AK1D1_RAT
ID AK1D1_RAT Reviewed; 326 AA.
AC P31210;
DT 01-JUL-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1993, sequence version 1.
DT 03-AUG-2022, entry version 141.
DE RecName: Full=Aldo-keto reductase family 1 member D1;
DE EC=1.3.1.3 {ECO:0000250|UniProtKB:P51857};
DE AltName: Full=3-oxo-5-beta-steroid 4-dehydrogenase;
DE AltName: Full=Delta(4)-3-ketosteroid 5-beta-reductase;
DE AltName: Full=Delta(4)-3-oxosteroid 5-beta-reductase;
GN Name=Akr1d1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1710579; DOI=10.1016/0014-5793(91)80591-p;
RA Onishi Y., Noshiro M., Shimosato T., Okuda K.;
RT "Molecular cloning and sequence analysis of cDNA encoding delta 4-3-
RT ketosteroid 5 beta-reductase of rat liver.";
RL FEBS Lett. 283:215-218(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE.
RC TISSUE=Liver;
RX PubMed=1789929; DOI=10.1515/bchm3.1991.372.2.1039;
RA Onishi Y., Noshiro M., Shimosato T., Okuda K.;
RT "Delta 4-3-Oxosteroid 5 beta-reductase. Structure and function.";
RL Biol. Chem. Hoppe-Seyler 372:1039-1049(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=8550030; DOI=10.1002/hep.510230116;
RA Zhu Y., Fillenwarth M.J., Crabb D., Lumeng L., Lin R.C.;
RT "Identification of the 37-kd rat liver protein that forms an acetaldehyde
RT adduct in vivo as delta 4-3-ketosteroid 5 beta-reductase.";
RL Hepatology 23:115-122(1996).
CC -!- FUNCTION: Catalyzes the stereospecific NADPH-dependent reduction of the
CC C4-C5 double bond of bile acid intermediates and steroid hormones
CC carrying a delta(4)-3-one structure to yield an A/B cis-ring junction.
CC This cis-configuration is crucial for bile acid biosynthesis and plays
CC important roles in steroid metabolism. Capable of reducing a broad
CC range of delta-(4)-3-ketosteroids from C18 (such as, 17beta-
CC hydroxyestr-4-en-3-one) to C27 (such as, 7alpha-hydroxycholest-4-en-3-
CC one). {ECO:0000250|UniProtKB:P51857}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5beta-cholestan-3-one + NADP(+) = cholest-4-en-3-one + H(+) +
CC NADPH; Xref=Rhea:RHEA:11524, ChEBI:CHEBI:15378, ChEBI:CHEBI:16074,
CC ChEBI:CHEBI:16175, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.3.1.3;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:11526;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4,5beta-dihydrocortisone + NADP(+) = cortisone + H(+) + NADPH;
CC Xref=Rhea:RHEA:14037, ChEBI:CHEBI:15378, ChEBI:CHEBI:16962,
CC ChEBI:CHEBI:18093, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.3.1.3;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:14039;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cortisol + H(+) + NADPH = 5beta-dihydrocortisol + NADP(+);
CC Xref=Rhea:RHEA:46644, ChEBI:CHEBI:732, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17650, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46645;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=corticosterone + H(+) + NADPH = 5beta-dihydrocorticosterone +
CC NADP(+); Xref=Rhea:RHEA:46664, ChEBI:CHEBI:15378, ChEBI:CHEBI:16827,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:86381;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46665;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=7alpha,12alpha-dihydroxycholest-4-en-3-one + H(+) + NADPH =
CC 7alpha,12alpha-dihydroxy-5beta-cholestan-3-one + NADP(+);
CC Xref=Rhea:RHEA:46632, ChEBI:CHEBI:2288, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:28477, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46633;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=7alpha-hydroxycholest-4-en-3-one + H(+) + NADPH = 7alpha-
CC hydroxy-5beta-cholestan-3-one + NADP(+); Xref=Rhea:RHEA:46640,
CC ChEBI:CHEBI:2290, ChEBI:CHEBI:15378, ChEBI:CHEBI:17899,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46641;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=epitestosterone + H(+) + NADPH = 5beta-dihydroepitestosterone
CC + NADP(+); Xref=Rhea:RHEA:46652, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:42534, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:86377; Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46653;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=androst-4-ene-3,17-dione + H(+) + NADPH = 5beta-androstane-
CC 3,17-dione + NADP(+); Xref=Rhea:RHEA:46656, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16422, ChEBI:CHEBI:16985, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46657;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + NADPH + progesterone = 5beta-pregnan-3,20-dione +
CC NADP(+); Xref=Rhea:RHEA:46660, ChEBI:CHEBI:15378, ChEBI:CHEBI:17026,
CC ChEBI:CHEBI:30154, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46661;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=21-hydroxyprogesterone + H(+) + NADPH = 5beta-
CC dihydrodeoxycorticosterone + NADP(+); Xref=Rhea:RHEA:46668,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16973, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:86384;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46669;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=aldosterone + H(+) + NADPH = 5beta-dihydroaldosterone +
CC NADP(+); Xref=Rhea:RHEA:46672, ChEBI:CHEBI:15378, ChEBI:CHEBI:27584,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349, ChEBI:CHEBI:86389;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46673;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=17beta-hydroxyandrosta-1,4-dien-3-one + H(+) + NADPH = 17beta-
CC hydroxy-5beta-androst-1-en-3-one + NADP(+); Xref=Rhea:RHEA:47076,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:34584, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:87331;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47077;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=17beta-hydroxyestr-4-en-3-one + H(+) + NADPH = 17beta-hydroxy-
CC 5beta-estran-3-one + NADP(+); Xref=Rhea:RHEA:47080, ChEBI:CHEBI:7466,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:87333; Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47081;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5beta-dihydrotestosterone + NADP(+) = H(+) + NADPH +
CC testosterone; Xref=Rhea:RHEA:46636, ChEBI:CHEBI:2150,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17347, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=1.3.1.3;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:46637;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=androst-4-ene-3,11,17-trione + H(+) + NADPH = 17beta-
CC hydroxyandrost-4-ene-3,11-dione + NADP(+); Xref=Rhea:RHEA:53484,
CC ChEBI:CHEBI:2495, ChEBI:CHEBI:15378, ChEBI:CHEBI:34133,
CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:53485;
CC Evidence={ECO:0000250|UniProtKB:P51857};
CC -!- ACTIVITY REGULATION: Subject to inhibition by high substrate
CC concentrations. Inhibited by testosterone concentrations above 10 uM.
