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 02-SEP-2026, entry version 153. 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 + NADPH + CC H(+); 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 + NADPH + H(+); 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 + NADPH + H(+) = 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 + NADPH + H(+) = 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 + NADPH + H(+) = 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 + NADPH + H(+) = 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 + NADPH + H(+) = 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 + NADPH + H(+) = 5beta- CC androstane-3,17-dione + NADP(+); Xref=Rhea:RHEA:46656, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16422, ChEBI:CHEBI:16985, CC ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; CC 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=progesterone + NADPH + H(+) = 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 + NADPH + H(+) = 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 + NADPH + H(+) = 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 + NADPH + H(+) = 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 + NADPH + H(+) = 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(+) = testosterone + NADPH + CC H(+); Xref=Rhea:RHEA:46636, ChEBI:CHEBI:2150, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:17347, ChEBI:CHEBI:57783, 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 + NADPH + H(+) = 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 FunCoup; Q8VCX1; 443. DR STRING; 10090.ENSMUSP00000048830; -. DR iPTMnet; Q8VCX1; -. DR PhosphoSitePlus; Q8VCX1; -. DR SwissPalm; Q8VCX1; -. DR jPOST; Q8VCX1; -. DR PaxDb; 10090-ENSMUSP00000048830; -. DR PeptideAtlas; Q8VCX1; -. DR ProteomicsDB; 285790; -. DR Antibodypedia; 32317; 243 antibodies from 27 providers. DR DNASU; 208665; -. DR Ensembl; ENSMUST00000040987.11; ENSMUSP00000048830.8; ENSMUSG00000038641.13. DR GeneID; 208665; -. DR KEGG; mmu:208665; -. DR UCSC; uc009bjg.2; mouse. DR AGR; MGI:2384785; -. 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; YCLQKNW; -. DR OrthoDB; 416253at2759; -. DR PhylomeDB; Q8VCX1; -. DR BRENDA; 1.3.1.3; 3474. 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 80 CRISPR screens. 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 cell types or tissues. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; ISO:GO_Central. DR GO; GO:0072582; F:17-beta-hydroxysteroid dehydrogenase (NADP+) activity; IEA:RHEA. DR GO; GO:0047568; F:3-oxo-5-beta-steroid 4-dehydrogenase activity; ISO:MGI. DR GO; GO:0004032; F:aldose reductase (NADPH) 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:GO_Central. DR GO; GO:0006699; P:bile acid biosynthetic process; ISO:MGI. DR GO; GO:0008207; P:C21-steroid hormone metabolic process; ISO:GO_Central. DR GO; GO:0006707; P:cholesterol catabolic process; ISO:GO_Central. DR GO; GO:0007586; P:digestion; ISO:GO_Central. DR CDD; cd19109; AKR_AKR1D1-3; 1. DR FunFam; 3.20.20.100:FF:000003; Aldo-keto reductase family 1 member C3; 1. DR Gene3D; 3.20.20.100; NADP-dependent oxidoreductase domain; 1. DR InterPro; IPR020471; AKR. DR InterPro; IPR044483; AKR1D1. DR InterPro; IPR018170; Aldo/ket_reductase_CS. DR InterPro; IPR036812; NAD(P)_OxRdtase_dom_sf. DR InterPro; IPR023210; NADP_OxRdtase_dom. DR PANTHER; PTHR11732; ALDO/KETO REDUCTASE; 1. DR Pfam; PF00248; Aldo_ket_red; 1. DR PIRSF; PIRSF000097; AKR; 1. DR PRINTS; PR00069; ALDKETRDTASE. DR SUPFAM; SSF51430; NAD(P)-linked oxidoreductase; 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 //