Leflunomide’s mechanism involves inhibition of which enzyme, leading to suppression of pyrimidine synthesis?

• A. Glucose-6-phosphate dehydrogenase
• B. Dihydroorotate dehydrogenase
• C. Xanthine oxidase
• D. Adenosine deaminase

Answer: (B)

Leflunomide works by blocking a key enzyme in the de novo synthesis of pyrimidines, which are needed for DNA replication in rapidly dividing cells. The targeted enzyme is dihydroorotate dehydrogenase, and inhibiting it stops the conversion of dihydroorotate to orotate, reducing the production of UMP and downstream pyrimidine nucleotides. Activated lymphocytes depend heavily on this de novo pathway to proliferate, so their DNA/RNA synthesis is suppressed, dampening the autoimmune response. The salvage pathway can’t fully compensate in these cells, making this inhibition particularly effective for reducing lymphocyte proliferation. The other enzymes listed are involved in different pathways (PPP NADPH production, purine degradation, or purine metabolism) and are not the mechanism Leflunomide uses to suppress pyrimidine synthesis.