10; AAD14012).
FT STRAND 7 9
FT STRAND 15 22
FT HELIX 33 44
FT STRAND 48 50
FT HELIX 53 55
FT HELIX 58 70
FT HELIX 76 78
FT STRAND 80 85
FT HELIX 87 89
FT HELIX 92 106
FT STRAND 111 116
FT STRAND 124 126
FT HELIX 144 156
FT STRAND 159 167
FT HELIX 170 177
FT STRAND 187 192
FT STRAND 194 197
FT HELIX 200 208
FT STRAND 212 217
FT TURN 225 227
FT HELIX 235 237
FT HELIX 239 248
FT HELIX 252 262
FT STRAND 266 270
FT HELIX 274 280
FT HELIX 281 285
FT HELIX 290 297
FT HELIX 309 311
SQ SEQUENCE 323 AA; 36788 MW; 9CB215478FBD29D5 CRC64;
MDSKYQCVKL NDGHFMPVLG FGTYAPAEVP KSKALEATKL AIEAGFRHID SAHLYNNEEQ
VGLAIRSKIA DGSVKREDIF YTSKLWCNSH RPELVRPALE RSLKNLQLDY VDLYLIHFPV
SVKPGEEVIP KDENGKILFD TVDLCATWEA VEKCKDAGLA KSIGVSNFNR RQLEMILNKP
GLKYKPVCNQ VECHPYFNQR KLLDFCKSKD IVLVAYSALG SHREEPWVDP NSPVLLEDPV
LCALAKKHKR TPALIALRYQ LQRGVVVLAK SYNEQRIRQN VQVFEFQLTS EEMKAIDGLN
RNVRYLTLDI FAGPPNYPFS DEY
//
MIM
600449
*RECORD*
*FIELD* NO
600449
*FIELD* TI
*600449 ALDO-KETO REDUCTASE FAMILY 1, MEMBER 1; AKR1C1
;;DIHYDRODIOL DEHYDROGENASE, TYPE I; DDH1; DD1;;
read moreALDO-KETO REDUCTASE C; HAKRC
*FIELD* TX
Dihydrodiol dehydrogenase (DD) and chlordecone reductase (CHDR; 600451)
belong to the aldo-keto reductase superfamily, which also includes
aldehyde reductase (ALR; 103830), aldose reductase (ALDR1; 103880),
3-alpha-hydroxysteroid dehydrogenase (3-alpha-HSD), and several other
closely related proteins. These enzymes catalyze the conversion of
aldehydes and ketones to their corresponding alcohols by utilizing NADH
and/or NADPH as cofactors and exist in cellular cytoplasm as monomeric
34- to 36-kD proteins. The enzymes display overlapping but distinct
substrate specificity. The importance of dihydrodiol dehydrogenase
activity in the detoxification of polycyclic aromatic hydrocarbons was
demonstrated by its ability to reduce the mutagenic activity of
benzo[a]pyrene in the Ames test. Chlordecone reductase is the enzyme
involved in the detoxification of organochloride pesticides. By
screening a human liver expression library with an antibody against rat
3-alpha-HSD, Qin et al. (1993) isolated cDNAs encoding 4 distinct human
aldo-keto reductases, HAKRa (CHDR), HAKRb (603966), HAKRc, and HAKRd
(DDH2; 600450). The predicted 323-amino acid HAKR proteins share more
than 85% identity and are approximately 65% identical to rat
3-alpha-HSD. Northern blot analysis revealed that HAKRc is expressed as
a 1.4-kb mRNA in several human tissues. By restriction mapping and DNA
sequencing of genomic clones, Qin et al. (1994) determined the structure
of the DDH1 gene. The gene spans approximately 16 kb and consists of 9
exons. Using a cDNA probe, Qin et al. (1994) found several additional
hybridizing DNA bands, suggesting the existence of multiple related
genes.
Stolz et al. (1993) identified HBAB (high affinity bile acid-binding
protein), a human liver dihydrodiol dehydrogenase that binds bile acid
with high affinity and has minimal 3-alpha-HSD activity. By screening a
human liver library with a rat 3-alpha-HSD cDNA, they isolated a
putative HBAB cDNA. However, the recombinant protein encoded by the cDNA
did not exhibit the high affinity bile acid binding of native HBAB. Hara
et al. (1996) determined that the HBAB cDNA isolated by Stolz et al.
(1993) encodes DD1 (HAKRc), while native HBAB protein appears to
correspond to DD2 (DDH2). Similarly, Hara et al. (1996) stated that c32,
the H37 cDNA isolated by Ciaccio et al. (1994), is identical to the DD1
cDNA, even though the native H37 protein probably corresponds to DD2.
Thus, DD2, HBAB, and H37 may be the same protein, but the cDNAs
previously isolated as those for these proteins may encode DD1.
Deyashiki et al. (1994) isolated cDNAs C9 and C14, which they stated
encoded DD2 (DDH2) and DD4 (CHDR), respectively. However, Hara et al.
(1996) demonstrated that the C9 cDNA encodes the DD1 enzyme.
