AK1C4_MACFA
ID AK1C4_MACFA Reviewed; 323 AA.
AC Q95JH5;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 90.
DE RecName: Full=Aldo-keto reductase family 1 member C4;
DE EC=1.1.1.- {ECO:0000250|UniProtKB:P17516};
DE EC=1.1.1.209 {ECO:0000250|UniProtKB:P17516};
DE EC=1.1.1.210 {ECO:0000250|UniProtKB:P17516};
DE EC=1.1.1.51 {ECO:0000250|UniProtKB:P17516};
DE EC=1.1.1.53 {ECO:0000250|UniProtKB:P17516};
DE EC=1.1.1.62 {ECO:0000250|UniProtKB:P17516};
DE AltName: Full=3-alpha-hydroxysteroid dehydrogenase type I;
DE Short=3-alpha-HSD1;
DE EC=1.1.1.357 {ECO:0000250|UniProtKB:P17516};
DE AltName: Full=3alpha-hydroxysteroid 3-dehydrogenase;
DE AltName: Full=Chlordecone reductase homolog;
DE Short=CDR;
DE EC=1.1.1.225 {ECO:0000250|UniProtKB:P17516};
DE AltName: Full=Dihydrodiol dehydrogenase 4 {ECO:0000303|PubMed:15618685};
DE Short=DD-4;
DE Short=DD4 {ECO:0000303|PubMed:15618685};
GN Name=AKR1C4;
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 2-23; 69-116; 137-153;
RP 184-246 AND 250-323.
RC TISSUE=Liver;
RX PubMed=15618685; DOI=10.2133/dmpk.17.348;
RA Higaki Y., Kamiya T., Usami N., Shintani S., Shiraishi H., Ishikura S.,
RA Yamamoto I., Hara A.;
RT "Molecular characterization of two monkey dihydrodiol dehydrogenases.";
RL Drug Metab. Pharmacokinet. 17:348-356(2002).
CC -!- FUNCTION: Cytosolic aldo-keto reductase that catalyzes the NADH and
CC NADPH-dependent reduction of ketosteroids to hydroxysteroids. Liver
CC specific enzyme that acts as NAD(P)(H)-dependent 3-, 17- and 20-
CC ketosteroid reductase on the steroid nucleus and side chain. Displays
CC the ability to catalyze both oxidation and reduction in vitro, but most
CC probably acts as a reductase in vivo since the oxidase activity
CC measured in vitro is inhibited by physiological concentration of NADPH.
CC Acts preferentially as a 3-alpha-hydroxysteroid dehydrogenase (HSD)
CC with a subsidiary 3-beta-HSD activity. Catalyzes efficiently the
CC transformation of the potent androgen 5-alpha-dihydrotestosterone
CC (5alpha-DHT or 17beta-hydroxy-5alpha-androstan-3-one) into the less
CC active form, 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol).
CC Catalyzes the reduction of estrone into 17beta-estradiol but with low
CC efficiency. Metabolizes a broad spectrum of natural and synthetic
CC therapeutic steroid and plays an important role in metabolism of
CC androgens, estrogens, progestereone and conjugated steroids. Catalyzes
CC the biotransformation of the pesticide chlordecone (kepone) to its
CC corresponding alcohol leading to increased biliary excretion of the
CC pesticide and concomitant reduction of its neurotoxicity since bile is
CC the major excretory route. {ECO:0000250|UniProtKB:P17516}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=chlordecone alcohol + NADP(+) = chlordecone + H(+) + NADPH;
CC Xref=Rhea:RHEA:14401, ChEBI:CHEBI:15378, ChEBI:CHEBI:16548,
CC ChEBI:CHEBI:17184, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC EC=1.1.1.225; Evidence={ECO:0000250|UniProtKB:P17516};
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;
CC EC=1.1.1.357; Evidence={ECO:0000250|UniProtKB:P17516};
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;
CC EC=1.1.1.357; Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5alpha-androstane-3alpha,17beta-diol + NADP(+) = 17beta-
CC hydroxy-5alpha-androstan-3-one + H(+) + NADPH; Xref=Rhea:RHEA:42116,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16330, ChEBI:CHEBI:36713,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42118;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5alpha-androstane-3beta,17beta-diol + NADP(+) = 17beta-
CC hydroxy-5alpha-androstan-3-one + H(+) + NADPH; Xref=Rhea:RHEA:16297,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16330, ChEBI:CHEBI:18329,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.210;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:16299;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5alpha-androstane-3alpha,17beta-diol + NAD(+) = 17beta-
CC hydroxy-5alpha-androstan-3-one + H(+) + NADH; Xref=Rhea:RHEA:42004,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16330, ChEBI:CHEBI:36713,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.53;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42005;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42006;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=17beta-estradiol + NADP(+) = estrone + H(+) + NADPH;
CC Xref=Rhea:RHEA:24616, ChEBI:CHEBI:15378, ChEBI:CHEBI:16469,
CC ChEBI:CHEBI:17263, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.62;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24617;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:24618;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=17beta-estradiol + NAD(+) = estrone + H(+) + NADH;
CC Xref=Rhea:RHEA:24612, ChEBI:CHEBI:15378, ChEBI:CHEBI:16469,
CC ChEBI:CHEBI:17263, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.62;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24613;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:24614;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(20S)-hydroxypregn-4-en-3-one + NADP(+) = H(+) + NADPH +
CC progesterone; Xref=Rhea:RHEA:42112, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17026, ChEBI:CHEBI:28453, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42113;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42114;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(20S)-hydroxypregn-4-en-3-one + NAD(+) = H(+) + NADH +
