Methotrexate impairs the synthesis of which cellular components due to folate antagonism?

• A. Proteins
• B. Purine nucleotides and thymidylate
• C. Fatty acids
• D. Ribosomal RNA

Answer: (B)

Folate fuels one-carbon transfer reactions essential for making DNA building blocks. Methotrexate inhibits dihydrofolate reductase, reducing the pool of active folate coenzymes needed for these reactions. Without those folate-derived one-carbon donors, two key processes stall: thymidylate synthesis from dUMP (via thymidylate synthase using 5,10-methylene-THF) and several steps in purine nucleotide synthesis (which rely on formyl-THF). The outcome is a shortage of purine nucleotides (AMP, GMP) and thymidylate (dTMP), leading to impaired DNA synthesis in rapidly dividing cells. Proteins, fatty acids, and ribosomal RNA aren’t directly blocked by this folate-dependent step, so the primary effect is on nucleotide production rather than these other macromolecules.