大自然是药物化合物的丰富来源，我们目前处方药物的 80% 都是由大自然生产的。费约果植物 Acca sellowiana 属于桃金娘科，原产于南美洲，目前在世界范围内种植以生产费约果果实。费约果是生物活性化合物的丰富来源，具有抗癌、抗炎、抗菌和抗真菌活性；然而，这些化合物的作用机制很大程度上尚不清楚。在这里，我们在模式生物酿酒酵母中使用化学遗传分析来研究非果果衍生的维斯卡金乙醇加合物（EtOH-维斯卡金）的作用机制。全基因组条形码测序 (Bar-seq) 分析显示，缺乏铁代谢、锌代谢、逆转录酶功能或线粒体功能基因的酵母菌株对 0.3 μM EtOH-vescalagin 高度敏感。这种处理增加了质膜上铁吸收蛋白的表达，这是对细胞内铁减少的补偿反应。同样，EtOH-vescalagin 增加了液泡膜中 Cot1 蛋白的表达，该蛋白将锌转运到液泡中，以防止锌在细胞质中积累。乙醇-维斯卡金的铁稳态机制需要retromer复合物中的每个单独的亚基，而锌稳态机制仅需要retromer复合物中的货物识别组件。在锌充足的条件下，逆转录体亚基或高亲和力铁转运蛋白的过表达抑制了乙醇-维斯卡金的生物活性，而在缺锌条件下，仅逆转录体亚基的过表达增加了乙醇-维斯卡金的生物活性。总之，这些结果表明 EtOH-vescalagin 生物活性始于细胞外铁螯合，并通过逆转录复合物进行细胞内锌转运。更广泛地说，这是第一份关于生物活性化合物的报告，以进一步描述锌代谢和逆转录酶功能之间鲜为人知的相互作用。© 作者 2024。由牛津大学出版社代表美国遗传学会出版。

Nature has been a rich source of pharmaceutical compounds, producing 80% of our currently prescribed drugs. The feijoa plant, Acca sellowiana, is classified in the family Myrtaceae, native to South America, and currently grown worldwide to produce feijoa fruit. Feijoa is a rich source of bioactive compounds with anticancer, anti-inflammatory, antibacterial and antifungal activities; however, the mechanism of action of these compounds are largely not known. Here we used chemical genetic analyses in the model organism Saccharomyces cerevisiae to investigate the mechanism of action of a feijoa-derived ethanol adduct of vescalagin (EtOH-vescalagin). Genome-wide barcode sequencing (Bar-seq) analysis revealed yeast strains lacking genes in iron metabolism, zinc metabolism, retromer function or mitochondrial function were hypersensitive to 0.3 µM EtOH-vescalagin. This treatment increased expression of iron uptake proteins at the plasma membrane, which was a compensatory response to reduced intracellular iron. Likewise, EtOH-vescalagin increased expression of the Cot1 protein in the vacuolar membrane that transports zinc into the vacuole to prevent cytoplasmic accumulation of zinc. Each individual subunit in the retromer complex was required for the iron homeostatic mechanism of EtOH-vescalagin, while only the cargo recognition component in the retromer complex was required for the zinc homeostatic mechanism. Overexpression of either retromer subunits or high-affinity iron transporters suppressed EtOH-vescalagin bioactivity in a zinc-replete condition, while overexpression of only retromer subunits increased EtOH-vescalagin bioactivity in a zinc-deficient condition. Together, these results indicate that EtOH-vescalagin bioactivity begins with extracellular iron chelation and proceeds with intracellular transport of zinc via the retromer complex. More broadly, this is the first report of a bioactive compound to further characterize the poorly understood interaction between zinc metabolism and retromer function.© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.