Khanna et al. (1995) isolated 2 genes encoding dihydrodiol
dehydrogenase, referred to as type I or DDH1, and type II or DDH2, as
well as 1 gene for chlordecone reductase (CHDR). However, sequence
analysis revealed that the type I gene of Khanna et al. (1995)
corresponded to either DD1 or DD2, the type 2 gene corresponded to
AKR1C4, and the CHDR gene corresponded to AKR1C3 (White, 1999). The 3
genes were found to have 9 exons with the same exon sizes and the same
exon/intron boundaries but with some variation in the sizes of their
corresponding introns. Using the polymerase chain reaction with
gene-specific primers to amplify gene sequences in human/hamster hybrid
DNA, Khanna et al. (1995) found that all 3 genes are located on
chromosome 10. By fluorescence in situ hybridization, they regionalized
the assignment to 10p15-p14.
*FIELD* RF
1. Ciaccio, P. J.; Jaiswal, A. K.; Tew, K. D.: Regulation of human
dihydrodiol dehydrogenase by Michael acceptor xenobiotics. J. Biol.
Chem. 269: 15558-15562, 1994.
2. Deyashiki, Y.; Ogasawara, A.; Nakayama, T.; Nakanishi, M.; Miyabe,
Y.; Sato, K.; Hara, A.: Molecular cloning of two human liver 3-alpha-hydroxysteroid/dihydrodiol
dehydrogenase isoenzymes that are identical with chlordecone reductase
and bile-acid binder. Biochem. J. 299: 545-552, 1994.
3. Hara, A.; Matsuura, K.; Tamada, Y.; Sato, K.; Miyabe, Y.; Deyashiki,
Y.; Ishida, N.: Relationship of human liver dihydrodiol dehydrogenases
to hepatic bile-acid-binding protein and oxidoreductase of human colon
cells. Biochem. J. 313: 373-376, 1996.
4. Khanna, M.; Qin, K.-N.; Klisak, I.; Belkin, S.; Sparkes, R. S.;
Cheng, K.-C.: Localization of multiple human dihydrodiol dehydrogenase
(DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome
10 by the polymerase chain reaction and fluorescence in situ hybridization. Genomics 25:
588-590, 1995.
5. Qin, K.-N.; Khanna, M.; Cheng, K.-C.: Structure of a gene coding
for human dihydrodiol dehydrogenase/bile acid-binding protein. Gene 149:
357-361, 1994.
6. Qin, K.-N.; New, M. I.; Cheng, K.-C.: Molecular cloning of multiple
cDNAs encoding human enzymes structurally related to 3-alpha-hydroxysteroid
dehydrogenase. J. Steroid Biochem. Molec. Biol. 46: 673-679, 1993.
7. Stolz, A.; Hammond, L.; Lou, H.; Takikawa, H.; Ronk, M.; Shively,
J. E.: cDNA cloning and expression of the human hepatic bile acid-binding
protein: a member of the monomeric reductase gene family. J. Biol.
Chem. 268: 10448-10457, 1993.
8. White, J.: Personal Communication. London, England 6/14/1999.
*FIELD* CN
Rebekah S. Rasooly - updated: 7/8/1999
*FIELD* CD
Victor A. McKusick: 3/9/1995
*FIELD* ED
carol: 10/17/2002
alopez: 7/8/1999
mark: 3/31/1995
mark: 3/28/1995
mark: 3/22/1995
carol: 3/10/1995
*RECORD*
*FIELD* NO
600449
*FIELD* TI
*600449 ALDO-KETO REDUCTASE FAMILY 1, MEMBER 1; AKR1C1
;;DIHYDRODIOL DEHYDROGENASE, TYPE I; DDH1; DD1;;
read moreALDO-KETO REDUCTASE C; HAKRC
*FIELD* TX
Dihydrodiol dehydrogenase (DD) and chlordecone reductase (CHDR; 600451)
belong to the aldo-keto reductase superfamily, which also includes
aldehyde reductase (ALR; 103830), aldose reductase (ALDR1; 103880),
3-alpha-hydroxysteroid dehydrogenase (3-alpha-HSD), and several other
closely related proteins. These enzymes catalyze the conversion of
aldehydes and ketones to their corresponding alcohols by utilizing NADH
and/or NADPH as cofactors and exist in cellular cytoplasm as monomeric
34- to 36-kD proteins. The enzymes display overlapping but distinct
substrate specificity. The importance of dihydrodiol dehydrogenase
activity in the detoxification of polycyclic aromatic hydrocarbons was
demonstrated by its ability to reduce the mutagenic activity of
benzo[a]pyrene in the Ames test. Chlordecone reductase is the enzyme
involved in the detoxification of organochloride pesticides. By
screening a human liver expression library with an antibody against rat
3-alpha-HSD, Qin et al. (1993) isolated cDNAs encoding 4 distinct human
aldo-keto reductases, HAKRa (CHDR), HAKRb (603966), HAKRc, and HAKRd
(DDH2; 600450). The predicted 323-amino acid HAKR proteins share more
than 85% identity and are approximately 65% identical to rat
3-alpha-HSD. Northern blot analysis revealed that HAKRc is expressed as
a 1.4-kb mRNA in several human tissues. By restriction mapping and DNA
sequencing of genomic clones, Qin et al. (1994) determined the structure
of the DDH1 gene. The gene spans approximately 16 kb and consists of 9
exons. Using a cDNA probe, Qin et al. (1994) found several additional
hybridizing DNA bands, suggesting the existence of multiple related
genes.
