1887

Abstract

Summary: Sterol side-chain (C-24) methylation was assayed by incorporation of radioactivity from [-C]methionine into the ergosterol fraction in cells of the pathogenic fungi and . Methylation at C-24 occurred after nuclear demethylation in all cases. The method was used to measure ergosterol biosynthesis inhibition by the allylamine antimycotics naftifine and SF 86-327, which are known to block squalene epoxidation. In cells treated with SF 86-327 (1 mg 1) to fully inhibit squalene epoxidation, C-24 methylation continued for several hours at about 40% of the control rate. This residual biosynthesis was probably due to methylation of endogenous sterol precursors. The degree of residual biosynthesis in the three fungi correlated well with their susceptibility to SF 86-327. The highly susceptible dermatophyte had negligible residual sterol biosynthesis. These differences were not due to inhibition of methionine uptake. For naftifine (100 mg 1) there was evidence of a second inhibitory action . A cell-free assay indicated that this was due to direct inhibition of the C-24 methyltransferase.

Loading

Article metrics loading...

/content/journal/micro/10.1099/00221287-131-7-1595
1985-07-01
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/micro/131/7/mic-131-7-1595.html?itemId=/content/journal/micro/10.1099/00221287-131-7-1595&mimeType=html&fmt=ahah

References

  1. Barton D. H. R., Corrie J. E. T., Marshall P. J., Widdowson D. A. 1973; Biosynthesis of terpenes and steroids. VII. Unified scheme for the biosynthesis of ergosterol in Saccharomyces cerevisiae . Bioorganic Chemistry 2:363–373
    [Google Scholar]
  2. Berg D., Regel E., Harenberg H. -E., Plempel M. 1984; Bifonazole and clotrimazole. Their mode of action and the possible reason for the fungicidal behaviour of bifonazole. Arzneimittel Forschung/Drug Research 34:1139–146
    [Google Scholar]
  3. Fryberg M., Oehlschlager A. C., Unrau A. M. 1973; Biosynthesis of ergosterol in yeast. Evidence for multiple pathways. Journal of the American Chemical Society 95:5747–5757
    [Google Scholar]
  4. Fryberg M., Oehlschlager A. C., Unrae A. M. 1975a; Sterol bipsynthesis in antibiotic sensitive and resistant Candida . Archives of Biochemistry and Biophysics 173:171–177
    [Google Scholar]
  5. Fryberg M., Avruch L., Oehlschlager A. C., Unrau A. M. 1975b; Nuclear demethylation and C-24 alkylation during ergosterol biosynthesis in Saccharomyces cerevisiae . Canadian Journal of Biochemistry 53:881–889
    [Google Scholar]
  6. Georgopoulos A., Petranyi G., Mieth H., Drews J. 1981; In vitro activity of naftifine, a new antifungal agent. Antimicrobial Agents and Chemotherapy 19:386–389
    [Google Scholar]
  7. Goad L. J., Lenton J. R., Knapp F. F., Goodwin T. W. 1974; Phytosterol side chain biosynthesis. Lipids 9:582–595
    [Google Scholar]
  8. Goulston G., Goad L. J., Goodwin T. W. 1967; Sterol biosynthesis in fungi. Biochemical Journal 102:15c–17c
    [Google Scholar]
  9. McCammon M. T., Parks L. W. 1981; Inhibition of sterol transmethylation by S-adenosylhomocysteine analogs. Journal of Bacteriology 145:106–112
    [Google Scholar]
  10. Moore J. T., Gaylor J. L. 1970; Investigation of an S-adenosylmethionine: ᐃ24-sterol methyltransferase in ergosterol biosynthesis in yeast. Journal of Biological Chemistry 245:4684–4688
    [Google Scholar]
  11. Nagai J., Kawamura S., Katsuki H. 1977; Occurrence of fatty acid esters of sterol intermediates in ergosterol synthesis by yeast during respiratory adaptation. Journal of Biochemistry 81:1665–1673
    [Google Scholar]
  12. Nishino T., Hata S., Osumi T., Katsuki H. 1980; Biosynthesis of ergosterol in cell-free system of yeast. Journal of Biochemistry 88:247–254
    [Google Scholar]
  13. Nishino T., Hata S., Taketani S., Yabusaki Y., Katsuki H. 1981; Subcellular localization of the enzymes involved in the late stage of ergosterol biosynthesis in yeast. Journal of Biochemistry 89:1391–1396
    [Google Scholar]
  14. Osumi T., Taketani S., Katsuki H., Kuhara T., Matsumoto I. 1978; Ergosterol biosynthesis in yeast. Pathways in the late stages and their variation under various conditions. Journal of Biochemistry 83:681–691
