Dihydropyrimidine dehydrogenase

Dihydropyrimidine Dehydrogenase

Dihydropyrimidine dehydrogenase (DPD) is an enzyme that plays a crucial role in the catabolism of pyrimidine bases, such as uracil and thymine. It is encoded by the DPYD gene in humans. DPD is a key enzyme in the metabolic pathway that breaks down these pyrimidines, which are essential components of nucleic acids.

Function

DPD catalyzes the reduction of uracil and thymine to dihydrouracil and dihydrothymine, respectively. This reaction is the first and rate-limiting step in the degradation of pyrimidines. The enzyme uses NADPH as a cofactor in this reduction process.

Clinical Significance

DPD deficiency can lead to a variety of clinical manifestations, ranging from asymptomatic to severe neurological disorders. One of the most significant implications of DPD deficiency is its impact on the metabolism of the chemotherapeutic drug 5-fluorouracil (5-FU). Patients with reduced DPD activity may experience severe toxicity when treated with 5-FU, as the drug is not adequately metabolized and cleared from the body.

DPD Deficiency

DPD deficiency is a rare autosomal recessive metabolic disorder. It can be diagnosed through genetic testing for mutations in the DPYD gene or by measuring the enzyme activity in peripheral blood mononuclear cells. Symptoms of DPD deficiency can include developmental delay, seizures, and intellectual disability.

Pharmacogenomics

The pharmacogenomics of DPD is an important area of study, particularly in the context of cancer treatment. Genetic variations in the DPYD gene can lead to reduced enzyme activity and increased risk of 5-FU toxicity. Testing for these genetic variants can help guide dosing and treatment decisions in patients undergoing chemotherapy.

Structure

DPD is a large enzyme composed of multiple subunits. It contains several cofactors, including flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and iron-sulfur clusters, which are essential for its catalytic activity.

Research

Ongoing research is focused on better understanding the genetic basis of DPD deficiency and developing strategies to mitigate the risks associated with 5-FU treatment. Studies are also exploring the role of DPD in other metabolic pathways and its potential implications in various diseases.

See Also

• Pyrimidine metabolism
• 5-fluorouracil
• Pharmacogenomics

References

• Van Kuilenburg, A. B. P., & Meinsma, R. (2016). Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil.
• Johnson, M. R., & Diasio, R. B. (2001). Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance.