IMU-838 is an orally available selective immune modulator that inhibits the intracellular metabolism of activated immune cells by blocking the enzyme dihydroorotate
dehydrogenase, or DHODH.
Began dosing patients in the Phase 1 dose-escalation trial of AG-636, an inhibitor of the metabolic enzyme dihydroorotate
dehydrogenase (DHODH), in advanced lymphoma.
LEF inhibits the mitochondrial enzyme dihydroorotate
dehydrogenase (DHODH), which plays a key role in the de novo synthesis of pyridine-containing ribonucleotides (rUMP).
This inhibition results in the collapse of the mitochondrial membrane potential that causes shutdown of mitochondrial metabolism and blockage of the dihydroorotate
dehydrogenase (Pf DHOD) enzyme, which participates in the fourth step of the de novo pyrimidine biosynthesis, which is essential to parasite nucleic acids synthesis, resulting in parasite death [12, 13].
Yan, "QSAR study on the antimalarial activity of Plasmodium falciparum dihydroorotate
dehydrogenase (P1DHODH) inhibitors," SAR and QSAR in Environmental Research, vol.
Copeland, "The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate
dehydrogenase," Biochemistry, vol.
The proposed mechanism of leflunomide in the treatment of autoimmune disease is the inhibition of mitochondrial dihydroorotate
dehydrogenase, which is involved in the synthesis of the RNA nucleotide uridine monophosphate.
The flavoenzyme dihydroorotate
dehydrogenase is a rate-limiting enzyme involved in the de novo synthesis of pyrimidines (reviewed in ).
In this biosynthetic pathway, dihydroorotase that converts glutamine to dihydroorotate
dehydrogenase that converts dihydroorotate
to orotic acid, uridine monophosphate synthetase that converts orotic acid to UMP, 5,-nucleotidase that converts UMP to uridine, uridine nucleosidase that converts uridine to uracil, uridine kinase (udk) that converts cytidine to CMP, uridine/cytidine monophosphate (UMP-CMP) kinase that converts CMP to CDP, nucleoside-diphosphate kinase (ndk) that converts UDP to UTP, apyrase that converts CTP to CDP, inosine triphosphate pyrophosphatase (ITPA) that converts UMP to UTP, CTP synthase that converts UTP to CTP, and cytidine deaminase (cdd) that converts cytidine to uridine were annotated in the H.
Leflunomide inhibits dihydroorotate
dehydrogenase and thereby blocks the de novo pathway of pyrimidine nucleotide synthesis, which is crucial for T-cell activation and proliferation.
Teriflunomide a selective immunosuppressant with anti-inflammatory properties inhibits lymphocyte proliferation by blocking dihydroorotate
dehydrogenase which is the rate limiting step in pyrimidine synthesis.
Mitochondrial role in the intraerythrocytic environment particularly focuses on mitochondrial metabolic pathways that relate to oxidative phosphorylation, including the tricarboxylic acid cycle, de novo pyrimidine biosynthesis via dihydroorotate
dehydrogenase, and the particularities of the electron transport chain.