    [Google Scholar]
  15. Paltauf G., Daum G., Zuder G., Högenauer G., Schulz G., Seidl G. 1982; Squalene and ergosterol biosynthesis in fungi treated with naftifine, a new antimycotic agent. Biochimica et biophysica acta 712:268–273
    [Google Scholar]
  16. Parks L. W. 1958; S-Adenosylmethionine and ergosterol synthesis. Journal of the American Chemical Society 80:2023–2024
    [Google Scholar]
  17. Parks L. W., Anding C., Ourisson G. 1974; Sterol transmethylation during aerobic adaptation of yeast. European Journal of Biochemistry 43:451–458
    [Google Scholar]
  18. Petranyi G., Ryder N. S., Stütz A. 1984; Allylamine derivatives: new class of synthetic antifungal agents inhibiting fungal squalene epoxidase. Science 224:1239–1241
    [Google Scholar]
  19. Pierce A. M., Pierce H. D., Unrau A. M., Oehlschlager A. C. 1978; Lipid composition and polyene antibiotic resistance of Candida albicans mutants. Canadian Journal of Biochemistry 56:135–142
    [Google Scholar]
  20. Popjak G. 1969; Enzymes of sterol biosynthesis in liver and intermediates of sterol biosynthesis. Methods in Enzymology 15:393–454
    [Google Scholar]
  21. Ryder N. S. 1984; Selective inhibition of squalene epoxidation by allylamine antimycotic agents. In Microbial Cell Wall Synthesis and Autolysis pp 313–321 Edited by Nombela C. Amsterdam: Elsevier;
    [Google Scholar]
  22. Ryder N. S. 1985; Specific inhibition of fungal sterol biosynthesis by SF 86-327, a new allylamine antimycotic agent. Antimicrobial Agents and Chemotherapy 27:252–256
    [Google Scholar]
  23. Ryder N. S., Dupont M. -C. 1984; Properties of a particulate squalene epoxidase from Candida albicans . Biochimica et Biophysica Acta 794:466–471
    [Google Scholar]
  24. Ryder N. S., Goad L. J. 1980; The effect of the 3-hydroxy-3-methylglutaryl CoA reductase inhibitor ML-236B on phytosterol synthesis in Acer pseudoplatanus tissue culture. Biochimica et biophysica acta 619:424–427
    [Google Scholar]
  25. Ryder N. S., Troke P. F. 1982; The activity of naftifine as a sterol synthesis inhibitor in Candida albicans . In Current Chemotherapy and Immunotherapy pp 1016–1017 Edited by Periti P., Grassi G. G. Washington DC: American Society for Microbiology;
    [Google Scholar]
  26. Ryder N. S., Seidl G., Troke P. F. 1984; Effect of the antimycotic drug naftifine on growth of and sterol biosynthesis in Candida albicans . Antimicrobial Agents and Chemotherapy 25:483–487
    [Google Scholar]
  27. Starr P. R., Parks L. W. 1972; Transmethylation of sterols in aerobically adapting Saccharomyces cerevisiae . Journal of Bacteriology 109:236–242
    [Google Scholar]
  28. Stütz A., Petranyi G. 1984; Synthesis and antifungal activity of (E)-N(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine (SF 86-327) and related allylamine derivatives with enhanced oral activity. Journal of Medicinal Chemistry 27:1539–1543
    [Google Scholar]
  29. Subden R. E., Safe L., Morris D. C., Brown R. G., Safe S. 1977; Eburicol, lichesterol, ergosterol and obtusifoliol from polyene antibiotic-resistant mutants of Candida albicans . Canadian Journal of Microbiology 23:751–754
    [Google Scholar]
  30. Taketani S., Nagai J., Katsuki H. 1978; Quantitative aspects of free and esterified sterols in Saccharomyces cerevisiae under various conditions. Biochimica et biophysica acta 528:416–423
    [Google Scholar]
  31. Van den Bossche H., Willemsens G., Cools W., Lauwers W. F. J., LeJeune L. 1978; Biochemical effects of miconazole on fungi. II. Inhibition of ergosterol biosynthesis in Candida albicans . Chemico-Biological Interactions 21:59–78
    [Google Scholar]
  32. Van den Bossche H., Willemsens G., Cools W., Cornelissen F., Lauwers W. F., Van Cutsem J. M. 1980; In vitro and in vivo effects of the antimycotic drug ketoconazole on sterol synthesis. Antimicrobial Agents and Chemotherapy 17:922–928
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/00221287-131-7-1595
Loading
/content/journal/micro/10.1099/00221287-131-7-1595
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error