Dihydropyrimidine Dehydrogenase
Overview
Dihydropyrimidine dehydrogenase (DPD) is an enzyme that plays a crucial role in the metabolism of pyrimidine bases, which are essential components of nucleic acids. This enzyme is encoded by the DPYD gene in humans. It is the initial and rate-limiting factor in the pathway of pyrimidine catabolism, and its deficiency can lead to a variety of metabolic disorders.
Structure and Function
DPD is a large, tetrameric enzyme that is found in the liver and other tissues. It catalyzes the reduction of uracil and thymine, which are two of the four bases in DNA, to dihydrouracil and dihydrothymine, respectively. This is the first step in the catabolic pathway that eventually leads to the degradation of these bases to beta-alanine, beta-aminoisobutyrate and carbon dioxide.
The enzyme has a complex structure, with each subunit containing a FAD, a FMN and four iron-sulfur clusters. The FAD and FMN are involved in the electron transfer process, while the iron-sulfur clusters are involved in the binding of the substrate.
Clinical Significance
DPD deficiency is a rare autosomal recessive metabolic disorder that results in an inability to break down uracil and thymine. This leads to an accumulation of these bases in the body, which can cause a variety of symptoms, including developmental delay, seizures, and an increased risk of infections.
In addition, DPD is also important in the metabolism of certain chemotherapeutic drugs, such as 5-fluorouracil. Individuals with DPD deficiency can experience severe toxicity when treated with these drugs, as they are unable to effectively metabolize them. Therefore, testing for DPD activity is often performed prior to the administration of these drugs.
DPD and Chemotherapy
As mentioned above, DPD plays a crucial role in the metabolism of certain chemotherapeutic drugs. The enzyme is responsible for the degradation of 5-fluorouracil, a drug that is commonly used in the treatment of various types of cancer, including colorectal, breast, and stomach cancers.
In individuals with normal DPD activity, the drug is rapidly metabolized and excreted from the body. However, in individuals with DPD deficiency, the drug can accumulate to toxic levels, leading to severe side effects such as myelosuppression, neurotoxicity, and gastrointestinal toxicity.
Therefore, testing for DPD activity is often performed prior to the administration of 5-fluorouracil or other drugs that are metabolized by the enzyme. This can help to identify individuals who are at risk of drug toxicity and allow for dose adjustments to be made.