Dihydroorotate dehydrogenase (quinone), mitochondrial (DHODH) (DHODH)

Dihydroorotate dehydrogenase (DHODH) is a key mitochondrial enzyme that catalyzes the fourth and rate-limiting step of the de novo pyrimidine biosynthesis pathway, specifically the oxidation of dihydroorotate to orotate [9, 12]. This reaction is uniquely coupled to the mitochondrial respiratory chain via the reduction of ubiquinone to ubiquinol, linking nucleotide metabolism directly to cellular energy production [12, 16]. In mice, as in humans, DHODH is essential for the proliferation of rapidly dividing cells, such as activated T-cells and malignant cells, which rely heavily on de novo synthesis rather than salvage pathways for pyrimidines [1, 10]. Consequently, DHODH has emerged as a significant therapeutic target for autoimmune diseases like rheumatoid arthritis and multiple sclerosis, as well as various malignancies including neuroblastoma and acute myeloid leukemia [1, 2, 6]. Pharmacological inhibition of DHODH by drugs such as leflunomide or brequinar leads to the depletion of intracellular pyrimidine pools, resulting in cell cycle arrest, induction of cell differentiation, or the promotion of ferroptosis [1, 16, 17]. While effective, targeting DHODH requires careful monitoring due to potential safety concerns such as hepatotoxicity and teratogenicity [10, 16].

Other names

Dihydroorotate oxidase [9, 14]DHOdehase [14]Dhodh [9, 15]

Inhibition of the de novo pyrimidine biosynthesis pathway by blocking the oxidation of dihydroorotate to orotate, which leads to the depletion of intracellular pyrimidine nucleotide pools (e.g., UMP, CTP, TTP). This depletion results in cell cycle arrest in the S-phase, induction of cell differentiation, or promotion of ferroptosis, particularly in rapidly proliferating cells like activated lymphocytes and various cancer cells [1, 2, 12, 16, 17].