AK1C4_HUMAN
ID AK1C4_HUMAN Reviewed; 323 AA.
AC P17516; Q5T6A3; Q8WW84; Q9NS54;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 05-OCT-2010, sequence version 3.
DT 03-AUG-2022, entry version 217.
DE RecName: Full=Aldo-keto reductase family 1 member C4;
DE EC=1.1.1.- {ECO:0000269|PubMed:10634139, ECO:0000269|PubMed:10998348, ECO:0000269|PubMed:11158055, ECO:0000269|PubMed:14672942, ECO:0000269|PubMed:19218247, ECO:0000269|PubMed:2427522, ECO:0000269|PubMed:7650035, ECO:0000269|PubMed:8172617};
DE EC=1.1.1.209 {ECO:0000269|PubMed:10998348, ECO:0000269|PubMed:7650035};
DE EC=1.1.1.210 {ECO:0000269|PubMed:14672942};
DE EC=1.1.1.51 {ECO:0000269|PubMed:10998348};
DE EC=1.1.1.53 {ECO:0000269|PubMed:10998348, ECO:0000269|PubMed:14672942};
DE EC=1.1.1.62 {ECO:0000269|PubMed:10998348};
DE AltName: Full=3-alpha-hydroxysteroid dehydrogenase type I {ECO:0000303|PubMed:11158055, ECO:0000303|PubMed:7650035};
DE Short=3-alpha-HSD1 {ECO:0000303|PubMed:11158055};
DE EC=1.1.1.357 {ECO:0000269|PubMed:10634139, ECO:0000269|PubMed:10998348, ECO:0000269|PubMed:11158055, ECO:0000269|PubMed:14672942, ECO:0000269|PubMed:19218247, ECO:0000269|PubMed:7650035, ECO:0000269|PubMed:8172617};
DE AltName: Full=3alpha-hydroxysteroid 3-dehydrogenase;
DE AltName: Full=Chlordecone reductase {ECO:0000303|PubMed:2427522};
DE Short=CDR;
DE EC=1.1.1.225 {ECO:0000269|PubMed:2427522};
DE AltName: Full=Dihydrodiol dehydrogenase 4;
DE Short=DD-4;
DE Short=DD4;
DE AltName: Full=HAKRA;
GN Name=AKR1C4; Synonyms=CHDR;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ARG-250.
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 structurally
RT related to 3 alpha-hydroxysteroid dehydrogenase.";
RL J. Steroid Biochem. Mol. Biol. 46:673-679(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], TISSUE SPECIFICITY, VARIANT ARG-250,
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=7650035; DOI=10.1074/jbc.270.34.20162;
RA Khanna M., Qin K.-N., Wang R.W., Cheng K.-C.;
RT "Substrate specificity, gene structure, and tissue-specific distribution of
RT multiple human 3 alpha-hydroxysteroid dehydrogenases.";
RL J. Biol. Chem. 270:20162-20168(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT ARG-250.
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA], VARIANTS CYS-145; ARG-250 AND VAL-311,
RP CATALYTIC ACTIVITY, AND FUNCTION.
RC TISSUE=Liver;
RX PubMed=10634139;
RA Kume T., Iwasa H., Shiraishi H., Yokoi T., Nagashima K., Otsuka M.,
RA Terada T., Takagi T., Hara A., Kamataki T.;
RT "Characterization of a novel variant (S145C/L311V) of 3alpha-
RT hydroxysteroid/dihydrodiol dehydrogenase in human liver.";
RL Pharmacogenetics 9:763-771(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND VARIANT ARG-250.
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., Watanabe K.,
RA 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, TISSUE
RP SPECIFICITY, VARIANT ARG-250, AND BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Liver;
RX PubMed=11158055; DOI=10.1210/jcem.86.2.7216;
RA Dufort I., Labrie F., Luu-The V.;
RT "Human types 1 and 3 3 alpha-hydroxysteroid dehydrogenases: differential
RT lability and tissue distribution.";
RL J. Clin. Endocrinol. Metab. 86:841-846(2001).
RN [7]
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., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., 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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANTS TYR-170 AND ARG-250.
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 2-323, AND VARIANT ARG-250.
RC TISSUE=Liver;
RX PubMed=2187532; DOI=10.1021/bi00456a034;
RA Winters C.J., Molowa D.T., Guzelian P.S.;
RT "Isolation and characterization of cloned cDNAs encoding human liver
RT chlordecone reductase.";
RL Biochemistry 29:1080-1087(1990).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-323, PROTEIN SEQUENCE OF 5-29; 76-131;
RP 184-201 AND 271-294, AND VARIANT ARG-250.
