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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
 
 
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