Stolz et al. (1993) identified HBAB (high affinity bile acid-binding
protein), a human liver dihydrodiol dehydrogenase that binds bile acid
with high affinity and has minimal 3-alpha-HSD activity. By screening a
human liver library with a rat 3-alpha-HSD cDNA, they isolated a
putative HBAB cDNA. However, the recombinant protein encoded by the cDNA
did not exhibit the high affinity bile acid binding of native HBAB. Hara
et al. (1996) determined that the HBAB cDNA isolated by Stolz et al.
(1993) encodes DD1 (HAKRc), while native HBAB protein appears to
correspond to DD2 (DDH2). Similarly, Hara et al. (1996) stated that c32,
the H37 cDNA isolated by Ciaccio et al. (1994), is identical to the DD1
cDNA, even though the native H37 protein probably corresponds to DD2.
Thus, DD2, HBAB, and H37 may be the same protein, but the cDNAs
previously isolated as those for these proteins may encode DD1.
Deyashiki et al. (1994) isolated cDNAs C9 and C14, which they stated
encoded DD2 (DDH2) and DD4 (CHDR), respectively. However, Hara et al.
(1996) demonstrated that the C9 cDNA encodes the DD1 enzyme.
Khanna et al. (1995) isolated 2 genes encoding dihydrodiol
dehydrogenase, referred to as type I or DDH1, and type II or DDH2, as
well as 1 gene for chlordecone reductase (CHDR). However, sequence
analysis revealed that the type I gene of Khanna et al. (1995)
corresponded to either DD1 or DD2, the type 2 gene corresponded to
AKR1C4, and the CHDR gene corresponded to AKR1C3 (White, 1999). The 3
genes were found to have 9 exons with the same exon sizes and the same
exon/intron boundaries but with some variation in the sizes of their
corresponding introns. Using the polymerase chain reaction with
gene-specific primers to amplify gene sequences in human/hamster hybrid
DNA, Khanna et al. (1995) found that all 3 genes are located on
chromosome 10. By fluorescence in situ hybridization, they regionalized
the assignment to 10p15-p14.
*FIELD* RF
1. Ciaccio, P. J.; Jaiswal, A. K.; Tew, K. D.: Regulation of human
dihydrodiol dehydrogenase by Michael acceptor xenobiotics. J. Biol.
Chem. 269: 15558-15562, 1994.
2. Deyashiki, Y.; Ogasawara, A.; Nakayama, T.; Nakanishi, M.; Miyabe,
Y.; Sato, K.; Hara, A.: Molecular cloning of two human liver 3-alpha-hydroxysteroid/dihydrodiol
dehydrogenase isoenzymes that are identical with chlordecone reductase
and bile-acid binder. Biochem. J. 299: 545-552, 1994.
3. Hara, A.; Matsuura, K.; Tamada, Y.; Sato, K.; Miyabe, Y.; Deyashiki,
Y.; Ishida, N.: Relationship of human liver dihydrodiol dehydrogenases
to hepatic bile-acid-binding protein and oxidoreductase of human colon
cells. Biochem. J. 313: 373-376, 1996.
4. Khanna, M.; Qin, K.-N.; Klisak, I.; Belkin, S.; Sparkes, R. S.;
Cheng, K.-C.: Localization of multiple human dihydrodiol dehydrogenase
(DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome
10 by the polymerase chain reaction and fluorescence in situ hybridization. Genomics 25:
588-590, 1995.
5. Qin, K.-N.; Khanna, M.; Cheng, K.-C.: Structure of a gene coding
for human dihydrodiol dehydrogenase/bile acid-binding protein. Gene 149:
357-361, 1994.
6. Qin, K.-N.; New, M. I.; Cheng, K.-C.: Molecular cloning of multiple
cDNAs encoding human enzymes structurally related to 3-alpha-hydroxysteroid
dehydrogenase. J. Steroid Biochem. Molec. Biol. 46: 673-679, 1993.
7. Stolz, A.; Hammond, L.; Lou, H.; Takikawa, H.; Ronk, M.; Shively,
J. E.: cDNA cloning and expression of the human hepatic bile acid-binding
protein: a member of the monomeric reductase gene family. J. Biol.
Chem. 268: 10448-10457, 1993.
8. White, J.: Personal Communication. London, England 6/14/1999.
*FIELD* CN
Rebekah S. Rasooly - updated: 7/8/1999
*FIELD* CD
Victor A. McKusick: 3/9/1995
*FIELD* ED
carol: 10/17/2002
alopez: 7/8/1999
mark: 3/31/1995
mark: 3/28/1995
mark: 3/22/1995
carol: 3/10/1995