大自然一直是药物化合物的丰富来源,生产我们目前处方药的80%。feijoa植物,Accasellowiana,归入桃金娘科,原产于南美洲,目前在世界各地种植,生产斐济果。Feijoa是具有抗癌的生物活性化合物的丰富来源,抗炎,抗菌和抗真菌活性;然而,这些化合物的作用机理在很大程度上是未知的。在这里,我们使用模型生物酿酒酵母中的化学遗传分析来研究费果衍生的vescalagin乙醇加合物(EtOH-vescalagin)的作用机理。全基因组条形码测序(Bar-seq)分析显示酵母菌株缺乏铁代谢基因,锌代谢,逆转录功能或线粒体功能对0.3µMEtOH-vescalagin过敏.这种治疗增加了质膜上铁摄取蛋白的表达,这是对细胞内铁减少的补偿反应。同样,EtOH-vescalagin增加了Cot1蛋白在液泡膜中的表达,将锌转运到液泡中,以防止锌的细胞质积累。EtOH-vescalagin的铁稳态机制需要retromer复合物中的每个亚基,而锌稳态机制只需要逆行复合物中的货物识别组件。在锌充足的条件下,逆转录亚基或高亲和力铁转运蛋白的过表达抑制了EtOH-vescalagin的生物活性,而仅反转录亚基的过表达在锌缺乏的条件下增加了EtOH-vescalagin的生物活性。一起,这些结果表明EtOH-vescalagin的生物活性始于细胞外铁螯合,并通过逆转录复合物进行锌的细胞内转运。更广泛地说,这是第一份关于生物活性化合物的报道,该化合物进一步表征了锌代谢和逆酶功能之间鲜为人知的相互作用。
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 is 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 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.