RC TISSUE=Liver;
RX PubMed=8172617; DOI=10.1042/bj2990545;
RA Deyashiki Y., Ogasawara A., Nakayama T., Nakanishi M., Miyabe Y., Sato K.,
RA Hara A.;
RT "Molecular cloning of two human liver 3 alpha-hydroxysteroid/dihydrodiol
RT dehydrogenase isoenzymes that are identical with chlordecone reductase and
RT bile-acid binder.";
RL Biochem. J. 299:545-552(1994).
RN [11]
RP PROTEIN SEQUENCE OF 40-54; 105-121; 162-175; 184-196; 277-291 AND 307-321,
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=1530633; DOI=10.1016/0006-291x(92)91260-w;
RA Binstock J.M., Iyer R.B., Hamby C.V., Fried V.A., Schwartz I.S.,
RA Weinstein B.I., Southren A.L.;
RT "Human hepatic 3 alpha-hydroxysteroid dehydrogenase: possible identity with
RT human hepatic chlordecone reductase.";
RL Biochem. Biophys. Res. Commun. 187:760-766(1992).
RN [12]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=2427522; DOI=10.1016/s0021-9258(18)67136-4;
RA Molowa D.T., Shayne A.G., Guzelian P.S.;
RT "Purification and characterization of chlordecone reductase from human
RT liver.";
RL J. Biol. Chem. 261:12624-12627(1986).
RN [13]
RP CATALYTIC ACTIVITY, FUNCTION, TISSUE SPECIFICITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND SUBSTRATE SPECIFICITY.
RX PubMed=10998348; DOI=10.1042/0264-6021:3510067;
RA Penning T.M., Burczynski M.E., Jez J.M., Hung C.F., Lin H.K., Ma H.,
RA Moore M., Palackal N., Ratnam K.;
RT "Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the
RT aldo-keto reductase superfamily: functional plasticity and tissue
RT distribution reveals roles in the inactivation and formation of male and
RT female sex hormones.";
RL Biochem. J. 351:67-77(2000).
RN [14]
RP CATALYTIC ACTIVITY, FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=14672942; DOI=10.1074/jbc.m313308200;
RA Steckelbroeck S., Jin Y., Gopishetty S., Oyesanmi B., Penning T.M.;
RT "Human cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto
RT reductase superfamily display significant 3beta-hydroxysteroid
RT dehydrogenase activity: implications for steroid hormone metabolism and
RT action.";
RL J. Biol. Chem. 279:10784-10795(2004).
RN [15]
RP CATALYTIC ACTIVITY, FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=19218247; DOI=10.1074/jbc.m809465200;
RA Jin Y., Duan L., Lee S.H., Kloosterboer H.J., Blair I.A., Penning T.M.;
RT "Human cytosolic hydroxysteroid dehydrogenases of the aldo-ketoreductase
RT superfamily catalyze reduction of conjugated steroids: implications for
RT phase I and phase II steroid hormone metabolism.";
RL J. Biol. Chem. 284:10013-10022(2009).
RN [16]
RP INVOLVEMENT IN SRXY8.
RX PubMed=21802064; DOI=10.1016/j.ajhg.2011.06.009;
RA Fluck C.E., Meyer-Boni M., Pandey A.V., Kempna P., Miller W.L.,
RA Schoenle E.J., Biason-Lauber A.;
RT "Why boys will be boys: two pathways of fetal testicular androgen
RT biosynthesis are needed for male sexual differentiation.";
RL Am. J. Hum. Genet. 89:201-218(2011).
RN [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH NADP.
RG Structural genomics consortium (SGC);
RT "Crystal structure of human 3-alpha hydroxysteroid/dihydrodiol
RT dehydrogenase (AKR1C4) complexed with NADP+.";
RL Submitted (FEB-2006) to the PDB data bank.
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:14672942, PubMed:10998348, PubMed:7650035, PubMed:1530633,
CC PubMed:11158055, PubMed:10634139, PubMed:19218247). Displays the
CC 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 (PubMed:14672942). Acts preferentially as a 3-alpha-hydroxysteroid
CC dehydrogenase (HSD) with a subsidiary 3-beta-HSD activity
CC (PubMed:14672942). Catalyzes efficiently the transformation of the
CC 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) (PubMed:11158055,
CC PubMed:10998348, PubMed:14672942). Catalyzes the reduction of estrone
CC into 17beta-estradiol but with low efficiency (PubMed:14672942).
