DPYS

Dihydropyrimidine dehydrogenase
250px Structure of dihydropyrimidine dehydrogenase
Identifiers
EC number	1.3.1.2
CAS number	9029-01-4
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

Dihydropyrimidine dehydrogenase (DPYD) is an enzyme that plays a crucial role in the catabolism of pyrimidine bases, specifically uracil and thymine. It is encoded by the DPYD gene in humans. This enzyme is a key component of the pyrimidine degradation pathway, which is essential for the proper metabolism and recycling of nucleotides.

Function

DPYD catalyzes the reduction of uracil and thymine to dihydrouracil and dihydrothymine, respectively. This reaction is the first and rate-limiting step in the catabolic pathway of pyrimidines. The enzyme uses NADPH as a cofactor to facilitate the reduction process. The activity of DPYD is crucial for maintaining the balance of pyrimidine nucleotides within the cell and for the detoxification of pyrimidine analog drugs.

Clinical significance

Mutations in the DPYD gene can lead to a deficiency in dihydropyrimidine dehydrogenase activity, resulting in a condition known as dihydropyrimidine dehydrogenase deficiency. This deficiency can cause a range of clinical symptoms, from neurological disorders to increased sensitivity to certain chemotherapeutic agents, such as 5-fluorouracil (5-FU) and capecitabine. Patients with DPYD deficiency may experience severe toxicity when treated with these drugs, as the impaired enzyme activity leads to the accumulation of toxic metabolites.

Genetics

The DPYD gene is located on chromosome 1p21.3. It consists of 23 exons and spans approximately 950 kilobases. Several polymorphisms and mutations have been identified in the DPYD gene, some of which are associated with reduced enzyme activity. The most common mutation associated with DPYD deficiency is the IVS14+1G>A splice site mutation, which leads to the skipping of exon 14 and results in a non-functional enzyme.

Testing and management

Genetic testing for DPYD mutations can be performed to identify individuals at risk for severe toxicity from fluoropyrimidine-based chemotherapy. Patients identified with DPYD deficiency may require dose adjustments or alternative therapies to avoid adverse effects. Management strategies include the use of reduced doses of 5-FU or the substitution with non-fluoropyrimidine chemotherapeutic agents.

Research directions

Ongoing research is focused on better understanding the structure and function of DPYD, as well as the development of more accurate and comprehensive genetic tests to predict fluoropyrimidine toxicity. Additionally, studies are exploring the potential for enzyme replacement therapies or other interventions to mitigate the effects of DPYD deficiency.

Also see

• Pyrimidine metabolism
• 5-Fluorouracil
• Pharmacogenomics
• Enzyme deficiency