ID DHRS4_MOUSE Reviewed; 279 AA. AC Q99LB2; G3X8V7; Q9EQU4; DT 10-OCT-2003, integrated into UniProtKB/Swiss-Prot. DT 03-OCT-2012, sequence version 3. DT 27-MAR-2024, entry version 160. DE RecName: Full=Dehydrogenase/reductase SDR family member 4 {ECO:0000250|UniProtKB:Q8WNV7}; DE EC=1.1.1.184 {ECO:0000250|UniProtKB:Q8WNV7}; DE EC=1.1.1.300 {ECO:0000250|UniProtKB:Q8WNV7}; DE AltName: Full=NADPH-dependent carbonyl reductase {ECO:0000250|UniProtKB:Q8WNV7}; DE Short=CR {ECO:0000250|UniProtKB:Q8WNV7}; DE AltName: Full=NADPH-dependent retinol dehydrogenase/reductase {ECO:0000250|UniProtKB:Q8WNV7}; DE Short=NDRD {ECO:0000250|UniProtKB:Q8WNV7}; DE Short=mouNRDR; DE AltName: Full=Peroxisomal short-chain alcohol dehydrogenase; DE Short=PSCD; DE AltName: Full=Short chain dehydrogenase/reductase family 25C member 2 {ECO:0000250|UniProtKB:Q9BTZ2}; DE Short=Protein SDR25C2 {ECO:0000250|UniProtKB:Q9BTZ2}; GN Name=Dhrs4 {ECO:0000312|MGI:MGI:90169}; Synonyms=D14Ucla2; 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 [MRNA]. RC STRAIN=C57BL/6J; TISSUE=Liver; RA Furukawa A., Ohnishi T., Huang D., Araki N., Ichikawa Y.; RT "cDNA cloning and characterization of peroxisomal short-chain dehydrogenase RT / reductase that reduce all-trans retinal to retinol."; RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases. RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Mammary tumor; 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 [5] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-221, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Pancreas, RC and Testis; 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). RN [6] RP SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-93; LYS-217; LYS-228 AND RP LYS-235, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001; RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.; RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic RT pathways."; RL Mol. Cell 50:919-930(2013). RN [7] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-93; LYS-106 AND LYS-217, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=23576753; DOI=10.1073/pnas.1302961110; RA Rardin M.J., Newman J.C., Held J.M., Cusack M.P., Sorensen D.J., Li B., RA Schilling B., Mooney S.D., Kahn C.R., Verdin E., Gibson B.W.; RT "Label-free quantitative proteomics of the lysine acetylome in mitochondria RT identifies substrates of SIRT3 in metabolic pathways."; RL Proc. Natl. Acad. Sci. U.S.A. 110:6601-6606(2013). CC -!- FUNCTION: NADPH-dependent oxidoreductase which catalyzes the reduction CC of a variety of compounds bearing carbonyl groups including CC ketosteroids, alpha-dicarbonyl compounds, aldehydes, aromatic ketones CC and quinones. Reduces all-trans-retinal and 9-cis retinal. Reduces 3- CC ketosteroids and benzil into 3alpha-hydroxysteroids and S-benzoin, CC respectively, in contrast to the stereoselectivity of primates DHRS4s CC which produce 3beta-hydroxysteroids and R-benzoin. In the reverse CC reaction, catalyzes the NADP-dependent oxidation of 3alpha- CC hydroxysteroids and alcohol, but with much lower efficiency. Involved CC in the metabolism of 3alpha-hydroxysteroids, retinoid, isatin and CC xenobiotic carbonyl compounds. {ECO:0000250|UniProtKB:Q8WNV7}. CC -!- CATALYTIC ACTIVITY: CC Reaction=a secondary alcohol + NADP(+) = a ketone + H(+) + NADPH; CC Xref=Rhea:RHEA:19257, ChEBI:CHEBI:15378, ChEBI:CHEBI:17087, CC ChEBI:CHEBI:35681, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; CC EC=1.1.1.184; Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:19259; CC Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC -!- CATALYTIC ACTIVITY: CC Reaction=3alpha-hydroxy-5beta-pregnan-20-one + NADP(+) = 5beta-pregnan- CC 3,20-dione + H(+) + NADPH; Xref=Rhea:RHEA:69016, ChEBI:CHEBI:1712, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30154, ChEBI:CHEBI:57783, CC ChEBI:CHEBI:58349; Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69017; CC Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC -!