ID DPYD_HUMAN Reviewed; 1025 AA.
AC Q12882; A2RRQ2; A2RRQ3; A8K5A2; A8MWG9; B1AN21; E9PFN1; Q16694; Q16761;
AC Q32NB0; Q96HL6; Q96TH1;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 13-NOV-2007, sequence version 2.
DT 27-MAR-2024, entry version 218.
DE RecName: Full=Dihydropyrimidine dehydrogenase [NADP(+)] {ECO:0000305};
DE Short=DHPDHase;
DE Short=DPD;
DE EC=1.3.1.2 {ECO:0000269|PubMed:1512248};
DE AltName: Full=Dihydrothymine dehydrogenase;
DE AltName: Full=Dihydrouracil dehydrogenase;
DE Flags: Precursor;
GN Name=DPYD {ECO:0000312|HGNC:HGNC:3012};
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] (ISOFORM 1), CATALYTIC ACTIVITY, FUNCTION, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Liver;
RX PubMed=8083224; DOI=10.1016/s0021-9258(17)31638-1;
RA Yokota H., Fernandez-Salguero P., Furuya H., Lin K., McBride O.W.,
RA Podschun B., Schnackerz K.D., Gonzalez F.J.;
RT "cDNA cloning and chromosome mapping of human dihydropyrimidine
RT dehydrogenase, an enzyme associated with 5-fluorouracil toxicity and
RT congenital thymine uraciluria.";
RL J. Biol. Chem. 269:23192-23196(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9135003;
RA Johnson M.R., Wang K., Tillmanns S., Albin N., Diasio R.B.;
RT "Structural organization of the human dihydropyrimidine dehydrogenase
RT gene.";
RL Cancer Res. 57:1660-1663(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=9464498; DOI=10.1016/s0304-3835(97)00377-7;
RA Ogura K., Nishiyama T., Takubo H., Kato A., Okuda H., Arakawa K.,
RA Fukushima M., Nagayama S., Kawaguchi Y., Watabe T.;
RT "Suicidal inactivation of human dihydropyrimidine dehydrogenase by (E)-5-
RT (2-bromovinyl)uracil derived from the antiviral, sorivudine.";
RL Cancer Lett. 122:107-113(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT DPYDD
RP ARG-29.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT DPYDD ARG-29.
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANTS
RP VAL-543 AND ILE-732.
RC TISSUE=Skin, and Uterus;
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 [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 581-635.
RC TISSUE=Liver;
RX PubMed=8892022; DOI=10.1007/bf01799841;
RA Vreken P., van Kuilenburg A.B.P., Meinsma R., Smit G.P.A., Bakker H.D.,
RA de Abreu R.A., van Gennip A.H.;
RT "A point mutation in an invariant splice donor site leads to exon skipping
RT in two unrelated Dutch patients with dihydropyrimidine dehydrogenase
RT deficiency.";
RL J. Inherit. Metab. Dis. 19:645-654(1996).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 581-635.
RX PubMed=9170156; DOI=10.1097/00008571-199704000-00012;
RA Fernandez-Salguero P.M., Sapone A., Wei X., Holt J.R., Jones S., Idle J.R.,
RA Gonzalez F.J.;
RT "Lack of correlation between phenotype and genotype for the polymorphically
RT expressed dihydropyrimidine dehydrogenase in a family of Pakistani
RT origin.";
RL Pharmacogenetics 7:161-163(1997).
RN [11]
RP PARTIAL PROTEIN SEQUENCE, FUNCTION, CATALYTIC ACTIVITY, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Liver;
RX PubMed=1512248; DOI=10.1016/s0021-9258(18)41899-6;
RA Lu Z.-H., Zhang R., Diasio R.B.;
RT "Purification and characterization of dihydropyrimidine dehydrogenase from
RT human liver.";
RL J. Biol. Chem. 267:17102-17109(1992).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-384, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-905, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [15]
RP IDENTIFICATION BY 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 [16]
RP VARIANTS DPYDD ARG-29; TRP-235 AND HIS-886.
