Dual physiological effects of antifungal sterol biosynthetic inhibitors on enzyme targets and on transcriptional regulation
✍ Scribed by Crowley, James H; Parks, Leo W
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 176 KB
- Volume
- 55
- Category
- Article
- ISSN
- 1526-498X
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✦ Synopsis
For many antifungal agents, enzymes leading to ergosterol biosynthesis are primary targets. Inhibition of ergosterol biosynthesis in treated cells results in the formation of aberrant sterols, lacking one or more structural features of esgosterol. Furthermore, the total sterol levels are often higher than the total sterol amounts in non-treated cells. The ERG3 gene, encoding the sterol C-5 desaturase, was used as a model for the regulation by some antifungal agents of genes encoding enzymes in ergosterol biosynthesis. Treatment of yeast cells with three sterol biosynthetic inhibitors with diþ erent targets in the ergosterol biosynthetic pathway led to an increase in ERG3 mRNA levels. The increase in ERG3 mRNA by drug treatment correlated with a decrease in ergosterol content within the cells. No correlation was evident between ERG3 mRNA and total sterol levels, as treatment with at least one inhibitor, fenpropimorph, led to a slight increase in total sterol, while ERG3 mRNA levels decreased. Treatment of cells with fenpropimorph and ketoconazole resulted in a decrease in ergosterol as a percentage of total sterol, while lovastatin caused an increase in the ergosterol percentage. These results indicate that a second indirect eþ ect of the antifungal sterol biosynthetic inhibitors is on transcriptional regulation. The physiology of the treated cell is aþ ected not only by a decrease in ergosterol but also by an enhanced accumulation of defective sterols.