CC Inhibited by the primary and secondary bile acids chenodeoxycholic acid
CC and ursodeoxycholic acid. {ECO:0000250|UniProtKB:P51857}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P51857}.
CC -!- PTM: The N-terminus is blocked.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
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DR EMBL; D17309; BAA04131.1; -; mRNA.
DR EMBL; S80431; AAB35916.2; -; mRNA.
DR PIR; S15835; S15835.
DR RefSeq; NP_620239.1; NM_138884.1.
DR AlphaFoldDB; P31210; -.
DR SMR; P31210; -.
DR STRING; 10116.ENSRNOP00000017675; -.
DR ChEMBL; CHEMBL5760; -.
DR iPTMnet; P31210; -.
DR PhosphoSitePlus; P31210; -.
DR jPOST; P31210; -.
DR PaxDb; P31210; -.
DR PRIDE; P31210; -.
DR GeneID; 192242; -.
DR KEGG; rno:192242; -.
DR UCSC; RGD:620752; rat.
DR CTD; 6718; -.
DR RGD; 620752; Akr1d1.
DR eggNOG; KOG1577; Eukaryota.
DR InParanoid; P31210; -.
DR OrthoDB; 1016440at2759; -.
DR PhylomeDB; P31210; -.
DR BioCyc; MetaCyc:MON-14304; -.
DR Reactome; R-RNO-193368; Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol.
DR Reactome; R-RNO-193775; Synthesis of bile acids and bile salts via 24-hydroxycholesterol.
DR Reactome; R-RNO-193807; Synthesis of bile acids and bile salts via 27-hydroxycholesterol.
DR SABIO-RK; P31210; -.
DR PRO; PR:P31210; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0047568; F:3-oxo-5-beta-steroid 4-dehydrogenase activity; IDA:MGI.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0047787; F:delta4-3-oxosteroid 5beta-reductase activity; IEA:UniProtKB-EC.
DR GO; GO:0047086; F:ketosteroid monooxygenase activity; IBA:GO_Central.
DR GO; GO:0016229; F:steroid dehydrogenase activity; IBA:GO_Central.
DR GO; GO:0008209; P:androgen metabolic process; ISO:RGD.
DR GO; GO:0006699; P:bile acid biosynthetic process; ISO:RGD.
DR GO; GO:0030573; P:bile acid catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0008207; P:C21-steroid hormone metabolic process; ISO:RGD.
DR GO; GO:0006707; P:cholesterol catabolic process; ISO:RGD.
DR GO; GO:0007586; P:digestion; ISO:RGD.
DR GO; GO:0008202; P:steroid metabolic process; IBA:GO_Central.
DR CDD; cd19109; AKR_AKR1D1-3; 1.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR020471; AKR.
DR InterPro; IPR044483; AKR1D1.
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 Bile acid catabolism; Cytoplasm; Direct protein sequencing;
KW Lipid degradation; Lipid metabolism; NADP; Oxidoreductase;
KW Reference proteome; Steroid metabolism.
FT CHAIN 1..326
FT /note="Aldo-keto reductase family 1 member D1"
FT /id="PRO_0000124672"
FT ACT_SITE 57
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 22..26
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 26
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 52
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 57
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 88
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 119
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 131
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 168..169
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 192
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 219..224
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 230
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 273..283
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P51857"
SQ SEQUENCE 326 AA; 37378 MW; 32D8266BFA62CE99 CRC64;
MNLSTANHHI PLNDGNSIPI IGLGTYSDPR PVPGKTFIAV KTAIDEGYRH IDGAYVYRNE
HEVGEAIREK VAEGKVKREE IFYCGKLWST DHDPEMVRPA LERTLQTLKL DYIDLYIIEM
PMAFKPGEEF YPKDENGRVI YHKSNLCATW EALEACKDAG LVKSLGVSNF NRRQLEVILN
KPGLKYKPVT NQVECHPYFT QTKLLEVSAS SMTSFIVAYS PLGTCRNPLW VNVSSPPLLK
DELLTSLGKK YNKTQAQIVL RFDIQRGLVV IPKSTTPERI KENFQIFDFS LTKEEMKDIE
ALNKNVRFVE MLMWSDHPEY PFHDEY