RX PubMed=9439663; DOI=10.1007/s004390050637;
RA Vreken P., van Kuilenburg A.B.P., Meinsma R., van Gennip A.H.;
RT "Dihydropyrimidine dehydrogenase (DPD) deficiency: identification and
RT expression of missense mutations C29R, R886H and R235W.";
RL Hum. Genet. 101:333-338(1997).
RN [17]
RP VARIANTS DPYDD ARG-29; TRP-235 AND HIS-886.
RX PubMed=9266349; DOI=10.1023/a:1005357307122;
RA Vreken P., van Kuilenburg A.B.P., Meinsma R., van Gennip A.H.;
RT "Identification of novel point mutations in the dihydropyrimidine
RT dehydrogenase gene.";
RL J. Inherit. Metab. Dis. 20:335-338(1997).
RN [18]
RP VARIANTS ASN-534 AND VAL-543.
RX PubMed=9472650; DOI=10.1038/bjc.1998.79;
RA Ridge S.A., Sludden J., Wei X., Sapone A., Brown O., Hardy S., Canney P.,
RA Fernandez-Salguero P., Gonzalez F.J., Cassidy J., McLeod H.L.;
RT "Dihydropyrimidine dehydrogenase pharmacogenetics in patients with
RT colorectal cancer.";
RL Br. J. Cancer 77:497-500(1998).
RN [19]
RP VARIANTS ASN-534; VAL-543 AND ILE-732.
RX PubMed=9723824; DOI=10.1046/j.1365-2125.1998.00751.x;
RA Ridge S.A., Sludden J., Brown O., Robertson L., Wei X., Sapone A.,
RA Fernandez-Salguero P.M., Gonzalez F.J., Vreken P., van Kuilenburg A.B.,
RA van Gennip A.H., McLeod H.L.;
RT "Dihydropyrimidine dehydrogenase pharmacogenetics in Caucasian subjects.";
RL Br. J. Clin. Pharmacol. 46:151-156(1998).
RN [20]
RP VARIANT [LARGE SCALE ANALYSIS] ARG-29.
RX PubMed=18987736; DOI=10.1038/nature07485;
RA Ley T.J., Mardis E.R., Ding L., Fulton B., McLellan M.D., Chen K.,
RA Dooling D., Dunford-Shore B.H., McGrath S., Hickenbotham M., Cook L.,
RA Abbott R., Larson D.E., Koboldt D.C., Pohl C., Smith S., Hawkins A.,
RA Abbott S., Locke D., Hillier L.W., Miner T., Fulton L., Magrini V.,
RA Wylie T., Glasscock J., Conyers J., Sander N., Shi X., Osborne J.R.,
RA Minx P., Gordon D., Chinwalla A., Zhao Y., Ries R.E., Payton J.E.,
RA Westervelt P., Tomasson M.H., Watson M., Baty J., Ivanovich J., Heath S.,
RA Shannon W.D., Nagarajan R., Walter M.J., Link D.C., Graubert T.A.,
RA DiPersio J.F., Wilson R.K.;
RT "DNA sequencing of a cytogenetically normal acute myeloid leukaemia
RT genome.";
RL Nature 456:66-72(2008).
CC -!- FUNCTION: Involved in pyrimidine base degradation (PubMed:1512248).
