DHRS4_MOUSE
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 03-AUG-2022, entry version 152.
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, and
RC 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};
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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; Q99LB2; -.
DR PRIDE; Q99LB2; -.
DR ProteomicsDB; 277451; -.
DR DNASU; 28200; -.
DR Ensembl; ENSMUST00000022821; ENSMUSP00000022821; ENSMUSG00000022210.
DR GeneID; 28200; -.
DR KEGG; mmu:28200; -.
DR UCSC; uc007tym.2; mouse.
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; WEVANVI; -.
DR OrthoDB; 1194344at2759; -.
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 76 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 264 other tissues.
DR ExpressionAtlas; Q99LB2; baseline and differential.
DR Genevisible; Q99LB2; MM.
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:0042574; P:retinal metabolic process; IDA:MGI.
DR GO; GO:0008202; P:steroid metabolic process; ISS:UniProtKB.
DR InterPro; IPR029511; DHRS4-like.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR020904; Sc_DH/Rdtase_CS.
DR InterPro; IPR002347; SDR_fam.
DR PANTHER; PTHR43943:SF8; PTHR43943:SF8; 1.
DR PRINTS; PR00081; GDHRDH.
DR PRINTS; PR00080; SDRFAMILY.
DR SUPFAM; SSF51735; SSF51735; 1.
DR PROSITE; PS00061; ADH_SHORT; 1.
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