CC Metabolizes a broad spectrum of natural and synthetic therapeutic
CC steroid and plays an important role in metabolism of androgens,
CC estrogens, progestereone and conjugated steroids (PubMed:10998348,
CC PubMed:14672942, PubMed:19218247). Catalyzes the biotransformation of
CC the pesticide chlordecone (kepone) to its corresponding alcohol leading
CC to increased biliary excretion of the pesticide and concomitant
CC reduction of its neurotoxicity since bile is the major excretory route
CC (PubMed:2427522). {ECO:0000269|PubMed:10634139,
CC ECO:0000269|PubMed:10998348, ECO:0000269|PubMed:11158055,
CC ECO:0000269|PubMed:14672942, ECO:0000269|PubMed:1530633,
CC ECO:0000269|PubMed:19218247, ECO:0000269|PubMed:2427522,
CC ECO:0000269|PubMed:7650035}.
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:10634139,
CC ECO:0000269|PubMed:10998348, ECO:0000269|PubMed:11158055,
CC ECO:0000269|PubMed:14672942, ECO:0000269|PubMed:19218247,
CC ECO:0000269|PubMed:7650035, ECO:0000269|PubMed:8172617};
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:10634139,
CC ECO:0000269|PubMed:10998348, ECO:0000269|PubMed:11158055,
CC ECO:0000269|PubMed:14672942, ECO:0000269|PubMed:19218247,
CC ECO:0000269|PubMed:7650035, ECO:0000269|PubMed:8172617};
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:0000269|PubMed:10998348, ECO:0000269|PubMed:11158055,
CC ECO:0000269|PubMed:14672942, ECO:0000269|PubMed:19218247};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42118;
CC Evidence={ECO:0000305|PubMed:10998348, ECO:0000305|PubMed:14672942,
CC ECO:0000305|PubMed:19218247};
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:0000269|PubMed:14672942};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:16299;
CC Evidence={ECO:0000305|PubMed:14672942};
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:0000269|PubMed:10998348, ECO:0000269|PubMed:14672942};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42005;
CC Evidence={ECO:0000305|PubMed:14672942};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42006;
CC Evidence={ECO:0000305|PubMed:10998348};
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:0000269|PubMed:10998348};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24617;
CC Evidence={ECO:0000305|PubMed:10998348};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:24618;
CC Evidence={ECO:0000305|PubMed:10998348};
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:0000269|PubMed:10998348};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:24613;
CC Evidence={ECO:0000305|PubMed:10998348};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:24614;
CC Evidence={ECO:0000305|PubMed:10998348};
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:0000269|PubMed:10998348,
CC ECO:0000269|PubMed:11158055};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42113;
CC Evidence={ECO:0000305|PubMed:10998348};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42114;
CC Evidence={ECO:0000269|PubMed:11158055, ECO:0000305|PubMed:10998348};
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:0000269|PubMed:10998348};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42109;
CC Evidence={ECO:0000305|PubMed:10998348};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:42110;
CC Evidence={ECO:0000305|PubMed:10998348};
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:0000269|PubMed:10998348, ECO:0000269|PubMed:7650035};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20378;
CC Evidence={ECO:0000305|PubMed:10998348};
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:0000269|PubMed:10998348};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14982;
CC Evidence={ECO:0000305|PubMed:10998348};
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:0000269|PubMed:10998348};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:14930;
CC Evidence={ECO:0000305|PubMed:10998348};
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:0000269|PubMed:19218247};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:53114;
CC Evidence={ECO:0000305|PubMed:19218247};
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:0000269|PubMed:19218247};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:53138;
CC Evidence={ECO:0000305|PubMed:19218247};
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:0000269|PubMed:14672942};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42125;
CC Evidence={ECO:0000305|PubMed:14672942};
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:0000269|PubMed:2187532};
CC -!- ACTIVITY REGULATION: Inhibited by nonsteroidal the anti-inflammatory
CC drugs (NSAID) flufenamic (PubMed:14672942). The oxidation reaction is
CC inhibited by low micromolar concentrations of NADPH (PubMed:14672942).