CC Catalyzes the reduction of uracil and thymine (PubMed:1512248). Also
CC involved the degradation of the chemotherapeutic drug 5-fluorouracil
CC (PubMed:1512248). {ECO:0000269|PubMed:1512248}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5,6-dihydrouracil + NADP(+) = H(+) + NADPH + uracil;
CC Xref=Rhea:RHEA:18093, ChEBI:CHEBI:15378, ChEBI:CHEBI:15901,
CC ChEBI:CHEBI:17568, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.3.1.2;
CC Evidence={ECO:0000269|PubMed:1512248};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18095;
CC Evidence={ECO:0000305|PubMed:1512248};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5,6-dihydrothymine + NADP(+) = H(+) + NADPH + thymine;
CC Xref=Rhea:RHEA:58284, ChEBI:CHEBI:15378, ChEBI:CHEBI:17821,
CC ChEBI:CHEBI:27468, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.3.1.2;
CC Evidence={ECO:0000269|PubMed:1512248};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:58286;
CC Evidence={ECO:0000305|PubMed:1512248};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:Q28943};
CC Note=Binds 2 FAD. {ECO:0000250|UniProtKB:Q28943};
CC -!- COFACTOR:
CC Name=FMN; Xref=ChEBI:CHEBI:58210;
CC Evidence={ECO:0000250|UniProtKB:Q28943};
CC Note=Binds 2 FMN. {ECO:0000250|UniProtKB:Q28943};
CC -!- COFACTOR:
CC Name=[4Fe-4S] cluster; Xref=ChEBI:CHEBI:49883;
CC Evidence={ECO:0000250|UniProtKB:Q28943};
CC Note=Binds 4 [4Fe-4S] clusters. Contains approximately 16 iron atoms
CC per subunit. {ECO:0000250|UniProtKB:Q28943};
CC -!- ACTIVITY REGULATION: Inactivated by 5-iodouracil.
CC {ECO:0000250|UniProtKB:Q28943}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=4.9 uM for uracil {ECO:0000269|PubMed:1512248};
CC KM=4.8 uM for thymine {ECO:0000269|PubMed:1512248};
CC KM=3.3 uM for 5-fluorouracil {ECO:0000269|PubMed:1512248};
CC KM=9.6 uM for NADPH (with uracil) {ECO:0000269|PubMed:1512248};
CC KM=15.8 uM for NADPH (with thymine) {ECO:0000269|PubMed:1512248};
CC KM=10.1 uM for NADPH (with 5-fluorouracil)
CC {ECO:0000269|PubMed:1512248};
CC Vmax=0.6 umol/min/mg enzyme for uracil {ECO:0000269|PubMed:1512248};
CC Vmax=0.7 umol/min/mg enzyme for thymine {ECO:0000269|PubMed:1512248};
CC Vmax=0.9 umol/min/mg enzyme for 5-fluorouracil
CC {ECO:0000269|PubMed:1512248};
CC -!- PATHWAY: Amino-acid biosynthesis; beta-alanine biosynthesis.
CC {ECO:0000269|PubMed:1512248}.
CC -!- SUBUNIT: Homodimer.
CC -!- INTERACTION:
CC Q12882; Q9HD26: GOPC; NbExp=3; IntAct=EBI-2839838, EBI-349832;
CC Q12882; Q9BS40: LXN; NbExp=3; IntAct=EBI-2839838, EBI-1044504;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q12882-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q12882-2; Sequence=VSP_044929, VSP_044930;
CC -!- TISSUE SPECIFICITY: Found in most tissues with greatest activity found
CC in liver and peripheral blood mononuclear cells.
CC -!- DISEASE: Dihydropyrimidine dehydrogenase deficiency (DPYDD)
CC [MIM:274270]: A metabolic disorder with large phenotypic variability,
CC ranging from no symptoms to a convulsive disorder with motor and
CC intellectual disability. It is characterized by persistent urinary
CC excretion of excessive amounts of uracil, thymine and 5-
CC hydroxymethyluracil. Patients suffering from this disease show a severe
CC reaction to the anticancer drug 5-fluorouracil.
CC {ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:16710414,
CC ECO:0000269|PubMed:9266349, ECO:0000269|PubMed:9439663}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the dihydropyrimidine dehydrogenase family.
CC {ECO:0000305}.
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DR EMBL; U09178; AAA57474.1; -; mRNA.
DR EMBL; U20938; AAB51366.1; -; mRNA.
DR EMBL; AB003063; BAA89789.1; -; mRNA.
