SUMMARY: Pyrimethamine (PY), an inhibitor of folate reductase, blocks mitochondrial protein synthesis in yeast, presumably by creating a shortage of formylmethionyl-tRNA. This has been established by measuring in intact cells the effect of the drug on the formation of cytochromes and , and on the incorporation of labelled leucine when cytoplasmic protein synthesis is suppressed by cycloheximide. As a result, growth of the organism in non-fermentable (glycerol) medium is arrested by relatively low concentrations of PY, which have little effect in fermentable (dextrose) medium where respiratory activity is not essential. However, higher drug concentrations do inhibit growth in dextrose medium, probably by preventing thymine synthesis. Under some conditions the budding process is modified, giving rise to abnormal elongated cells. The inhibitory effect of PY is prevented by exogenous tetrahydrofolate.

Prolonged exposure to low concentrations of the drug, or shorter exposure to higher concentrations, leads to an induction of mitochondrial petite mutants and cell death, presumably as a consequence of thymine starvation. Petite mutants are particularly susceptible to killing by PY. Those induced by the drug are of the suppressible type, and hence would appear to result from a modification to (rather than a loss of) the mitochondrial DNA.


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