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DPYD_HUMAN
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   03-AUG-2022, entry version 209.
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; 11.
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   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; Q12882; -.
DR   PeptideAtlas; Q12882; -.
DR   PRIDE; Q12882; -.
DR   ProteomicsDB; 20139; -.
DR   ProteomicsDB; 58999; -. [Q12882-1]
DR   Antibodypedia; 33674; 250 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   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   Orphanet; 240839; Prediction of 5-fluorouracil toxicity.
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; WPAIGKE; -.
DR   OrthoDB; 1261760at2759; -.
DR   PhylomeDB; Q12882; -.
DR   TreeFam; TF105791; -.
DR   BioCyc; MetaCyc:HS06975-MON; -.
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; 12 hits in 1070 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 188 other 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:0051536; F:iron-sulfur cluster binding; IBA:GO_Central.
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   Gene3D; 1.10.1060.10; -; 1.
DR   Gene3D; 3.20.20.70; -; 1.
DR   Gene3D; 3.50.50.60; -; 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.
DR   InterPro; IPR028261; DPD_II.
DR   InterPro; IPR044512; DPYD.
DR   InterPro; IPR036188; FAD/NAD-bd_sf.
DR   InterPro; IPR023753; FAD/NAD-binding_dom.
DR   InterPro; IPR009051; Helical_ferredxn.
DR   PANTHER; PTHR43073; PTHR43073; 1.
DR   Pfam; PF01180; DHO_dh; 1.
DR   Pfam; PF14691; Fer4_20; 1.
DR   Pfam; PF07992; Pyr_redox_2; 1.
DR   TIGRFAMs; TIGR01037; pyrD_sub1_fam; 1.
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
 
 
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