- CATALYTIC ACTIVITY: CC Reaction=5beta-dihydrotestosterone + H(+) + NADPH = 5beta-androstane- CC 3alpha,17beta-diol + NADP(+); Xref=Rhea:RHEA:69028, ChEBI:CHEBI:2150, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:36714, ChEBI:CHEBI:57783, CC ChEBI:CHEBI:58349; Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:69029; CC Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC -!- CATALYTIC ACTIVITY: CC Reaction=all-trans-retinol + NADP(+) = all-trans-retinal + H(+) + CC NADPH; Xref=Rhea:RHEA:25033, ChEBI:CHEBI:15378, ChEBI:CHEBI:17336, CC ChEBI:CHEBI:17898, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; CC EC=1.1.1.300; Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:25035; CC Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H(+) + isatin + NADPH = 3-hydroxyindolin-2-one + NADP(+); CC Xref=Rhea:RHEA:68608, ChEBI:CHEBI:15378, ChEBI:CHEBI:27539, CC ChEBI:CHEBI:28536, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; CC Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:68609; CC Evidence={ECO:0000250|UniProtKB:Q8WNV7}; CC -!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:Q8WNV7}. CC -!- SUBCELLULAR LOCATION: Peroxisome {ECO:0000250|UniProtKB:Q8WNV7}. CC -!- DOMAIN: The C-terminus peroxisomal targeting signal tripeptide is CC important for peroxisomal import. Once in the peroxisome, it is CC involved in intersubunit interactions. {ECO:0000250|UniProtKB:Q8WNV7}. CC -!- DOMAIN: Three specific residues, Phe-177, Leu-180 and Asn-196 are CC conserved between non-primate mammals whereas the respective residues CC are serine, phenylalanine and threonine in primates. The two residues CC at positions 177 and 180 are molecular determinants responsible for the CC stereoselective reduction of 3-ketosteroids and benzil. The presence of CC an asparagine at position 196 is important for the maintenance of the CC quaternary structure resulting in stability at cold temperature and CC improved catalytic activity toward retinal. CC {ECO:0000250|UniProtKB:Q8WNV7}. CC -!- MISCELLANEOUS: Primate DHRS4s display different stereoselectivity and CC catalytic efficiency in the oxidoreduction of some substrates as CC compared to other mammal DHRS4s due to a difference in conserved amino CC acid residues. {ECO:0000250|UniProtKB:Q8WNV7}. CC -!- SIMILARITY: Belongs to the short-chain dehydrogenases/reductases (SDR) CC family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAH03484.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAB18776.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={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; AB045132; BAB18776.1; ALT_INIT; mRNA. DR EMBL; AC159002; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH466535; EDL36299.1; -; Genomic_DNA. DR EMBL; BC003484; AAH03484.1; ALT_INIT; mRNA. DR EMBL; BC054361; AAH54361.1; -; mRNA. DR CCDS; CCDS27111.1; -. DR RefSeq; NP_001033027.2; NM_001037938.2. DR AlphaFoldDB; Q99LB2; -. DR SMR; Q99LB2; -. DR BioGRID; 205827; 17. DR IntAct; Q99LB2; 2. DR STRING; 10090.ENSMUSP00000022821; -. DR iPTMnet; Q99LB2; -. DR PhosphoSitePlus; Q99LB2; -. DR SwissPalm; Q99LB2; -. DR EPD; Q99LB2; -. DR jPOST; Q99LB2; -. DR MaxQB; Q99LB2; -. DR PaxDb; 10090-ENSMUSP00000022821; -. DR ProteomicsDB; 277451; -. DR Pumba; Q99LB2; -. DR DNASU; 28200; -. DR Ensembl; ENSMUST00000022821.8; ENSMUSP00000022821.7; ENSMUSG00000022210.8. DR GeneID; 28200; -. DR KEGG; mmu:28200; -. DR UCSC; uc007tym.2; mouse. DR AGR; MGI:90169; -. DR CTD; 10901; -. DR MGI; MGI:90169; Dhrs4. DR VEuPathDB; HostDB:ENSMUSG00000022210; -. DR eggNOG; KOG0725; Eukaryota. DR GeneTree; ENSGT00940000158919; -. DR HOGENOM; CLU_010194_1_1_1; -. DR InParanoid; Q99LB2; -. DR OMA; VYLCCKA; -. DR OrthoDB; 34796at2759; -. DR PhylomeDB; Q99LB2; -. DR TreeFam; TF315405; -. DR Reactome; R-MMU-5365859; RA biosynthesis pathway. DR Reactome; R-MMU-9033241; Peroxisomal protein import. DR BioGRID-ORCS; 28200; 3 hits in 81 CRISPR screens. DR ChiTaRS; Dhrs4; mouse. DR PRO; PR:Q99LB2; -. DR Proteomes; UP000000589; Chromosome 14. DR RNAct; Q99LB2; Protein. DR Bgee; ENSMUSG00000022210; Expressed in right kidney and 266 other cell types or tissues. DR ExpressionAtlas; Q99LB2; baseline and differential. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; ISO:MGI. DR GO; GO:0005778; C:peroxisomal membrane; ISO:MGI. DR GO; GO:0005777; C:peroxisome; IDA:MGI. DR GO; GO:0000253; F:3-keto sterol reductase activity; ISO:MGI. DR GO; GO:0018455; F:alcohol dehydrogenase [NAD(P)+] activity; ISO:MGI. DR GO; GO:0004090; F:carbonyl reductase (NADPH) activity; ISO:MGI. DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB. DR GO; GO:0052650; F:NADP-retinol dehydrogenase activity; ISS:UniProtKB. DR GO; GO:0016655; F:oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor; ISO:MGI. DR GO; GO:0001758; F:retinal dehydrogenase activity; IDA:MGI. DR GO; GO:0042180; P:cellular ketone metabolic process; ISS:UniProtKB. DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IEA:Ensembl. DR GO; GO:0042574; P:retinal metabolic process; IDA:MGI. DR GO; GO:0008202; P:steroid metabolic process; ISS:UniProtKB. DR CDD; cd08936; CR_SDR_c; 1. DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1. DR InterPro; IPR036291; NAD(P)-bd_dom_sf. DR InterPro; IPR020904; Sc_DH/Rdtase_CS. DR InterPro; IPR002347; SDR_fam. DR PANTHER; PTHR43943; DEHYDROGENASE/REDUCTASE (SDR FAMILY) MEMBER 4; 1. DR PANTHER; PTHR43943:SF8; DEHYDROGENASE_REDUCTASE SDR FAMILY MEMBER 4-RELATED; 1. DR Pfam; PF13561; adh_short_C2; 1. DR PRINTS; PR00081; GDHRDH. DR PRINTS; PR00080; SDRFAMILY. DR SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1. DR PROSITE; PS00061; ADH_SHORT; 1. DR Genevisible; Q99LB2; MM. PE 1: Evidence at protein level; KW Acetylation; NADP; Oxidoreductase; Peroxisome; Phosphoprotein; KW Reference proteome. FT CHAIN 1..279 FT /note="Dehydrogenase/reductase SDR family member 4" FT /id="PRO_0000054648" FT MOTIF 277..279 FT /note="Peroxisomal targeting signal" FT ACT_SITE 183 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10001" FT BINDING 37..61 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:Q8WNV7" FT BINDING 170 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:Q99714" FT BINDING 187 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:Q8WNV7" FT SITE 177 FT /note="Responsible for the stereoselective reduction of 3- FT ketosteroids into 3alpha-hydroxysteroids and benzil into S- FT benzoin" FT /evidence="ECO:0000250|UniProtKB:Q8WNV7" FT SITE 180 FT /note="Responsible for the stereoselective reduction of 3- FT ketosteroids into 3alpha-hydroxysteroids and benzil into S- FT benzoin" FT /evidence="ECO:0000250|UniProtKB:Q8WNV7" FT SITE 196 FT /note="Important for the maintenance of the quaternary FT structure, the catalytic activity and cold stability" FT /evidence="ECO:0000250|UniProtKB:Q8WNV7" FT MOD_RES 93 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0007744|PubMed:23576753" FT MOD_RES 93 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0007744|PubMed:23806337" FT MOD_RES 106 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:23576753" FT MOD_RES 217 FT /note="N6-acetyllysine; alternate" FT /evidence="ECO:0007744|PubMed:23576753" FT MOD_RES 217 FT /note="N6-succinyllysine; alternate" FT /evidence="ECO:0007744|PubMed:23806337" FT MOD_RES 221 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:21183079" FT MOD_RES 228 FT /note="N6-succinyllysine" FT /evidence="ECO:0007744|PubMed:23806337" FT MOD_RES 235 FT /note="N6-succinyllysine" FT /evidence="ECO:0007744|PubMed:23806337" FT CONFLICT 109 FT /note="Q -> R (in Ref. 4; AAH03484/AAH54361)" FT /evidence="ECO:0000305" SQ SEQUENCE 279 AA; 29885 MW; 985668BDE2935072 CRC64; MQKAGRLLGG WTQAWMSVRM ASSGLTRRNP LSNKVALVTA STDGIGFAIA RRLAEDGAHV VVSSRKQQNV DRAVATLQGE GLSVTGIVCH VGKAEDREKL ITTALKRHQG IDILVSNAAV NPFFGNLMDV TEEVWDKVLS INVTATAMMI KAVVPEMEKR GGGSVVIVGS VAGFTRFPSL GPYNVSKTAL LGLTKNFAAE LAPKNIRVNC LAPGLIKTRF SSVLWEEKAR EDFIKEAMQI RRLGKPEDCA GIVSFLCSED ASYINGETVV VGGGTPSRL //