CC {ECO:0000269|PubMed:14672942}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=10.5 uM for 5alpha-androstane-3alpha,17beta-diol
CC {ECO:0000269|PubMed:10998348};
CC KM=8.3 uM for 17beta-hydroxy-5alpha-androstan-3-one
CC {ECO:0000269|PubMed:10998348};
CC KM=0.8 uM for 17beta-hydroxy-5alpha-androstan-3-one
CC {ECO:0000269|PubMed:11158055};
CC KM=1.44 uM for 5alpha-androstan-3,17-dione
CC {ECO:0000269|PubMed:10998348};
CC KM=5.04 uM for 3alpha-hydroxy-5alpha-androstan-17-
CC one...(androsterone) {ECO:0000269|PubMed:10998348};
CC Vmax=55.5 nmol/min/mg enzyme for 5alpha-androstane-3alpha,17beta-diol
CC oxydation {ECO:0000269|PubMed:10998348};
CC Vmax=51.9 nmol/min/mg enzyme for 17beta-hydroxy-5alpha-androstan-3-
CC one reduction {ECO:0000269|PubMed:10998348};
CC Vmax=55.5 nmol/min/mg enzyme for 5alpha-androstane-3alpha,17beta-diol
CC oxidation {ECO:0000269|PubMed:10998348};
CC Vmax=48.4 nmol/min/mg enzyme for 5alpha-androstan-3,17-dione
CC reduction {ECO:0000269|PubMed:10998348};
CC Vmax=55.5 nmol/min/mg enzyme for 3alpha-hydroxy-5alpha-androstan-17-
CC one oxydation {ECO:0000269|PubMed:10998348};
CC Note=kcat is 1.99 min(-1) for 17beta-hydroxy-5alpha-androstan-3-one
CC reduction. kcat is 1.79 min(-1) for 5alpha-androstan-3,17-dione
CC reduction. kcat is 2.1 min(-1) for 5alpha-androstane-3alpha,17beta-
CC diol oxydation. kcat is 1.39.1 min(-1) for 3alpha-hydroxy-5alpha-
CC androstan-17-one oxydation (PubMed:10998348). kcat is 2.1 min(-1) for
CC 5alpha-androstane-3alpha,17beta-diol oxydation (PubMed:10998348).
CC kcat is 3.07 min(-1) for 5alpha-dihydrotestosterone sulfate
CC (PubMed:19218247). kcat is 3.28 min(-1) for 5alpha-
CC dihydrotestosterone 17-O-(beta-D-glucuronate) (PubMed:19218247).
CC {ECO:0000269|PubMed:10998348, ECO:0000269|PubMed:19218247};
CC -!- PATHWAY: Steroid metabolism. {ECO:0000269|PubMed:14672942}.
CC -!- SUBUNIT: Monomer. {ECO:0000269|Ref.18}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:Q04828}.
CC -!- TISSUE SPECIFICITY: Liver specific. {ECO:0000269|PubMed:10998348,
CC ECO:0000269|PubMed:11158055, ECO:0000269|PubMed:7650035}.
CC -!- PTM: The N-terminus is blocked.
CC -!- POLYMORPHISM: The allele with Cys-145/Val-311 shows a three- to five-
CC fold decrease in catalytic efficiency for xenobiotic and steroidal
CC substrates compared to the Ser-145/Leu-311 allele.
CC {ECO:0000269|PubMed:10634139}.
CC -!- DISEASE: 46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of sex
CC development. Affected individuals have a 46,XY karyotype but present as
CC phenotypically normal females. {ECO:0000269|PubMed:21802064}. Note=The
CC gene represented in this entry may act as a disease modifier. A
CC splicing mutation resulting in loss of AKR1C4 exon 2 has been found in
CC affected individuals carrying a causative mutation in AKR1C2
CC (PubMed:21802064). These patients manifest a more severe disease
CC phenotype than individuals only carrying mutations in AKR1C2.
CC {ECO:0000269|PubMed:21802064}.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA35658.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; S68287; AAD14010.1; -; mRNA.
DR EMBL; AB045829; BAA99542.1; -; mRNA.
DR EMBL; AB031085; BAA92885.1; -; mRNA.
DR EMBL; AB032163; BAA92893.1; -; Genomic_DNA.
DR EMBL; AL355303; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC020744; AAH20744.1; -; mRNA.
DR EMBL; M33375; AAA35658.1; ALT_INIT; mRNA.
DR EMBL; D26125; BAA05122.1; -; mRNA.
DR CCDS; CCDS7064.1; -.