DR EMBL; BT006740; AAP35386.1; -; mRNA.
DR EMBL; AK291217; BAF83906.1; -; mRNA.
DR EMBL; AC091608; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC093576; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC099787; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC114878; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC138135; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL356457; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BX908805; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471097; EAW73002.1; -; Genomic_DNA.
DR EMBL; BC008379; AAH08379.1; -; mRNA.
DR EMBL; BC064027; AAH64027.1; -; mRNA.
DR EMBL; BC108742; AAI08743.1; -; mRNA.
DR EMBL; BC131777; AAI31778.1; -; mRNA.
DR EMBL; BC131778; AAI31779.1; -; mRNA.
DR EMBL; X95670; CAA64973.1; -; Genomic_DNA.
DR EMBL; U57655; AAB07049.1; -; Genomic_DNA.
DR CCDS; CCDS30777.1; -. [Q12882-1]
DR CCDS; CCDS53346.1; -. [Q12882-2]
DR PIR; A54718; A54718.
DR RefSeq; NP_000101.2; NM_000110.3. [Q12882-1]
DR RefSeq; NP_001153773.1; NM_001160301.1. [Q12882-2]
DR AlphaFoldDB; Q12882; -.
DR SMR; Q12882; -.
DR BioGRID; 108140; 15.
DR IntAct; Q12882; 21.
DR STRING; 9606.ENSP00000359211; -.
DR BindingDB; Q12882; -.
DR ChEMBL; CHEMBL3172; -.
DR DrugBank; DB02303; (5S)-5-Iododihydro-2,4(1H,3H)-pyrimidinedione.
DR DrugBank; DB03554; 5-Iodouracil.
DR DrugBank; DB03048; 6-Carboxymethyluracil.
DR DrugBank; DB01101; Capecitabine.
DR DrugBank; DB03516; Eniluracil.
DR DrugBank; DB03147; Flavin adenine dinucleotide.
DR DrugBank; DB03247; Flavin mononucleotide.
DR DrugBank; DB00544; Fluorouracil.
DR DrugBank; DB09257; Gimeracil.
DR DrugBank; DB02338; NADPH.
DR DrugBank; DB09327; Tegafur-uracil.
DR DrugBank; DB03419; Uracil.
DR DrugCentral; Q12882; -.
DR CarbonylDB; Q12882; -.
DR GlyGen; Q12882; 3 sites, 1 O-linked glycan (3 sites).
DR iPTMnet; Q12882; -.
DR MetOSite; Q12882; -.
DR PhosphoSitePlus; Q12882; -.
DR BioMuta; DPYD; -.
DR DMDM; 160332325; -.
DR EPD; Q12882; -.
DR jPOST; Q12882; -.
DR MassIVE; Q12882; -.
DR MaxQB; Q12882; -.
DR PaxDb; 9606-ENSP00000359211; -.
DR PeptideAtlas; Q12882; -.
DR ProteomicsDB; 20139; -.
DR ProteomicsDB; 58999; -. [Q12882-1]
DR Pumba; Q12882; -.
DR Antibodypedia; 33674; 290 antibodies from 34 providers.
DR DNASU; 1806; -.
DR Ensembl; ENST00000306031.5; ENSP00000307107.5; ENSG00000188641.14. [Q12882-2]
DR Ensembl; ENST00000370192.8; ENSP00000359211.3; ENSG00000188641.14. [Q12882-1]
DR GeneID; 1806; -.
DR KEGG; hsa:1806; -.
DR MANE-Select; ENST00000370192.8; ENSP00000359211.3; NM_000110.4; NP_000101.2.
DR UCSC; uc001drv.4; human. [Q12882-1]
DR AGR; HGNC:3012; -.
DR CTD; 1806; -.
DR DisGeNET; 1806; -.
DR GeneCards; DPYD; -.
DR HGNC; HGNC:3012; DPYD.
DR HPA; ENSG00000188641; Tissue enhanced (liver).
