Skip Header

 
Contribute Send feedback

Reviewed, UniProtKB/Swiss-Prot Q12882 (DPYD_HUMAN)

Last modified November 25, 2008. Version 90. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Dihydropyrimidine dehydrogenase [NADP+]
      Short name=DHPDHase
      Short name=DPD
    EC=1.3.1.2
Alternative name(s):
    Dihydrouracil dehydrogenase
    Dihydrothymine dehydrogenase
Gene names
Name: DPYD
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

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. Also involved the degradation of the chemotherapeutic drug 5-fluorouracil.

Catalytic activity

5,6-dihydrouracil + NADP(+) = uracil + NADPH.

Cofactor

Binds 2 FAD.

Binds 2 FMN.

Binds 2 4Fe-4S clusters. Contains approximately 33 iron atoms per molecule.

Pathway

Amino-acid biosynthesis; beta-alanine biosynthesis.

Subunit structure

Homodimer.

Subcellular location

Cytoplasm.

Tissue specificity

Found in most tissues with greatest activity found in liver and peripheral blood mononuclear cells.

Involvement in disease

Defects in DPYD are the cause of dihydropyrimidine dehydrogenase deficiency (DPYD deficiency) [MIM:274270]; also known as hereditary thymine-uraciluria or familial pyrimidinemia. DPYD deficiency is a disease characterized by persistent urinary excretion of excessive amounts of uracil, thymine and 5-hydroxymethyluracil. Patients suffering from this disease show a severe reaction to the anticancer drug 5-fluorouracil. This reaction includes stomatitis, Leukopenia, thrombocytopenia, hair loss, diarrhea, fever, marked weight loss, cerebellar ataxia, and neurologic symptoms, progressing to semicoma.

Sequence similarities

Belongs to the dihydropyrimidine dehydrogenase family.

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

Ontologies

Keywords

   Cellular componentCytoplasm
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   DomainRepeat
   Ligand4Fe-4S
FAD
FMN
Flavoprotein
Iron
Iron-sulfur
Metal-binding
NADP
   Molecular functionOxidoreductase
   PTMPhosphoprotein
   Technical termDirect protein sequencing

Gene Ontology (GO)

   Biological process'de novo' pyrimidine base biosynthetic process

Inferred from electronic annotation. Source: InterPro

oxidation reduction

Inferred from electronic annotation. Source: UniProtKB-KW

purine base catabolic process

Inferred from mutant phenotype. Source: UniProtKB

thymidine catabolic process Ref.9

Inferred from direct assay. Source: UniProtKB

thymine catabolic process

Inferred from direct assay. Source: UniProtKB

uracil catabolic process Ref.9

Inferred from direct assay. Source: UniProtKB

   Cellular componentcytosol Ref.1

Inferred from direct assay. Source: UniProtKB

   Molecular function4 iron, 4 sulfur cluster binding

Inferred from electronic annotation. Source: UniProtKB-KW

FAD binding

Inferred from sequence or structural similarity. Source: UniProtKB

NADP binding

Inferred from sequence or structural similarity. Source: UniProtKB

dihydroorotate oxidase activity

Inferred from electronic annotation. Source: InterPro

dihydropyrimidine dehydrogenase (NADP+) activity Ref.1 Ref.9

Inferred from direct assay. Source: UniProtKB

dihydrouracil dehydrogenase (NAD+) activity Ref.1

Inferred from Experiment. Source: Reactome

electron carrier activity

Inferred from electronic annotation. Source: InterPro

iron ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein homodimerization activity Ref.9

Inferred from direct assay. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Propeptide1 – 33
PRO_0000021114
Chain4 – 10251022Dihydropyrimidine dehydrogenase [NADP+]
PRO_0000021115

Regions

Domain69 – 100324Fe-4S ferredoxin-type 1
Domain944 – 976334Fe-4S ferredoxin-type 2
Domain978 – 1007304Fe-4S ferredoxin-type 3
Nucleotide binding335 – 35117NADP Potential
Nucleotide binding471 – 48111FAD Potential
Region661 – 67818Uracil binding Potential

Sites

Metal binding9531Iron-sulfur 1 (4Fe-4S) Potential
Metal binding9561Iron-sulfur 1 (4Fe-4S) Potential
Metal binding9591Iron-sulfur 1 (4Fe-4S) Potential
Metal binding9631Iron-sulfur 1 (4Fe-4S) Potential
Metal binding9861Iron-sulfur 2 (4Fe-4S) Potential
Metal binding9891Iron-sulfur 2 (4Fe-4S) Potential
Metal binding9921Iron-sulfur 2 (4Fe-4S) Potential
Metal binding9961Iron-sulfur 2 (4Fe-4S) Potential

