Dihydropyrimidinase

Dihydropyrimidinase (DHPase) is a zinc-dependent metalloenzyme that participates in the catabolism of pyrimidines. Belonging to the amidohydrolase superfamily, it hydrolyzes the saturated rings of 5,6-dihydropyrimidines produced from uracil and thymine. In most organisms, its substrates include 5,6-dihydrouracil and 5,6-dihydrothymine, which it converts to N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyrate, respectively. The reaction opens the dihydropyrimidine ring and introduces a carbamyl group on the amino end.

The enzyme uses zinc ions in its active site to activate a water molecule that attacks the dihydropyrimidine ring. It operates in the cytosol of cells and works downstream of dihydropyrimidine dehydrogenase, which reduces uracil and thymine to the dihydro forms. β-ureidopropionase then completes degradation to β-alanine or β-aminoisobutyric acid, respectively.

In humans, dihydropyrimidinase is encoded by the DPYS gene. Defects in DPYS lead to dihydropyrimidinuria, characterized by elevated urinary dihydrouracil and dihydrothymine, with variable clinical features from asymptomatic to neurodevelopmental problems. Diagnosis is typically based on metabolic profiling, and management centers on monitoring and supportive care, with ongoing research into enzyme replacement or gene-based therapies.