Iron participates as an essential cofactor in the biosynthesis of critical cellular components, including DNA, proteins and lipids. The ergosterol biosynthetic pathway, which is an important target of antifungal treatments, depends on iron in four enzymatic steps. Our results in the model yeast Saccharomyces cerevisiae show that the expression of ergosterol biosynthesis (ERG) genes is tightly modulated by iron availability probably through the iron-dependent variation of sterol and heme levels. Whereas the transcription factors Upc2 and Ecm22 are responsible for the activation of ERG genes upon iron deficiency, the heme-dependent factor Hap1 triggers their Tup1-mediated transcriptional repression. The combined regulation by both activating and repressing regulatory factors allows for the fine-tuning of ERG transcript levels along the progress of iron deficiency, avoiding the accumulation of toxic sterol intermediates and enabling efficient adaptation to rapidly changing conditions. The lack of these regulatory factors leads to changes in the yeast sterol profile upon iron-deficient conditions. Both environmental iron availability and specific regulatory factors should be considered in ergosterol antifungal treatments.

中文翻译：

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麦角甾醇生物合成基因的转录调控响应缺铁


铁作为重要的辅助因子参与关键细胞成分（包括 DNA、蛋白质和脂质）的生物合成。麦角甾醇生物合成途径是抗真菌治疗的重要靶标，在四个酶促步骤中依赖于铁。我们在模型酵母酿酒酵母中的结果表明，麦角甾醇生物合成（ ERG ）基因的表达受到铁可用性的严格调节，可能是通过甾醇和血红素水平的铁依赖性变化。转录因子 Upc2 和 Ecm22 负责缺铁时ERG基因的激活，而血红素依赖性因子 Hap1 则触发 Tup1 介导的转录抑制。激活和抑制调节因子的联合调节允许随着缺铁的进展对ERG转录水平进行微调，避免有毒甾醇中间体的积累，并能够有效适应快速变化的条件。这些调节因子的缺乏会导致缺铁条件下酵母甾醇谱的变化。在麦角甾醇抗真菌治疗中应考虑环境铁的可用性和特定的调节因素。