Amino acid modifications

Modified residue5771Phosphoserine

Natural variations

Natural variant291C → R in allele DPYD*9A and allele DPYD*9B; loss of activity. dbSNP rs1801265.
VAR_005173
Natural variant2351R → W in allele DPYD*8; loss of activity. dbSNP rs1801266.
VAR_005174
Natural variant5341S → N in allele DPYD*4; low activity. dbSNP rs1801158.
VAR_005175
Natural variant5431I → V in allele DPYD*5. dbSNP rs1801159.
VAR_005176
Natural variant7321V → I: dbSNP rs1801160.
VAR_014760
Natural variant8861R → H in allele DPYD*9B; 25% of activity. dbSNP rs1801267.
VAR_005177
Natural variant9951V → F in allele DPYD*10; low activity. dbSNP rs1801268.
VAR_005178

Experimental info

Sequence conflict8451E → G in BAF83906. Ref.4
Sequence conflict9101N → S in AAA57474. Ref.1
Sequence conflict10241V → G in AAI31779. Ref.6

Sequences

Sequence LengthMass (Da)Tools
Q12882-1 [UniParc].

Last modified November 13, 2007. Version 2.
Checksum: 0201943955AB2C21

FASTA1,025111,401
        10         20         30         40         50         60 
MAPVLSKDSA DIESILALNP RTQTHATLCS TSAKKLDKKH WKRNPDKNCF NCEKLENNFD 

        70         80         90        100        110        120 
DIKHTTLGER GALREAMRCL KCADAPCQKS CPTNLDIKSF ITSIANKNYY GAAKMIFSDN 

       130        140        150        160        170        180 
PLGLTCGMVC PTSDLCVGGC NLYATEEGPI NIGGLQQFAT EVFKAMSIPQ IRNPSLPPPE 

       190        200        210        220        230        240 
KMSEAYSAKI ALFGAGPASI SCASFLARLG YSDITIFEKQ EYVGGLSTSE IPQFRLPYDV 

       250        260        270        280        290        300 
VNFEIELMKD LGVKIICGKS LSVNEMTLST LKEKGYKAAF IGIGLPEPNK DAIFQGLTQD 

       310        320        330        340        350        360 
QGFYTSKDFL PLVAKGSKAG MCACHSPLPS IRGVVIVLGA GDTAFDCATS ALRCGARRVF 

       370        380        390        400        410        420 
IVFRKGFVNI RAVPEEMELA KEEKCEFLPF LSPRKVIVKG GRIVAMQFVR TEQDETGKWN 

       430        440        450        460        470        480 
EDEDQMVHLK ADVVISAFGS VLSDPKVKEA LSPIKFNRWG LPEVDPETMQ TSEAWVFAGG 

       490        500        510        520        530        540 
DVVGLANTTV ESVNDGKQAS WYIHKYVQSQ YGASVSAKPE LPLFYTPIDL VDISVEMAGL 

       550        560        570        580        590        600 
KFINPFGLAS ATPATSTSMI RRAFEAGWGF ALTKTFSLDK DIVTNVSPRI IRGTTSGPMY 

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

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

       730        740        750        760        770        780 
ARAAKEGGAN GVTATNTVSG LMGLKSDGTP WPAVGIAKRT TYGGVSGTAI RPIALRAVTS 

       790        800        810        820        830        840 
IARALPGFPI LATGGIDSAE SGLQFLHSGA SVLQVCSAIQ NQDFTVIEDY CTGLKALLYL 

       850        860        870        880        890        900 
KSIEELQDWD GQSPATVSHQ KGKPVPRIAE LMDKKLPSFG PYLEQRKKII AENKIRLKEQ 

       910        920        930        940        950        960 
NVAFSPLKRN CFIPKRPIPT IKDVIGKALQ YLGTFGELSN VEQVVAMIDE EMCINCGKCY 

       970        980        990       1000       1010       1020 
MTCNDSGYQA IQFDPETHLP TITDTCTGCT LCLSVCPIVD CIKMVSRTTP YEPKRGVPLS 


