AK1D1_MOUSE
ID AK1D1_MOUSE Reviewed; 325 AA.
AC Q8VCX1;
DT 07-JUN-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2002, sequence version 1.
DT 03-AUG-2022, entry version 135.
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 Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; 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 [2]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-228, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
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 -!- SIMILARITY: Belongs to the aldo/keto reductase family. {ECO:0000305}.
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DR EMBL; BC018333; AAH18333.1; -; mRNA.
DR CCDS; CCDS20007.1; -.
DR RefSeq; NP_663339.1; NM_145364.2.
DR RefSeq; XP_006505888.1; XM_006505825.1.
DR AlphaFoldDB; Q8VCX1; -.
DR SMR; Q8VCX1; -.
DR STRING; 10090.ENSMUSP00000048830; -.
DR iPTMnet; Q8VCX1; -.
DR PhosphoSitePlus; Q8VCX1; -.
DR SwissPalm; Q8VCX1; -.
DR EPD; Q8VCX1; -.
DR jPOST; Q8VCX1; -.
DR MaxQB; Q8VCX1; -.
DR PaxDb; Q8VCX1; -.
DR PeptideAtlas; Q8VCX1; -.
DR PRIDE; Q8VCX1; -.
DR ProteomicsDB; 285790; -.
DR Antibodypedia; 32317; 260 antibodies from 26 providers.
DR DNASU; 208665; -.
DR Ensembl; ENSMUST00000040987; ENSMUSP00000048830; ENSMUSG00000038641.
DR GeneID; 208665; -.
DR KEGG; mmu:208665; -.
DR UCSC; uc009bjg.2; mouse.
DR CTD; 6718; -.
DR MGI; MGI:2384785; Akr1d1.
DR VEuPathDB; HostDB:ENSMUSG00000038641; -.
DR eggNOG; KOG1577; Eukaryota.
DR GeneTree; ENSGT00940000155961; -.
DR HOGENOM; CLU_023205_0_0_1; -.
DR InParanoid; Q8VCX1; -.
DR OMA; AFKPGNE; -.
DR OrthoDB; 1016440at2759; -.
DR PhylomeDB; Q8VCX1; -.
DR TreeFam; TF106492; -.
DR Reactome; R-MMU-193368; Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol.
DR Reactome; R-MMU-193775; Synthesis of bile acids and bile salts via 24-hydroxycholesterol.
DR Reactome; R-MMU-193807; Synthesis of bile acids and bile salts via 27-hydroxycholesterol.
DR BioGRID-ORCS; 208665; 3 hits in 75 CRISPR screens.
DR ChiTaRS; Akr1d1; mouse.
DR PRO; PR:Q8VCX1; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; Q8VCX1; protein.
DR Bgee; ENSMUSG00000038641; Expressed in left lobe of liver and 50 other tissues.
DR Genevisible; Q8VCX1; MM.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0047568; F:3-oxo-5-beta-steroid 4-dehydrogenase activity; ISO: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:MGI.
DR GO; GO:0006699; P:bile acid biosynthetic process; ISO:MGI.
DR GO; GO:0030573; P:bile acid catabolic process; IEA:UniProtKB-KW.
DR GO; GO:0008207; P:C21-steroid hormone metabolic process; ISO:MGI.
DR GO; GO:0006707; P:cholesterol catabolic process; ISO:MGI.
DR GO; GO:0007586; P:digestion; ISO:MGI.
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; Lipid degradation; Lipid metabolism; NADP;
KW Oxidoreductase; Phosphoprotein; Reference proteome; Steroid metabolism.
FT CHAIN 1..325
FT /note="Aldo-keto reductase family 1 member D1"
FT /id="PRO_0000124670"
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 218..223
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 229
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT BINDING 272..282
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P51857"
FT MOD_RES 228
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
SQ SEQUENCE 325 AA; 37290 MW; 1866A0DA4C5DDA98 CRC64;
MNLSAAHHQI SLSDGNNIPL IGLGTYSDPR PVPGKTYVAV KTAIDEGYRH IDGAYVYHNE
HEVGEAIREK IAEGKVKREE IFYCGKLWNT EHVPSMVLPA LERTLKALKL DYIDLYIIEL
PMAFKPGKEI YPRDENGRII YDKTNLCATW EALEACKDAG LVKSLGVSNF NRRQLELILN
KPGLKYKPVT NQVECHPYFT QTKLLKFCQQ HDIVIVAHSP LGTCRNPSWV NVSSPPLLND
ELLTSLGKKY NKTQAQIVLR FNIQRGIVVI PKSFTPERIK ENFQIFDFSL TEEEMKDIDA
LNKNVRYVEL LMWSDHPEYP FHDEY