CC progesterone; Xref=Rhea:RHEA:42108, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17026, ChEBI:CHEBI:28453, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945; Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42109;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42110;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3alpha-hydroxy-5alpha-androstan-17-one + NADP(+) = 5alpha-
CC androstan-3,17-dione + H(+) + NADPH; Xref=Rhea:RHEA:20377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15994, ChEBI:CHEBI:16032,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.209;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20378;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NADP(+) + testosterone = androst-4-ene-3,17-dione + H(+) +
CC NADPH; Xref=Rhea:RHEA:14981, ChEBI:CHEBI:15378, ChEBI:CHEBI:16422,
CC ChEBI:CHEBI:17347, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.51;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14982;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=NAD(+) + testosterone = androst-4-ene-3,17-dione + H(+) +
CC NADH; Xref=Rhea:RHEA:14929, ChEBI:CHEBI:15378, ChEBI:CHEBI:16422,
CC ChEBI:CHEBI:17347, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.1.1.51;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14930;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=3alpha-hydroxy-5alpha-androstane 17-O-(beta-D-glucuronate) +
CC NADP(+) = 5alpha-dihydrotestosterone 17-O-(beta-D-glucuronate) + H(+)
CC + NADPH; Xref=Rhea:RHEA:53112, ChEBI:CHEBI:15378, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:133519, ChEBI:CHEBI:136914;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:53114;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(3beta,5alpha,17beta)-3-hydroxy-androstan-17-yl sulfate +
CC NADP(+) = 5alpha-dihydrotestosterone sulfate + H(+) + NADPH;
CC Xref=Rhea:RHEA:53136, ChEBI:CHEBI:15378, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:133105, ChEBI:CHEBI:136982;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:53138;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5alpha-androstane-3alpha,17beta-diol + NAD(+) = 3alpha-
CC hydroxy-5alpha-androstan-17-one + H(+) + NADH; Xref=Rhea:RHEA:42124,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16032, ChEBI:CHEBI:36713,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42125;
CC Evidence={ECO:0000250|UniProtKB:P17516};
CC -!- PATHWAY: Steroid metabolism. {ECO:0000250|UniProtKB:P17516}.
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:P17516}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q04828}.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
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DR EMBL; AB070211; BAB63208.1; -; mRNA.
DR RefSeq; NP_001270628.1; NM_001283699.1.
DR AlphaFoldDB; Q95JH5; -.
DR SMR; Q95JH5; -.
DR GeneID; 102117205; -.
DR CTD; 1109; -.
DR OrthoDB; 1016440at2759; -.
DR BRENDA; 1.3.1.20; 1793.
DR Proteomes; UP000233100; Unplaced.
DR GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR GO; GO:0044594; F:17-beta-hydroxysteroid dehydrogenase (NAD+) activity; IEA:RHEA.
DR GO; GO:0047024; F:5alpha-androstane-3beta,17beta-diol dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047044; F:androstan-3-alpha,17-beta-diol dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047023; F:androsterone dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047743; F:chlordecone reductase activity; IEA:UniProtKB-EC.
DR GO; GO:0035410; F:dihydrotestosterone 17-beta-dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047045; F:testosterone 17-beta-dehydrogenase (NADP+) activity; IEA:RHEA.
DR GO; GO:0047035; F:testosterone dehydrogenase (NAD+) activity; IEA:RHEA.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR CDD; cd19108; AKR_AKR1C1-35; 1.
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 Cytoplasm; Direct protein sequencing; Lipid metabolism; NADP;
KW Oxidoreductase; Reference proteome.
FT CHAIN 1..323
FT /note="Aldo-keto reductase family 1 member C4"
FT /id="PRO_0000124641"
FT ACT_SITE 55
FT /note="Proton donor"
FT /evidence="ECO:0000250"
FT BINDING 20..24
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P17516"
FT BINDING 50
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P17516"
FT BINDING 117
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 166..167
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P17516"
FT BINDING 190
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P17516"
FT BINDING 216..221
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P17516"
FT BINDING 270..280
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P17516"
FT SITE 54
FT /note="Important for substrate specificity"
FT /evidence="ECO:0000250|UniProtKB:P14550"
FT SITE 84
FT /note="Lowers pKa of active site Tyr"
FT /evidence="ECO:0000250"
SQ SEQUENCE 323 AA; 37117 MW; 3E7F2E78815AA196 CRC64;
MDPKYQRVAL NDGHFMPVLG FGTYAPPEVP RNRVVEVTKL AIEAGFRHID SAYLYNNEEQ
VGLAIRSKIA DGSVKREDIF YTSKLWCTFF RPQLVQPALE SSLKKLQLDY VDLYLIHFPM
ALKPGETPLP KDENGKVMFD TVDLCAIWEA MEKCKDAGLA KSIGVSNFNR RQLEMILNNP
GLKYKPVCNQ VECHPYLNQS KLLDFCKSKD IVLVAHSALG TQRHKLWVDQ NSPALLEDPV
LCALAKKHKR SPALIALRYQ LQRGVVVLAK SYNEQRIREN VQVFEFQLTS EDMKVLDDLN
RNFRYVVMDF LVDHPDYPFS DEY