VNPVC 

« Hide

References

« Hide 'large scale' 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: 8083224] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
Tissue: Liver.
[2]"Structural organization of the human dihydropyrimidine dehydrogenase gene."
Johnson M.R., Wang K., Tillmanns S., Albin N., Diasio R.B.
Cancer Res. 57:1660-1663(1997) [PubMed: 9135003] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE.
[3]"Suicidal inactivation of human dihydropyrimidine dehydrogenase by (E)-5-(2-bromovinyl)uracil derived from the antiviral, sorivudine."
Ogura K., Nishiyama T., Takubo H., Kato A., Okuda H., Arakawa K., Fukushima M., Nagayama S., Kawaguchi Y., Watabe T.
Cancer Lett. 122:107-113(1998) [PubMed: 9464498] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT ARG-29.
[5]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed: 16710414] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS VAL-543 AND ILE-732.
[7]"A point mutation in an invariant splice donor site leads to exon skipping in two unrelated Dutch patients with dihydropyrimidine dehydrogenase deficiency."
Vreken P., van Kuilenburg A.B.P., Meinsma R., Smit G.P.A., Bakker H.D., de Abreu R.A., van Gennip A.H.
J. Inherit. Metab. Dis. 19:645-654(1996) [PubMed: 8892022] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 581-635.
Tissue: Liver.
[8]"Lack of correlation between phenotype and genotype for the polymorphically expressed dihydropyrimidine dehydrogenase in a family of Pakistani origin."
Fernandez-Salguero P.M., Sapone A., Wei X., Holt J.R., Jones S., Idle J.R., Gonzalez F.J.
Pharmacogenetics 7:161-163(1997) [PubMed: 9170156] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 581-635.
[9]"Purification and characterization of dihydropyrimidine dehydrogenase from human liver."
Lu Z.-H., Zhang R., Diasio R.B.
J. Biol. Chem. 267:17102-17109(1992) [PubMed: 1512248] [Abstract]
Cited for: CHARACTERIZATION, PARTIAL PROTEIN SEQUENCE.
Tissue: Liver.
[10]"Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column."
Imami K., Sugiyama N., Kyono Y., Tomita M., Ishihama Y.
Anal. Sci. 24:161-166(2008) [PubMed: 18187866] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-577, MASS SPECTROMETRY.
[11]"Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and expression of missense mutations C29R, R886H and R235W."
Vreken P., van Kuilenburg A.B.P., Meinsma R., van Gennip A.H.
Hum. Genet. 101:333-338(1997) [PubMed: 9439663] [Abstract]
Cited for: VARIANTS ARG-29; TRP-235 AND HIS-886.
[12]"Identification of novel point mutations in the dihydropyrimidine dehydrogenase gene."
Vreken P., van Kuilenburg A.B.P., Meinsma R., van Gennip A.H.
J. Inherit. Metab. Dis. 20:335-338(1997) [PubMed: 9266349] [Abstract]
Cited for: VARIANTS ARG-29; TRP-235 AND HIS-886.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

U09178 mRNA. Translation: AAA57474.1.
U20938 mRNA. Translation: AAB51366.1.
AB003063 mRNA. Translation: BAA89789.1.
AK291217 mRNA. Translation: BAF83906.1.
AC091608 Genomic DNA. No translation available.
BC131777 mRNA. Translation: AAI31778.1.
BC131778 mRNA. Translation: AAI31779.1.
X95670 Genomic DNA. Translation: CAA64973.1.
U57655 Genomic DNA. Translation: AAB07049.1.
PIRA54718.
RefSeqNP_000101.2.
UniGeneHs.335034

3D structure databases

HSSPHSSP built from PDB template 1GTE based on UniProtKB Q28943.
SMRQ12882. Positions 2-1017.
ModBaseSearch...

PTM databases

PhosphoSiteQ12882.

Genome annotation databases

EnsemblENSG00000188641. Homo sapiens. [Contig view]
GeneID1806.
KEGGhsa:1806.

Organism-specific databases

H-InvDBHIX0000804.
HGNCHGNC:3012. DPYD.
MIM274270. gene+phenotype.
Orphanet1675. Dihydropyrimidine dehydrogenase deficiency.
PharmGKBPA145.
GenAtlasSearch...
GeneCardsSearch...

Phylogenomic databases

HOGENOMQ12882.
HOVERGENQ12882.

Enzyme and pathway databases

ReactomeREACT_1698. Nucleotide metabolism.

Gene expression databases

ArrayExpressQ12882.
CleanEx