DR MalaCards; DPYD; -.
DR MIM; 274270; phenotype.
DR MIM; 612779; gene.
DR neXtProt; NX_Q12882; -.
DR OpenTargets; ENSG00000188641; -.
DR Orphanet; 293948; 1p21.3 microdeletion syndrome.
DR Orphanet; 1675; Dihydropyrimidine dehydrogenase deficiency.
DR PharmGKB; PA145; -.
DR VEuPathDB; HostDB:ENSG00000188641; -.
DR eggNOG; KOG1799; Eukaryota.
DR GeneTree; ENSGT00500000044896; -.
DR HOGENOM; CLU_003991_0_0_1; -.
DR InParanoid; Q12882; -.
DR OMA; SIHCQLQ; -.
DR OrthoDB; 1211169at2759; -.
DR PhylomeDB; Q12882; -.
DR TreeFam; TF105791; -.
DR BioCyc; MetaCyc:HS06975-MONOMER; -.
DR BRENDA; 1.3.1.2; 2681.
DR PathwayCommons; Q12882; -.
DR Reactome; R-HSA-73621; Pyrimidine catabolism.
DR SignaLink; Q12882; -.
DR SIGNOR; Q12882; -.
DR UniPathway; UPA00131; -.
DR BioGRID-ORCS; 1806; 15 hits in 1150 CRISPR screens.
DR ChiTaRS; DPYD; human.
DR GeneWiki; DPYD; -.
DR GenomeRNAi; 1806; -.
DR Pharos; Q12882; Tclin.
DR PRO; PR:Q12882; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q12882; Protein.
DR Bgee; ENSG00000188641; Expressed in germinal epithelium of ovary and 190 other cell types or tissues.
DR Genevisible; Q12882; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0051539; F:4 iron, 4 sulfur cluster binding; IEA:UniProtKB-KW.
DR GO; GO:0017113; F:dihydropyrimidine dehydrogenase (NADP+) activity; IDA:UniProtKB.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0050661; F:NADP binding; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0002058; F:uracil binding; IBA:GO_Central.
DR GO; GO:0019483; P:beta-alanine biosynthetic process; IEA:UniProtKB-UniPathway.
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:0006145; P:purine nucleobase catabolic process; IMP:UniProtKB.
DR GO; GO:0006208; P:pyrimidine nucleobase catabolic process; IMP:UniProtKB.
DR GO; GO:0006214; P:thymidine catabolic process; IDA:UniProtKB.
DR GO; GO:0006210; P:thymine catabolic process; IDA:UniProtKB.
DR GO; GO:0046050; P:UMP catabolic process; IEA:Ensembl.
DR GO; GO:0006212; P:uracil catabolic process; IDA:UniProtKB.
DR CDD; cd02940; DHPD_FMN; 1.
DR Gene3D; 3.30.70.20; -; 1.
DR Gene3D; 3.20.20.70; Aldolase class I; 1.
DR Gene3D; 1.10.1060.10; Alpha-helical ferredoxin; 1.
DR Gene3D; 3.50.50.60; FAD/NAD(P)-binding domain; 2.
DR InterPro; IPR017896; 4Fe4S_Fe-S-bd.
DR InterPro; IPR017900; 4Fe4S_Fe_S_CS.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR005720; Dihydroorotate_DH_cat.
DR InterPro; IPR028261; DPD_II.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR023753; FAD/NAD-binding_dom.
DR InterPro; IPR009051; Helical_ferredxn.
DR PANTHER; PTHR43073; DIHYDROPYRIMIDINE DEHYDROGENASE [NADP(+)]; 1.
DR PANTHER; PTHR43073:SF2; DIHYDROPYRIMIDINE DEHYDROGENASE [NADP(+)]; 1.
DR Pfam; PF01180; DHO_dh; 1.
DR Pfam; PF14691; Fer4_20; 1.
DR Pfam; PF14697; Fer4_21; 1.
DR Pfam; PF07992; Pyr_redox_2; 1.
