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Dihydroorotate dehydrogenase (DHODH) mediates the fourth step ofde novo pyrimidine biosynthesis and is a proven drug target for inducing immunosuppression in therapy of human disease as well as a rapidly emerging drug target for treatment of malaria. InToxoplasma gondii , disruption of the first, fifth, or sixth step ofde novo pyrimidine biosynthesis induced uracil auxotrophy. However, previous attempts to generate uracil auxotrophy by genetically deleting the mitochondrion-associated DHODH ofT. gondii (Tg DHODH) failed. To further address the essentiality ofTg DHODH, mutant gene alleles deficient inTg DHODH activity were designed to ablate the enzyme activity. Replacement of the endogenousDHODH gene with catalytically deficientDHODH gene alleles induced uracil auxotrophy. Catalytically deficientTg DHODH localized to the mitochondria, and parasites retained mitochondrial membrane potential. These results show thatTg DHODH is essential for the synthesis of pyrimidines and suggest thatTg DHODH is required for a second essential function independent of its role in pyrimidine biosynthesis.

Pyrimidine Pathway-Dependent and -Independent Functions of the Toxoplasma gondii Mitochondrial Dihydroorotate Dehydrogenase