1887

Abstract

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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/content/journal/micro/10.1099/00221287-83-2-283
1974-08-01
2024-04-25
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References

  1. Bianchetti R., Lucchini G., Sartirana M. L. 1971; Endogenous synthesis of formyl-methionine peptides in isolated mitochondria and chloroplasts. Biochemical and Biophysical Research Communica-tions 42:97–102
    [Google Scholar]
  2. Borst P. 1972; Mitochondrial nucleic acids. Annual Reviews of Biochemistry 41:333–376
    [Google Scholar]
  3. Evans I.H., Linstead D., Rhodes P. M., Wilkie D. 1973; Inhibition of RNA synthesis in mito-chondria by daunomycin. Biochimica et biophysica acta 312:323–336
    [Google Scholar]
  4. Geils G. F., Scott C. W. Jun Baugh C. M., Butterworth C. E. Jun 1971; Treatment ofmeningeal leukemia with pyrimethamine. Blood 38:131–137
    [Google Scholar]
  5. Linstead D., Evans I. H., Wilkie D. 1974; Mitochondrial genetic factors in the cellular response to chlorimipramine in Saccharomyces cerevisiae . In The Biogenesis of Mitochondria pp 179–193 Kroon A. M., Saccone C. Edited by New York and London: Academic Press;
    [Google Scholar]
  6. Mortimer R. K., Hawthorne D. C. 1969; Yeast genetics. In The Yeasts 1 pp 385–460 Rose A. H., Harrison J. S. Edited by London: Academic Press;
    [Google Scholar]
  7. Ramirez C., Miller J. J. 1962; Observations on vegetative nuclear division in Saccharomyces cerevisiae . Canadian Journal of Microbiology 8:603–607
    [Google Scholar]
  8. Rudland P. S., Clark B. F. C. 1972; Polypeptide chain initiation and the role of methionine tRNA. In The Mechanism of Protein Synthesis and its Regulation pp 55–86 Bosch L. Edited by London and Amsterdam: North Holland Publishing;
    [Google Scholar]
  9. Stacey K. A., Simson E. 1965; Improved method for the isolation of thymine-requiring mutants of Escherichia coli . Journal of Bacteriology 90:554–555
    [Google Scholar]
  10. Wilkie D. 1970; Analysis of mitochondrial drug resistance in Saccharomyces cerevisiae . Symposia of the Society for Experimental Biology 24:71–83
    [Google Scholar]
  11. Wilkie D. 1972; The yeast cell in the antimitochondrial activity of drugs. Medical and Biological Illustration 22:119–124
    [Google Scholar]
  12. Williamson D. H., Maroudas N., Wilkie D. 1971; Induction of the cytoplasmic petite mutation in Saccharomyces cerevisiae by antibacterial antibiotics. Molecular and General Genetics 111:209–223
    [Google Scholar]
  13. Wintersberger U., Hirsch J. 1973; Induction of cytoplasmic respiratory deficient mutants in yeast by the folic acid analogue, methotrexate. I. Studies on the mechanism of petite induction. Molecular and General Genetics 126:61–70
    [Google Scholar]
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