DPYS_HUMAN
ID DPYS_HUMAN Reviewed; 519 AA.
AC Q14117;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 03-AUG-2022, entry version 186.
DE RecName: Full=Dihydropyrimidinase;
DE Short=DHP;
DE Short=DHPase;
DE EC=3.5.2.2 {ECO:0000250|UniProtKB:Q55DL0};
DE AltName: Full=Dihydropyrimidine amidohydrolase;
DE AltName: Full=Hydantoinase;
GN Name=DPYS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=8973361; DOI=10.1016/s0378-1119(96)00445-3;
RA Hamajima N., Matsuda K., Sakata S., Tamaki N., Sasaki M., Nonaka M.;
RT "A novel gene family defined by human dihydropyrimidinase and three related
RT proteins with differential tissue distribution.";
RL Gene 180:157-163(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS DPYSD ARG-68; ARG-334;
RP ARG-360; ARG-435 AND THR-490.
RX PubMed=9718352; DOI=10.1086/302022;
RA Hamajima N., Kouwaki M., Vreken P., Matsuda K., Sumi S., Imaeda M.,
RA Ohba S., Kidouchi K., Nonaka M., Sasaki M., Tamaki N., Endo Y.,
RA de Abreu R., Rottevell J., van Kuilenburg A., van Gennip A., Togari H.,
RA Wada Y.;
RT "Dihydropyrimidinase deficiency: structural organization, chromosomal
RT localization, and mutation analysis of the human dihydropyrimidinase
RT gene.";
RL Am. J. Hum. Genet. 63:717-726(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, Kidney, and Stomach;
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 [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-79, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [5]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) IN COMPLEX WITH ZINC IONS, AND
RP COFACTOR.
RG Structural genomics consortium (SGC);
RT "The crystal structure of human dihydropyrimidinase.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Catalyzes the second step of the reductive pyrimidine
CC degradation, the reversible hydrolytic ring opening of
CC dihydropyrimidines. Can catalyze the ring opening of 5,6-dihydrouracil
CC to N-carbamyl-alanine and of 5,6-dihydrothymine to N-carbamyl-amino
CC isobutyrate.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5,6-dihydrouracil + H2O = 3-(carbamoylamino)propanoate + H(+);
CC Xref=Rhea:RHEA:16121, ChEBI:CHEBI:11892, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:15901; EC=3.5.2.2;
CC Evidence={ECO:0000250|UniProtKB:Q55DL0};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000269|Ref.5};
CC Note=Binds 2 Zn(2+) ions per subunit. {ECO:0000269|Ref.5};
CC -!- SUBUNIT: Homotetramer. {ECO:0000305|Ref.5}.
CC -!- INTERACTION:
CC Q14117; Q92624: APPBP2; NbExp=3; IntAct=EBI-12275416, EBI-743771;
CC Q14117; P46379-2: BAG6; NbExp=3; IntAct=EBI-12275416, EBI-10988864;
CC Q14117; P28329-3: CHAT; NbExp=3; IntAct=EBI-12275416, EBI-25837549;
CC Q14117; O14645: DNALI1; NbExp=3; IntAct=EBI-12275416, EBI-395638;
CC Q14117; P22607: FGFR3; NbExp=3; IntAct=EBI-12275416, EBI-348399;
CC Q14117; Q14957: GRIN2C; NbExp=3; IntAct=EBI-12275416, EBI-8285963;
CC Q14117; P06396: GSN; NbExp=3; IntAct=EBI-12275416, EBI-351506;
CC Q14117; P01112: HRAS; NbExp=3; IntAct=EBI-12275416, EBI-350145;
CC Q14117; O14901: KLF11; NbExp=3; IntAct=EBI-12275416, EBI-948266;
CC Q14117; Q9BVL2: NUP58; NbExp=3; IntAct=EBI-12275416, EBI-2811583;
CC Q14117; Q9UMX0: UBQLN1; NbExp=3; IntAct=EBI-12275416, EBI-741480;
CC -!- TISSUE SPECIFICITY: Liver and kidney.
CC -!- PTM: Carboxylation allows a single lysine to coordinate two zinc ions.
CC {ECO:0000250}.
CC -!- DISEASE: Dihydropyrimidinase deficiency (DPYSD) [MIM:222748]: An
CC autosomal recessive disorder of pyrimidine metabolism characterized by
CC dihydropyrimidinuria. It is associated with a variable clinical
CC phenotype characterized by epileptic or convulsive attacks, dysmorphic
CC features and severe developmental delay, and congenital microvillous
CC atrophy. Most patients are, however, asymptomatic.
CC {ECO:0000269|PubMed:9718352}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the metallo-dependent hydrolases superfamily.
CC Hydantoinase/dihydropyrimidinase 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; D78011; BAA11189.1; -; mRNA.
DR EMBL; AB004678; BAA33067.1; -; Genomic_DNA.
DR EMBL; BC034395; AAH34395.1; -; mRNA.
DR CCDS; CCDS6302.1; -.
