Center for Bioinformatics
Oxidoreductases | Transferases | Hydrolases | Lyases | Isomerases | Ligases

Basic Information

Enzyme Number

1.3.1.2

Official Name

dihydropyrimidine dehydrogenase (NADP+)

Name from literature

dihydropyrimidine dehydrogenase

Pathway from literature

5-fluorouracil (5-FU) chemotherapy catabolic pathway

Pathway from KEGG

Metabolism of Other Amino Acids; beta-Alanine metabolism; map00410

Xenobiotics Biodegradation and Metabolism; Drug metabolism - other enzymes; map00983

Nucleotide Metabolism; Pyrimidine metabolism; map00240

Organisms

Human (9606)

Genome localization

1p22[1806 ],

Comments

Also acts on dihydrothymine.

Rate-limiting Description

"In humans, 80-90% of an administered dose of 5-fluorouracil (5-FU) is degraded by dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), the initial rate-limiting enzyme in pyrimidine catabolism." (10473079)

"An alternate approach involves the inhibition of gastrointestinal degradation via coadministration of an inhibitor of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in 5-FU catabolism." (10887632)

"Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive molecule." (10853015)

Regulatory Information

Upstream transcription factor

6667;6670

Regulatory type

Detail

key enzyme;

"Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolic catabolism of chemotherapeutic agent 5-fluorouracil (5FU) and its derivatives, including capecitabine." (17350823)

transcriptional factor;"Sp1(6667),Sp3(6670)"

"Sp1 is a strong activator, while Sp3 by its own is a weak activator of the DPYD promoter." (16806531)

transcriptional factor;Sp1(6667)

"active transcription machinery for DPYD is present in RKO colorectal cancer cells, but promoter binding of Sp1, a transactivator of DPYD, was inhibited, which on subsequent examination was shown to be associated with dense promoter methylation" (17612628)

phosphorylation;

Q12882

phosphorylation;

Q12882:from_uniprot:577_Phosphoserine

Gene ontology

Gene ontology

GO:0050661 (F) NADP binding [Q12882 ];
GO:0050660 (F) FAD binding [Q12882 ];
GO:0006210 (P) thymine catabolic process [Q12882 ];
GO:0006145 (P) purine base catabolic process [Q12882 ];
GO:0006207 (P) 'de novo' pyrimidine base biosynthetic process [Q12882 ];
GO:0004159 (F) dihydrouracil dehydrogenase (NAD+) activity [Q12882 ];
GO:0042803 (F) protein homodimerization activity [Q12882 ];
GO:0051539 (F) 4 iron, 4 sulfur cluster binding [Q12882 ];
GO:0005829 (C) cytosol [Q12882 ];
GO:0005506 (F) iron ion binding [Q12882 ];
GO:0017113 (F) dihydropyrimidine dehydrogenase (NADP+) act... [Q12882 ];
GO:0004158 (F) dihydroorotate oxidase activity [Q12882 ];
GO:0009055 (F) electron carrier activity [Q12882 ];
GO:0006212 (P) uracil catabolic process [Q12882 ];
GO:0006214 (P) thymidine catabolic process [Q12882 ];
GO:0055114 (P) oxidation reduction [Q12882 ];

Tissue expression

Tissue From HPRD

Leukocyte [02036 ];
Intestine [02036 ];
Pancreas [02036 ];
Liver [02036 ];

Tissue specificity

Found in most tissues with greatest activity found in liver and peripheral blood mononuclear cells [Q12882 ];

Subcellular localization

Localization

cytoplasm [Q12882 ];

Disease relevance

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 [Q12882 ];

Links

SwissProt

Q12882

Entrez Gene

1806

HPRD

02036



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  Last Modified: 2009-03-24  
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