DR PRINTS; PR00419; ADXRDTASE.
DR SUPFAM; SSF54862; 4Fe-4S ferredoxins; 1.
DR SUPFAM; SSF46548; alpha-helical ferredoxin; 1.
DR SUPFAM; SSF51395; FMN-linked oxidoreductases; 1.
DR SUPFAM; SSF51971; Nucleotide-binding domain; 2.
DR PROSITE; PS00198; 4FE4S_FER_1; 1.
DR PROSITE; PS51379; 4FE4S_FER_2; 3.
PE 1: Evidence at protein level;
KW 4Fe-4S; Acetylation; Alternative splicing; Cytoplasm;
KW Direct protein sequencing; Disease variant; FAD; Flavoprotein; FMN; Iron;
KW Iron-sulfur; Metal-binding; NADP; Nucleotide-binding; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Repeat.
FT PROPEP 1..3
FT /id="PRO_0000021114"
FT CHAIN 4..1025
FT /note="Dihydropyrimidine dehydrogenase [NADP(+)]"
FT /id="PRO_0000021115"
FT DOMAIN 69..100
FT /note="4Fe-4S ferredoxin-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00711"
FT DOMAIN 944..976
FT /note="4Fe-4S ferredoxin-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00711"
FT DOMAIN 978..1007
FT /note="4Fe-4S ferredoxin-type 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00711"
FT ACT_SITE 671
FT /note="Proton acceptor"
FT /evidence="ECO:0000250"
FT BINDING 79
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 82
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 87
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 91
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 129
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 130
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 136
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 140
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="1"
FT /evidence="ECO:0000250"
FT BINDING 156
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="2"
FT /evidence="ECO:0000250"
FT BINDING 194..198
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 218..226
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 235
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 261
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 340..343
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 364..365
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 371
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 437..439
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 480..489
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250"
FT BINDING 481..487
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 550
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250"
FT BINDING 574..575
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250"
FT BINDING 609
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 668..670
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 709
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250"
FT BINDING 736..737
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 767
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250"
FT BINDING 793..795
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250"
FT BINDING 816..817
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000250"
FT BINDING 953
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 956
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 959
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 963
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="3"
FT /evidence="ECO:0000250"
FT BINDING 986
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="4"
FT /evidence="ECO:0000250"
FT BINDING 989
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="4"
FT /evidence="ECO:0000250"