DR PIR; JC5315; JC5315.
DR RefSeq; NP_001376.1; NM_001385.2.
DR PDB; 2VR2; X-ray; 2.80 A; A=1-519.
DR PDBsum; 2VR2; -.
DR AlphaFoldDB; Q14117; -.
DR SMR; Q14117; -.
DR BioGRID; 108141; 8.
DR IntAct; Q14117; 14.
DR STRING; 9606.ENSP00000276651; -.
DR ChEMBL; CHEMBL2465; -.
DR MEROPS; M38.973; -.
DR iPTMnet; Q14117; -.
DR PhosphoSitePlus; Q14117; -.
DR BioMuta; DPYS; -.
DR DMDM; 3122049; -.
DR jPOST; Q14117; -.
DR MassIVE; Q14117; -.
DR MaxQB; Q14117; -.
DR PaxDb; Q14117; -.
DR PeptideAtlas; Q14117; -.
DR PRIDE; Q14117; -.
DR ProteomicsDB; 59824; -.
DR Antibodypedia; 13364; 314 antibodies from 27 providers.
DR DNASU; 1807; -.
DR Ensembl; ENST00000351513.7; ENSP00000276651.2; ENSG00000147647.13.
DR GeneID; 1807; -.
DR KEGG; hsa:1807; -.
DR MANE-Select; ENST00000351513.7; ENSP00000276651.2; NM_001385.3; NP_001376.1.
DR UCSC; uc003yly.5; human.
DR CTD; 1807; -.
DR DisGeNET; 1807; -.
DR GeneCards; DPYS; -.
DR HGNC; HGNC:3013; DPYS.
DR HPA; ENSG00000147647; Group enriched (kidney, liver).
DR MalaCards; DPYS; -.
DR MIM; 222748; phenotype.
DR MIM; 613326; gene.
DR neXtProt; NX_Q14117; -.
DR OpenTargets; ENSG00000147647; -.
DR Orphanet; 38874; Dihydropyrimidinuria.
DR PharmGKB; PA146; -.
DR VEuPathDB; HostDB:ENSG00000147647; -.
DR eggNOG; KOG2584; Eukaryota.
DR GeneTree; ENSGT01030000234527; -.
DR HOGENOM; CLU_015572_2_2_1; -.
DR InParanoid; Q14117; -.
DR OMA; SAETHHM; -.
DR OrthoDB; 719800at2759; -.
DR PhylomeDB; Q14117; -.
DR TreeFam; TF314706; -.
DR BioCyc; MetaCyc:HS07460-MON; -.
DR PathwayCommons; Q14117; -.
DR Reactome; R-HSA-73621; Pyrimidine catabolism.
DR SignaLink; Q14117; -.
DR BioGRID-ORCS; 1807; 6 hits in 1066 CRISPR screens.
DR EvolutionaryTrace; Q14117; -.
DR GeneWiki; DPYS; -.
DR GenomeRNAi; 1807; -.
DR Pharos; Q14117; Tbio.
DR PRO; PR:Q14117; -.
DR Proteomes; UP000005640; Chromosome 8.
DR RNAct; Q14117; protein.
DR Bgee; ENSG00000147647; Expressed in right lobe of liver and 116 other tissues.
DR ExpressionAtlas; Q14117; baseline and differential.
DR Genevisible; Q14117; HS.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0004157; F:dihydropyrimidinase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB.
DR GO; GO:0051219; F:phosphoprotein binding; IEA:Ensembl.
DR GO; GO:0008270; F:zinc ion binding; NAS:UniProtKB.
DR GO; GO:0006248; P:CMP catabolic process; IEA:Ensembl.
DR GO; GO:0006249; P:dCMP catabolic process; IEA:Ensembl.
DR GO; GO:0046079; P:dUMP catabolic process; IEA:Ensembl.
DR GO; GO:0006208; P:pyrimidine nucleobase catabolic process; IDA:UniProtKB.
DR GO; GO:0006210; P:thymine catabolic process; ISS:UniProtKB.
DR GO; GO:0046050; P:UMP catabolic process; IEA:Ensembl.
DR GO; GO:0006212; P:uracil catabolic process; IDA:UniProtKB.
DR CDD; cd01314; D-HYD; 1.
DR Gene3D; 2.30.40.10; -; 1.
DR InterPro; IPR006680; Amidohydro-rel.
DR InterPro; IPR011778; Hydantoinase/dihydroPyrase.
DR InterPro; IPR011059; Metal-dep_hydrolase_composite.
DR InterPro; IPR032466; Metal_Hydrolase.
DR Pfam; PF01979; Amidohydro_1; 1.
DR SUPFAM; SSF51338; SSF51338; 2.
DR SUPFAM; SSF51556; SSF51556; 1.
DR TIGRFAMs; TIGR02033; D-hydantoinase; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Disease variant; Hydrolase; Metal-binding; Phosphoprotein;
KW Reference proteome; Zinc.
FT CHAIN 1..519
FT /note="Dihydropyrimidinase"
FT /id="PRO_0000165906"
FT BINDING 67
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|Ref.5, ECO:0007744|PDB:2VR2"
FT BINDING 69
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|Ref.5, ECO:0007744|PDB:2VR2"
FT BINDING 159
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /note="via carbamate group"
FT /evidence="ECO:0000269|Ref.5, ECO:0007744|PDB:2VR2"
FT BINDING 159
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /note="via carbamate group"
FT /evidence="ECO:0000269|Ref.5, ECO:0007744|PDB:2VR2"
FT BINDING 164
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9P903"
FT BINDING 192
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|Ref.5, ECO:0007744|PDB:2VR2"
FT BINDING 248
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|Ref.5, ECO:0007744|PDB:2VR2"
FT BINDING 326
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|Ref.5, ECO:0007744|PDB:2VR2"
FT BINDING 347
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q9P903"
FT MOD_RES 79
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 159
FT /note="N6-carboxylysine"
FT /evidence="ECO:0000250"
FT MOD_RES 256
FT /note="N6-succinyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9EQF5"
FT MOD_RES 510
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9EQF6"
FT VARIANT 68
FT /note="T -> R (in DPYSD)"
FT /evidence="ECO:0000269|PubMed:9718352"
FT /id="VAR_002267"
FT VARIANT 334
FT /note="Q -> R (in DPYSD; dbSNP:rs121964923)"
FT /evidence="ECO:0000269|PubMed:9718352"
FT /id="VAR_002268"
FT VARIANT 360
FT /note="W -> R (in DPYSD; dbSNP:rs121964924)"
FT /evidence="ECO:0000269|PubMed:9718352"
FT /id="VAR_002269"
FT VARIANT 435
FT /note="G -> R (in DPYSD; dbSNP:rs267606773)"
FT /evidence="ECO:0000269|PubMed:9718352"
FT /id="VAR_002270"
FT VARIANT 490
FT /note="R -> T (in DPYSD)"
FT /evidence="ECO:0000269|PubMed:9718352"
FT /id="VAR_002271"
FT STRAND 6..11
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 13..15
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 20..22
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 24..28
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 31..36
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 50..53
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 57..61
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 63..68
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 75..78
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 85..91
FT /evidence="ECO:0007829|PDB:2VR2"
FT TURN 92..94
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 95..102
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 110..121
FT /evidence="ECO:0007829|PDB:2VR2"
FT TURN 122..124
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 126..135
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 140..151
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 157..164
FT /evidence="ECO:0007829|PDB:2VR2"
FT TURN 165..168
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 172..185
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 188..192
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 196..208
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 215..219
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 223..240
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 244..249
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 252..263
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 268..273
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 274..278
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 282..285
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 289..293
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 307..316
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 332..335
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 336..338
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 342..344
FT /evidence="ECO:0007829|PDB:2VR2"
FT TURN 352..354
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 355..363
FT /evidence="ECO:0007829|PDB:2VR2"
FT TURN 364..367
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 371..378
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 380..385
FT /evidence="ECO:0007829|PDB:2VR2"
FT TURN 389..391
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 403..413
FT /evidence="ECO:0007829|PDB:2VR2"
FT TURN 416..418
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 420..422
FT /evidence="ECO:0007829|PDB:2VR2"
FT TURN 427..430
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 432..442
FT /evidence="ECO:0007829|PDB:2VR2"
FT STRAND 445..449
FT /evidence="ECO:0007829|PDB:2VR2"
FT HELIX 470..482
FT /evidence="ECO:0007829|PDB:2VR2"
SQ SEQUENCE 519 AA; 56630 MW; 882E33D7C49D6ECC CRC64;
MAAPSRLLIR GGRVVNDDFS EVADVLVEDG VVRALGHDLL PPGGAPAGLR VLDAAGKLVL
PGGIDTHTHM QFPFMGSRSI DDFHQGTKAA LSGGTTMIID FAIPQKGGSL IEAFETWRSW
ADPKVCCDYS LHVAVTWWSD QVKEEMKILV QDKGVNSFKM FMAYKDLYMV TDLELYEAFS
RCKEIGAIAQ VHAENGDLIA EGAKKMLALG ITGPEGHELC RPEAVEAEAT LRAITIASAV
NCPLYIVHVM SKSAAKVIAD ARRDGKVVYG EPIAASLGTD GTHYWNKEWH HAAHHVMGPP
LRPDPSTPDF LMNLLANDDL TTTGTDNCTF NTCQKALGKD DFTKIPNGVN GVEDRMSVIW
EKGVHSGKMD ENRFVAVTST NAAKIFNLYP RKGRIAVGSD ADIVIWDPKG TRTISAKTHH
QAVNFNIFEG MVCHGVPLVT ISRGKVVYEA GVFSVTAGDG KFIPRKPFAE YIYKRIKQRD
RTCTPTPVER APYKGEVATL KSRVTKEDAT AGTRKQAHP
