Dihydropyrimidine dehydrogenase

Dihydropyrimidine dehydrogenase
Properties of human protein
Mass / length primary structure	1022 amino acids
Secondary to quaternary structure	Homodimer
Cofactor	FAD, FMN, ( 4Fe-4S )
Identifier
Gene name	DPYD
External IDs	OMIM : 274270 ; UniProt : Q12882 ;
Enzyme classification
EC, category	1.3.1.2 , oxidoreductase
Response type	Redox reaction
Substrate	5,6-dihydrouracil + NADP +
Products	Uracil + NADPH + H +
Occurrence
Parent taxon	Eukaryotes , bacteria
	Orthologue

The dihydropyrimidine dehydrogenase (DPD) is an enzyme from the group of oxidoreductases , comprising a step in the degradation of endogenous pyrimidines such as uracil and thymine catalyzed. In addition, it breaks down various cytostatics such as 5-fluorouracil (5-FU) and capecitabine . A hereditary disease, the DPD deficiency (E79 according to ICD-10), means that these cytostatics accumulate in the body during cancer therapy and can cause life-threatening poisoning. Blood tests for this genetic disorder are available commercially.

Catalyzed reactions

+ NADPH / H ⁺ + NADP ⁺ ${\ displaystyle \ rightleftharpoons}$

Uracil is hydrogenated to dihydrouracil .

+ NADPH / H ⁺ + NADP ⁺ ${\ displaystyle \ rightleftharpoons}$

Thymine is hydrogenated to 5,6-dihydrothymine .

The catalyzed reaction is reversible and rate-determining, that is, an equilibrium is established depending on the availability of the starting and end products. The enzyme is found in all eukaryotes, including the slime mold Dictyostelium , and in many bacteria. A close relative in plants is dihydroorotate reductase .

Importance and inhibition

In about 5% of the patients who received 5-fluorouracil as a cytostatic agent, severe symptoms of intoxication including cardiac arrhythmia occurred. Occasional deaths have been reported. The reason for these reactions is a genetic, reduced activity of the dihydropyrimidine dehydrogenase.

The enzyme is inhibited by various substances, among others

Bromovinyluracil , a breakdown product of the virostat brivudine (this is why the simultaneous administration of 5-FU or its precursors and brivudine can lead to dangerous interactions),
Uracil ,
Eniluracil .

Individual evidence

↑ S. Maurer, J. Thödtmann: The mammary carcinoma: diagnosis and therapy. Govi-Verlag, Eschborn, 2003, ISBN 978-3-7741-0996-4 .
↑ Uniprot entry
↑ H. Müller: Genetic tests: Answers to questions from medical practice. Karger Publishers, 2005, ISBN 978-3-8055-7820-2 .

Web links

Wikibooks: Pyrimidine Metabolism - Learning and Teaching Materials

reactome: uracil + NADPH + H + ⇒ 5,6-dihydrouracil + NADP +
reactome: thymine + NADPH + H + ⇒ 5,6-dihydrothymine + NADP +

[1] S. Maurer, J. Thödtmann: The mammary carcinoma: diagnosis and therapy. Govi-Verlag, Eschborn, 2003, ISBN 978-3-7741-0996-4 .

[2] Uniprot entry

[3] H. Müller: Genetic tests: Answers to questions from medical practice. Karger Publishers, 2005, ISBN 978-3-8055-7820-2 .