DR PIR; A57407; A57407.
DR PIR; S59620; S59620.
DR RefSeq; NP_001809.3; NM_001818.3.
DR PDB; 2FVL; X-ray; 2.40 A; A/B/C=1-323.
DR PDBsum; 2FVL; -.
DR AlphaFoldDB; P17516; -.
DR SMR; P17516; -.
DR BioGRID; 107534; 5.
DR IntAct; P17516; 3.
DR STRING; 9606.ENSP00000369814; -.
DR BindingDB; P17516; -.
DR ChEMBL; CHEMBL4999; -.
DR DrugBank; DB13751; Glycyrrhizic acid.
DR DrugBank; DB06077; Lumateperone.
DR DrugBank; DB00959; Methylprednisolone.
DR DrugBank; DB00461; Nabumetone.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB00717; Norethisterone.
DR DrugBank; DB00776; Oxcarbazepine.
DR DrugCentral; P17516; -.
DR SwissLipids; SLP:000000805; -.
DR iPTMnet; P17516; -.
DR PhosphoSitePlus; P17516; -.
DR SwissPalm; P17516; -.
DR BioMuta; AKR1C4; -.
DR DMDM; 308153631; -.
DR jPOST; P17516; -.
DR MassIVE; P17516; -.
DR MaxQB; P17516; -.
DR PaxDb; P17516; -.
DR PeptideAtlas; P17516; -.
DR PRIDE; P17516; -.
DR ProteomicsDB; 53480; -.
DR Antibodypedia; 24066; 299 antibodies from 37 providers.
DR DNASU; 1109; -.
DR Ensembl; ENST00000263126.3; ENSP00000263126.1; ENSG00000198610.11.
DR Ensembl; ENST00000380448.5; ENSP00000369814.1; ENSG00000198610.11.
DR GeneID; 1109; -.
DR KEGG; hsa:1109; -.
DR MANE-Select; ENST00000263126.3; ENSP00000263126.1; NM_001818.5; NP_001809.4.
DR UCSC; uc001ihw.2; human.
DR CTD; 1109; -.
DR DisGeNET; 1109; -.
DR GeneCards; AKR1C4; -.
DR HGNC; HGNC:387; AKR1C4.
DR HPA; ENSG00000198610; Tissue enriched (liver).
DR MalaCards; AKR1C4; -.
DR MIM; 600451; gene.
DR MIM; 614279; phenotype.
DR neXtProt; NX_P17516; -.
DR OpenTargets; ENSG00000198610; -.
DR Orphanet; 443087; 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency.
DR PharmGKB; PA24680; -.
DR VEuPathDB; HostDB:ENSG00000198610; -.
DR eggNOG; KOG1577; Eukaryota.
DR GeneTree; ENSGT00940000163771; -.
DR HOGENOM; CLU_023205_0_0_1; -.
DR InParanoid; P17516; -.
DR OMA; YSSECAL; -.
DR OrthoDB; 1016440at2759; -.
DR PhylomeDB; P17516; -.
DR TreeFam; TF106492; -.
DR BioCyc; MetaCyc:HS10739-MON; -.
DR BRENDA; 1.1.1.357; 2681.
DR PathwayCommons; P17516; -.
DR Reactome; R-HSA-193368; Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol.
DR Reactome; R-HSA-193775; Synthesis of bile acids and bile salts via 24-hydroxycholesterol.
DR Reactome; R-HSA-193807; Synthesis of bile acids and bile salts via 27-hydroxycholesterol.
DR Reactome; R-HSA-975634; Retinoid metabolism and transport.
DR SABIO-RK; P17516; -.
DR SignaLink; P17516; -.
DR SIGNOR; P17516; -.
DR BioGRID-ORCS; 1109; 8 hits in 1031 CRISPR screens.
DR ChiTaRS; AKR1C4; human.
DR EvolutionaryTrace; P17516; -.
DR GeneWiki; 3-alpha-HSD; -.
DR GenomeRNAi; 1109; -.
DR Pharos; P17516; Tchem.
DR PRO; PR:P17516; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; P17516; protein.
DR Bgee; ENSG00000198610; Expressed in right lobe of liver and 50 other tissues.
DR Genevisible; P17516; HS.
DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
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:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0004033; F:aldo-keto reductase (NADP) activity; TAS:Reactome.
DR GO; GO:0047044; F:androstan-3-alpha,17-beta-diol dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0047023; F:androsterone dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0032052; F:bile acid binding; IBA:GO_Central.
