AK1C4_MACFU
ID AK1C4_MACFU Reviewed; 323 AA.
AC Q95JH4;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 83.
DE RecName: Full=Aldo-keto reductase family 1 member C4;
DE EC=1.1.1.- {ECO:0000269|PubMed:15618685};
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:0000269|PubMed:15618685};
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 {ECO:0000303|PubMed:15618685};
DE Short=DD4 {ECO:0000303|PubMed:15618685};
DE AltName: Full=HAKRA;
GN Name=AKR1C4;
OS Macaca fuscata fuscata (Japanese macaque).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9543;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, FUNCTION, CATALYTIC
RP ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND SUBSTRATE SPECIFICITY.
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
CC (PubMed:15618685). Displays the ability to catalyze both oxidation and
CC reduction in vitro, but most probably acts as a reductase in vivo since
CC the oxidase activity measured in vitro is inhibited by physiological
CC concentration of NADPH (By similarity). Acts preferentially as a 3-
CC alpha-hydroxysteroid dehydrogenase (HSD) with a subsidiary 3-beta-HSD
CC activity (PubMed:15618685). Catalyzes efficiently the transformation of
CC the potent androgen 5-alpha-dihydrotestosterone (5alpha-DHT or 17beta-
CC hydroxy-5alpha-androstan-3-one) into the less active form, 5-alpha-
CC androstan-3-alpha,17-beta-diol (3-alpha-diol). Catalyzes the reduction
CC of estrone into 17beta-estradiol but with low efficiency. Metabolizes a
CC broad spectrum of natural and synthetic therapeutic steroid and plays
CC an important role in metabolism of androgens, estrogens, progestereone
CC and conjugated steroids. Catalyzes the biotransformation of the
CC pesticide chlordecone (kepone) to its corresponding alcohol leading to
CC increased biliary excretion of the pesticide and concomitant reduction
CC of its neurotoxicity since bile is the major excretory route (By
CC similarity). {ECO:0000250|UniProtKB:P17516,
CC ECO:0000269|PubMed:15618685}.
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:0000269|PubMed:15618685};
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:0000269|PubMed:15618685};
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 -!- ACTIVITY REGULATION: Potently inhibited by benzbromarone,
CC 3',3'',5',5''-tetrabromophenolphthalein (TBPP) and o-cresolphthalein.
CC {ECO:0000269|PubMed:15618685}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.6 uM for 5alpha-pregnane-3alpha,21-diol-20-one
CC {ECO:0000269|PubMed:15618685};
CC KM=0.3 uM for 5-alpha-pregnan-20-alpha-ol-3-one
CC {ECO:0000269|PubMed:15618685};
CC KM=0.7 uM for 3alpha-hydroxy-5alpha-androstan-17-one
CC {ECO:0000269|PubMed:15618685};
CC KM=0.3 uM for 5-beta-pregnan-20-alpha-ol-3-one
CC {ECO:0000269|PubMed:15618685};
CC KM=25 uM for trans-benzene dihydrodiol {ECO:0000269|PubMed:15618685};
CC KM=420 uM for (s)-tetralol {ECO:0000269|PubMed:15618685};
CC Note=kcat is 4.9 min(-1) for 5-beta-pregnan-20-alpha-ol-3-one as
CC substrate. kcat is 4.9 min(-1) for 3alpha-hydroxy-5alpha-androstan-
CC 17-one as substrate. kcat is 23 min(-1) for 5alpha-pregnane-
CC 3alpha,21-diol-20-one. {ECO:0000269|PubMed:15618685};
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 -!- TISSUE SPECIFICITY: High expression in liver. Also expressed in kidney.
CC {ECO:0000269|PubMed:15618685}.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
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DR EMBL; AB070212; BAB63209.2; -; mRNA.
DR AlphaFoldDB; Q95JH4; -.
DR SMR; Q95JH4; -.
DR BRENDA; 1.3.1.20; 3123.
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; Lipid metabolism; NADP; Oxidoreductase.
FT CHAIN 1..323
FT /note="Aldo-keto reductase family 1 member C4"
FT /id="PRO_0000124642"
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"
FT SITE 84
FT /note="Lowers pKa of active site Tyr"
FT /evidence="ECO:0000250|UniProtKB:P14550"
SQ SEQUENCE 323 AA; 37103 MW; 38382E7AD7EB7AFA CRC64;
MDPKYQRVAL NDGHFMPVLG FGSYAPPEVP 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
