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Q28943 (DPYD_PIG) Reviewed, UniProtKB/Swiss-Prot

Last modified April 3, 2013. Version 110. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Dihydropyrimidine dehydrogenase [NADP(+)]
Short name=DHPDHase
Short name=DPD
EC=1.3.1.2
Alternative name(s):
Dihydrothymine dehydrogenase
Dihydrouracil dehydrogenase
Gene names
Name:DPYD
OrganismSus scrofa (Pig) [Reference proteome]
Taxonomic identifier9823 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Cetartiodactyla › Suina › Suidae › Sus

Protein attributes

Sequence length1025 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Involved in pyrimidine base degradation. Catalyzes the reduction of uracil and thymine. Ref.2 Ref.3 Ref.4

Catalytic activity

5,6-dihydrouracil + NADP+ = uracil + NADPH. Ref.2 Ref.3

Cofactor

Binds 4 4Fe-4S clusters. Contains approximately 16 iron atoms per subunit. Ref.2 Ref.3 Ref.4 Ref.5

FAD. Ref.2 Ref.3 Ref.4 Ref.5

FMN. Ref.2 Ref.3 Ref.4 Ref.5

Pathway

Amino-acid biosynthesis; beta-alanine biosynthesis.

Subunit structure

Homodimer. Ref.2 Ref.4

Subcellular location

Cytoplasm.

Sequence similarities

Belongs to the dihydropyrimidine dehydrogenase family.

Contains 3 4Fe-4S ferredoxin-type domains.

Ontologies

Keywords
   Cellular componentCytoplasm
   DomainRepeat
   Ligand4Fe-4S
FAD
FMN
Flavoprotein
Iron
Iron-sulfur
Metal-binding
NADP
Nucleotide-binding
   Molecular functionOxidoreductase
   PTMAcetylation
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processUMP biosynthetic process

Inferred from electronic annotation. Source: InterPro

beta-alanine biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-UniPathway

thymidine catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

uracil catabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_function4 iron, 4 sulfur cluster binding

Inferred from electronic annotation. Source: UniProtKB-KW

FMN binding

Inferred from direct assay Ref.2. Source: UniProtKB

NADP binding

Inferred from direct assay PubMed 11988088PubMed 8373446. Source: UniProtKB

dihydroorotate oxidase activity

Inferred from electronic annotation. Source: InterPro

dihydropyrimidine dehydrogenase (NADP+) activity

Inferred from direct assay PubMed 8373446Ref.2. Source: UniProtKB

flavin adenine dinucleotide binding

Inferred from direct assay PubMed 11988088. Source: UniProtKB

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein homodimerization activity

Inferred from direct assay PubMed 11988088PubMed 8373446. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Propeptide1 – 33
PRO_0000021116
Chain4 – 10251022Dihydropyrimidine dehydrogenase [NADP(+)]
PRO_0000021117

Regions

Domain69 – 100324Fe-4S ferredoxin-type 1
Domain944 – 976334Fe-4S ferredoxin-type 2
Domain978 – 1007304Fe-4S ferredoxin-type 3
Nucleotide binding194 – 1985FAD
Nucleotide binding218 – 2269FAD
Nucleotide binding340 – 3434NADP
Nucleotide binding364 – 3652NADP
Nucleotide binding437 – 4393NADP
Nucleotide binding480 – 48910FAD
Nucleotide binding481 – 4877NADP
Nucleotide binding574 – 5752FMN
Nucleotide binding793 – 7953FMN
Nucleotide binding816 – 8172FMN
Region668 – 6703Substrate binding
Region736 – 7372Substrate binding

Sites

Active site6711Proton acceptor Ref.5
Metal binding791Iron-sulfur 1 (4Fe-4S)
Metal binding821Iron-sulfur 1 (4Fe-4S)
Metal binding871Iron-sulfur 1 (4Fe-4S)
Metal binding911Iron-sulfur 2 (4Fe-4S)
Metal binding1301Iron-sulfur 2 (4Fe-4S)
Metal binding1361Iron-sulfur 2 (4Fe-4S)
Metal binding1401Iron-sulfur 1 (4Fe-4S)
Metal binding1561Iron-sulfur 2 (4Fe-4S)
Metal binding9531Iron-sulfur 3 (4Fe-4S)
Metal binding9561Iron-sulfur 3 (4Fe-4S)
Metal binding9591Iron-sulfur 3 (4Fe-4S)
Metal binding9631Iron-sulfur 3 (4Fe-4S)
Metal binding9861Iron-sulfur 4 (4Fe-4S)
Metal binding9891Iron-sulfur 4 (4Fe-4S)
Metal binding9921Iron-sulfur 4 (4Fe-4S)
Metal binding9961Iron-sulfur 4 (4Fe-4S)
Binding site1291FAD; via carbonyl oxygen
Binding site2351FAD
Binding site2611FAD; via amide nitrogen and carbonyl oxygen
Binding site3711NADP
Binding site5501FMN
Binding site6091Substrate
Binding site7091FMN
Binding site7671FMN; via amide nitrogen