DR GO; GO:0015125; F:bile acid transmembrane transporter activity; TAS:ProtInc.
DR GO; GO:0047743; F:chlordecone reductase activity; IDA:UniProtKB.
DR GO; GO:0035410; F:dihydrotestosterone 17-beta-dehydrogenase activity; IEA:UniProtKB-EC.
DR GO; GO:0009055; F:electron transfer activity; TAS:UniProtKB.
DR GO; GO:0047086; F:ketosteroid monooxygenase activity; IBA:GO_Central.
DR GO; GO:0016655; F:oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor; IDA:UniProtKB.
DR GO; GO:0001758; F:retinal dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0016229; F:steroid dehydrogenase activity; IBA:GO_Central.
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:0008209; P:androgen metabolic process; TAS:ProtInc.
DR GO; GO:0015721; P:bile acid and bile salt transport; TAS:ProtInc.
DR GO; GO:0006699; P:bile acid biosynthetic process; TAS:Reactome.
DR GO; GO:0071395; P:cellular response to jasmonic acid stimulus; IDA:UniProtKB.
DR GO; GO:0044597; P:daunorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0044598; P:doxorubicin metabolic process; IMP:UniProtKB.
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:0001523; P:retinoid metabolic process; TAS:Reactome.
DR GO; GO:0008202; P:steroid metabolic process; IBA:GO_Central.
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 3D-structure; 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_0000124640"
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:0000269|Ref.18"
FT BINDING 50
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|Ref.18"
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:0000269|Ref.18"
FT BINDING 190
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|Ref.18"
FT BINDING 216..221
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|Ref.18"
FT BINDING 270..280
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|Ref.18"
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"
FT VARIANT 135
FT /note="G -> E (in dbSNP:rs11253043)"
FT /id="VAR_028240"
FT VARIANT 145
FT /note="S -> C (in dbSNP:rs3829125)"
FT /evidence="ECO:0000269|PubMed:10634139"
FT /id="VAR_013290"
FT VARIANT 170
FT /note="C -> Y (in dbSNP:rs17851824)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_028241"
FT VARIANT 250
FT /note="Q -> R (in dbSNP:rs4880718)"
FT /evidence="ECO:0000269|PubMed:10634139,
FT ECO:0000269|PubMed:10672042, ECO:0000269|PubMed:11158055,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:2187532,
FT ECO:0000269|PubMed:7626489, ECO:0000269|PubMed:7650035,
FT ECO:0000269|PubMed:8172617, ECO:0000269|PubMed:8274401"
FT /id="VAR_028242"
FT VARIANT 311
FT /note="L -> V (in dbSNP:rs17134592)"
FT /evidence="ECO:0000269|PubMed:10634139"
FT /id="VAR_013291"
FT HELIX 3..5
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 7..9
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 15..22
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 33..44
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 53..55
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 58..71
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 76..78
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 80..85
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 87..89
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 92..106
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 111..117
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 124..126
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 144..156
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 159..167
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 170..177
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 187..192
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 200..208
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 212..217
FT /evidence="ECO:0007829|PDB:2FVL"
FT TURN 225..227
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 235..237
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 239..247
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 252..262
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 266..270
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 274..280
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 281..285
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 290..297
FT /evidence="ECO:0007829|PDB:2FVL"
FT HELIX 309..311
FT /evidence="ECO:0007829|PDB:2FVL"
FT STRAND 318..321
FT /evidence="ECO:0007829|PDB:2FVL"
SQ SEQUENCE 323 AA; 37067 MW; E728CE4B420E8C58 CRC64;
MDPKYQRVEL NDGHFMPVLG FGTYAPPEVP RNRAVEVTKL AIEAGFRHID SAYLYNNEEQ
VGLAIRSKIA DGSVKREDIF YTSKLWCTFF QPQMVQPALE SSLKKLQLDY VDLYLLHFPM
ALKPGETPLP KDENGKVIFD TVDLSATWEV MEKCKDAGLA KSIGVSNFNC RQLEMILNKP
GLKYKPVCNQ VECHPYLNQS KLLDFCKSKD IVLVAHSALG TQRHKLWVDP NSPVLLEDPV
LCALAKKHKQ TPALIALRYQ LQRGVVVLAK SYNEQRIREN IQVFEFQLTS EDMKVLDGLN
RNYRYVVMDF LMDHPDYPFS DEY
