Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH)

Plasmodium falciparum dihydroorotate dehydrogenase is an essential mitochondrial enzyme that catalyzes the rate-limiting step in the de novo pyrimidine biosynthetic pathway, specifically the oxidation of dihydroorotate to orotic acid, utilizing flavin mononucleotide (FMN) and ubiquinone as cofactors. Unlike humans, P. falciparum relies entirely on de novo synthesis for pyrimidines, making this enzyme crucial for nucleic acid synthesis, cell growth, and parasite survival[1][2][5][7]. Due to its central metabolic role and major differences from the human homolog, PfDHODH is a validated and highly selective drug target for the treatment and prevention of malaria; several potent, selective inhibitors (notably DSM265) have demonstrated clinical efficacy in both blood and liver stages of malaria infection. Drug resistance is an ongoing concern, with various point mutations and gene amplification events in PfDHODH correlating to resistance phenotypes, supporting the continued development of new inhibitor classes and combination therapies[4][6][5][2].

Other names

PfDHODHP. falciparum DHODHPlasmodium DHODHdihydroorotate dehydrogenase (Plasmodium falciparum)malaria DHODH

Inhibition of dihydroorotate dehydrogenase, blocking de novo pyrimidine biosynthesis, resulting in parasite death[1][2][7][5]. Selective inhibition of mitochondrial DHODH enzyme, leading to depletion of pyrimidine nucleotides in the parasite