Amino acid modifications

Modified residue3841N6-acetyllysine By similarity

Experimental info

Mutagenesis1261C → A: No effect on enzyme activity. Reduced iron content. Ref.3
Mutagenesis1561Q → E: Loss of enzyme activity. Reduces iron content. Ref.3
Mutagenesis2351R → A or K: Loss of enzyme activity. Loss of FAD binding. Ref.3
Mutagenesis6701S → A: Strongly reduced affinity for uracil. Reduces enzyme activity by 30%. Ref.3
Mutagenesis6711C → A: Reduces catalytic activity by 99%. Ref.2
Mutagenesis6731H → Q: Reduces activity by 50%.

Secondary structure

1 ...................................................................................................................................................................................... 1025
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q28943 [UniParc].

Last modified November 1, 1997. Version 1.
Checksum: B8D553AD862845D0

FASTA1,025111,424
        10         20         30         40         50         60 
MAPVLSKDVA DIESILALNP RTQSHAALHS TLAKKLDKKH WKRNPDKNCF HCEKLENNFG 

        70         80         90        100        110        120 
DIKHTTLGER GALREAMRCL KCADAPCQKS CPTHLDIKSF ITSISNKNYY GAAKMIFSDN 

       130        140        150        160        170        180 
PLGLTCGMVC PTSDLCVGGC NLYATEEGSI NIGGLQQFAS EVFKAMNIPQ IRNPCLPSQE 

       190        200        210        220        230        240 
KMPEAYSAKI ALLGAGPASI SCASFLARLG YSDITIFEKQ EYVGGLSTSE IPQFRLPYDV 

       250        260        270        280        290        300 
VNFEIELMKD LGVKIICGKS LSENEITLNT LKEEGYKAAF IGIGLPEPKT DDIFQGLTQD 

       310        320        330        340        350        360 
QGFYTSKDFL PLVAKSSKAG MCACHSPLPS IRGAVIVLGA GDTAFDCATS ALRCGARRVF 

       370        380        390        400        410        420 
LVFRKGFVNI RAVPEEVELA KEEKCEFLPF LSPRKVIVKG GRIVAVQFVR TEQDETGKWN 

       430        440        450        460        470        480 
EDEDQIVHLK ADVVISAFGS VLRDPKVKEA LSPIKFNRWD LPEVDPETMQ TSEPWVFAGG 

       490        500        510        520        530        540 
DIVGMANTTV ESVNDGKQAS WYIHKYIQAQ YGASVSAKPE LPLFYTPVDL VDISVEMAGL 

       550        560        570        580        590        600 
KFINPFGLAS AAPTTSSSMI RRAFEAGWGF ALTKTFSLDK DIVTNVSPRI VRGTTSGPMY 

       610        620        630        640        650        660 
GPGQSSFLNI ELISEKTAAY WCQSVTELKA DFPDNIVIAS IMCSYNKNDW MELSRKAEAS 

       670        680        690        700        710        720 
GADALELNLS CPHGMGERGM GLACGQDPEL VRNICRWVRQ AVQIPFFAKL TPNVTDIVSI 

       730        740        750        760        770        780 
ARAAKEGGAD GVTATNTVSG LMGLKADGTP WPAVGAGKRT TYGGVSGTAI RPIALRAVTT 

       790        800        810        820        830        840 
IARALPGFPI LATGGIDSAE SGLQFLHSGA SVLQVCSAVQ NQDFTVIQDY CTGLKALLYL 

       850        860        870        880        890        900 
KSIEELQGWD GQSPGTESHQ KGKPVPRIAE LMGKKLPNFG PYLEQRKKII AEEKMRLKEQ 

       910        920        930        940        950        960 
NAAFPPLERK PFIPKKPIPA IKDVIGKALQ YLGTFGELSN IEQVVAVIDE EMCINCGKCY 

       970        980        990       1000       1010       1020 
MTCNDSGYQA IQFDPETHLP TVTDTCTGCT LCLSVCPIID CIRMVSRTTP YEPKRGLPLA 