FT BINDING 992
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="4"
FT /evidence="ECO:0000250"
FT BINDING 996
FT /ligand="[4Fe-4S] cluster"
FT /ligand_id="ChEBI:CHEBI:49883"
FT /ligand_label="4"
FT /evidence="ECO:0000250"
FT MOD_RES 384
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:19608861"
FT MOD_RES 905
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 162..173
FT /note="VFKAMSIPQIRN -> TLILAFSLMNHL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.4"
FT /id="VSP_044929"
FT VAR_SEQ 174..1025
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.4"
FT /id="VSP_044930"
FT VARIANT 29
FT /note="C -> R (in DPYDD; allele DPYD*9A and allele DPYD*9B;
FT loss of activity; dbSNP:rs1801265)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:16710414, ECO:0000269|PubMed:18987736,
FT ECO:0000269|PubMed:9266349, ECO:0000269|PubMed:9439663"
FT /id="VAR_005173"
FT VARIANT 166
FT /note="M -> V (in dbSNP:rs2297595)"
FT /id="VAR_054034"
FT VARIANT 235
FT /note="R -> W (in DPYDD; allele DPYD*8; loss of activity;
FT dbSNP:rs1801266)"
FT /evidence="ECO:0000269|PubMed:9266349,
FT ECO:0000269|PubMed:9439663"
FT /id="VAR_005174"
FT VARIANT 534
FT /note="S -> N (in allele DPYD*4; dbSNP:rs1801158)"
FT /evidence="ECO:0000269|PubMed:9472650,
FT ECO:0000269|PubMed:9723824"
FT /id="VAR_005175"
FT VARIANT 543
FT /note="I -> V (in allele DPYD*5; dbSNP:rs1801159)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:9472650, ECO:0000269|PubMed:9723824"
FT /id="VAR_005176"
FT VARIANT 732
FT /note="V -> I (in dbSNP:rs1801160)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:9723824"
FT /id="VAR_014760"
FT VARIANT 886
FT /note="R -> H (in DPYDD; allele DPYD*9B; 25% of activity;
FT dbSNP:rs1801267)"
FT /evidence="ECO:0000269|PubMed:9266349,
FT ECO:0000269|PubMed:9439663"
FT /id="VAR_005177"
FT VARIANT 995
FT /note="V -> F (in allele DPYD*10; low activity;
FT dbSNP:rs1801268)"
FT /id="VAR_005178"
FT CONFLICT 131
FT /note="P -> S (in Ref. 6; AAI08743)"
FT /evidence="ECO:0000305"
FT CONFLICT 845
FT /note="E -> G (in Ref. 5; BAF83906)"
FT /evidence="ECO:0000305"
FT CONFLICT 910
FT /note="N -> S (in Ref. 1; AAA57474)"
FT /evidence="ECO:0000305"
FT CONFLICT 1024
FT /note="V -> G (in Ref. 8; AAI31779)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1025 AA; 111401 MW; 0201943955AB2C21 CRC64;
MAPVLSKDSA DIESILALNP RTQTHATLCS TSAKKLDKKH WKRNPDKNCF NCEKLENNFD
DIKHTTLGER GALREAMRCL KCADAPCQKS CPTNLDIKSF ITSIANKNYY GAAKMIFSDN
PLGLTCGMVC PTSDLCVGGC NLYATEEGPI NIGGLQQFAT EVFKAMSIPQ IRNPSLPPPE
KMSEAYSAKI ALFGAGPASI SCASFLARLG YSDITIFEKQ EYVGGLSTSE IPQFRLPYDV
VNFEIELMKD LGVKIICGKS LSVNEMTLST LKEKGYKAAF IGIGLPEPNK DAIFQGLTQD
QGFYTSKDFL PLVAKGSKAG MCACHSPLPS IRGVVIVLGA GDTAFDCATS ALRCGARRVF
IVFRKGFVNI RAVPEEMELA KEEKCEFLPF LSPRKVIVKG GRIVAMQFVR TEQDETGKWN
EDEDQMVHLK ADVVISAFGS VLSDPKVKEA LSPIKFNRWG LPEVDPETMQ TSEAWVFAGG
DVVGLANTTV ESVNDGKQAS WYIHKYVQSQ YGASVSAKPE LPLFYTPIDL VDISVEMAGL
KFINPFGLAS ATPATSTSMI RRAFEAGWGF ALTKTFSLDK DIVTNVSPRI IRGTTSGPMY
GPGQSSFLNI ELISEKTAAY WCQSVTELKA DFPDNIVIAS IMCSYNKNDW TELAKKSEDS
GADALELNLS CPHGMGERGM GLACGQDPEL VRNICRWVRQ AVQIPFFAKL TPNVTDIVSI
ARAAKEGGAN GVTATNTVSG LMGLKSDGTP WPAVGIAKRT TYGGVSGTAI RPIALRAVTS
IARALPGFPI LATGGIDSAE SGLQFLHSGA SVLQVCSAIQ NQDFTVIEDY CTGLKALLYL
KSIEELQDWD GQSPATVSHQ KGKPVPRIAE LMDKKLPSFG PYLEQRKKII AENKIRLKEQ
NVAFSPLKRN CFIPKRPIPT IKDVIGKALQ YLGTFGELSN VEQVVAMIDE EMCINCGKCY
MTCNDSGYQA IQFDPETHLP TITDTCTGCT LCLSVCPIVD CIKMVSRTTP YEPKRGVPLS
VNPVC
//