VNPVC

« Hide

References

[1]"cDNA cloning and chromosome mapping of human dihydropyrimidine dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and congenital thymine uraciluria."
Yokota H., Fernandez-Salguero P., Furuya H., Lin K., McBride O.W., Podschun B., Schnackerz K.D., Gonzalez F.J.
J. Biol. Chem. 269:23192-23196(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
Tissue: Liver.
[2]"Porcine recombinant dihydropyrimidine dehydrogenase: comparison of the spectroscopic and catalytic properties of the wild-type and C671A mutant enzymes."
Rosenbaum K., Jahnke K., Curti B., Hagen W.R., Schnackerz K.D., Vanoni M.A.
Biochemistry 37:17598-17609(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, COFACTOR, MUTAGENESIS OF CYS-671.
[3]"Insights into the mechanism of dihydropyrimidine dehydrogenase from site-directed mutagenesis targeting the active site loop and redox cofactor coordination."
Lohkamp B., Voevodskaya N., Lindqvist Y., Dobritzsch D.
Biochim. Biophys. Acta 1804:2198-2206(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, CATALYTIC ACTIVITY, COFACTOR, MUTAGENESIS OF CYS-126; GLN-156; ARG-235 AND SER-670.
[4]"Crystal structure of dihydropyrimidine dehydrogenase, a major determinant of the pharmacokinetics of the anti-cancer drug 5-fluorouracil."
Dobritzsch D., Schneider G., Schnackerz K.D., Lindqvist Y.
EMBO J. 20:650-660(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEXES WITH 5-FLUOROURACIL; FAD; FMN; 4FE-4S IRON-SULFUR CLUSTER AND NADP, FUNCTION, SUBUNIT, COFACTOR.
[5]"Crystal structure of the productive ternary complex of dihydropyrimidine dehydrogenase with NADPH and 5-iodouracil. Implications for mechanism of inhibition and electron transfer."
Dobritzsch D., Ricagno S., Schneider G., Schnackerz K.D., Lindqvist Y.
J. Biol. Chem. 277:13155-13166(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) IN COMPLEX WITH 5-IODOURACIL; FAD; FMN; 4FE-4S IRON-SULFUR CLUSTER AND NADP, COFACTOR, ACTIVE SITE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ		U09179 mRNA. Translation: AAA57475.1.
PIRB54718.
RefSeqNP_999209.1. NM_214044.2.
UniGeneSsc.153.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1GT8X-ray3.30A/B/C/D1-1025[»]
1GTEX-ray1.65A/B/C/D1-1025[»]
1GTHX-ray2.25A/B/C/D1-1025[»]
1H7WX-ray1.90A/B/C/D1-1025[»]
1H7XX-ray2.01A/B/C/D1-1025[»]
ProteinModelPortalQ28943.
SMRQ28943. Positions 2-1020.
ModBaseSearch...

Protein-protein interaction databases

STRING9823.ENSSSCP00000007333.

Proteomic databases

PaxDbQ28943.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID397109.
KEGGssc:397109.

Organism-specific databases

CTD1806.

Phylogenomic databases

eggNOGCOG0167.
HOGENOMHOG000007797.
HOVERGENHBG004351.
KOK00207.
OrthoDBEOG44J2H8.

Enzyme and pathway databases

UniPathwayUPA00131.

Family and domain databases

Gene3D1.10.1060.10. 1 hit.
3.20.20.70. 1 hit.
InterProIPR017896. 4Fe4S_Fe-S-bd.
IPR017900. 4Fe4S_Fe_S_CS.
IPR013785. Aldolase_TIM.
IPR005720. Dihydroorotate_DH.
IPR012135. Dihydroorotate_DH_1_2.
IPR012285. Fum_reductase_C.
IPR009051. Helical_ferredxn.
[Graphical view]
PfamPF01180. DHO_dh. 1 hit.
[Graphical view]
SUPFAMSSF46548. Helical_ferredxn. 1 hit.
TIGRFAMsTIGR01037. pyrD_sub1_fam. 1 hit.
PROSITEPS00198. 4FE4S_FER_1. 1 hit.
PS51379. 4FE4S_FER_2. 3 hits.
[Graphical view]
ProtoNetSearch...

Other

DrugBankDB00544. Fluorouracil.
EvolutionaryTraceQ28943.

Entry information

Entry nameDPYD_PIG
AccessionPrimary (citable) accession number: Q28943
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: November 1, 1997
Last modified: April 3, 2013
This is version 110 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

PATHWAY comments

Index of metabolic and biosynthesis pathways

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents