The Cellular Response To Iron Starvation And Intoxication

铁缺乏是世界上资源贫乏地区的一个严重的公共卫生问题，然而在分子水平上关于细胞对铁缺乏的适应知之甚少。我们在S.酿酒酵母，揭示了多种代谢途径的调节响应于铁的可用性。值得注意的是，在缺铁培养基中生长的酵母中，含有铁硫簇酶的几种蛋白质和途径被下调。这些转录变化表明，改变铁水平可能会改变通过这些途径的代谢物的流量。 铁是参与许多细胞过程的酶的重要辅因子，但关于铁缺乏对细胞代谢或铁蛋白的影响知之甚少。以前的研究主要集中在缺铁细胞中转录本和蛋白质水平的变化，但这些变化可能并不反映通过代谢途径的运输活性或通量的变化。我们分析了在富铁和贫铁培养基中生长的酵母的代谢组和转录组，以确定当铁的可用性福尔斯下降时，哪些生物合成过程发生了改变。缺铁导致葡萄糖代谢、氨基酸生物合成和脂质生物合成的变化，这些变化是由于特定的铁依赖性酶的缺乏。铁硫蛋白表现出铁辅因子的损失，但氨基酸的合成得以维持。麦角固醇和鞘脂生物合成途径在血红素和二铁酶起作用的点上有块，并且这些酶中的大多数在没有它们的铁辅因子的情况下表达。缺铁细胞表现出铁酶活性的急剧消耗，但由于大多数铁依赖性酶的表达量大大过量，在缺铁期间活性的丧失并不总是破坏代谢。氨基酸稳态是稳健的，但缺铁损害脂质合成，改变细胞膜的性质和功能。

Iron deficiency is a serious public health problem in resource-poor areas of the world, yet little is known at the molecular level regarding the cellular adaptation to iron deficiency. We performed microarray analyses in S. cerevisiae which revealed that multiple metabolic pathways are regulated in response to iron availability. Notably, several proteins and pathways containing iron-sulfur cluster enzymes are down-regulated in yeast grown in iron-poor media. These transcriptional changes suggested that changing iron levels may alter the flux of metabolites through these pathways. Iron is an essential cofactor for enzymes involved in numerous cellular processes, yet little is known about the impact of iron deficiency on cellular metabolism or iron proteins. Previous studies have focused on changes in transcript and proteins levels in iron-deficient cells, yet these changes may not reflect changes in transport activity or flux through a metabolic pathway. We analyzed the metabolomes and transcriptomes of yeast grown in iron-rich and iron-poor media to determine which biosynthetic processes are altered when iron availability falls. Iron deficiency led to changes in glucose metabolism, amino acid biosynthesis, and lipid biosynthesis that were due to deficiencies in specific iron-dependent enzymes. Iron-sulfur proteins exhibited loss of iron cofactors, yet amino acid synthesis was maintained. Ergosterol and sphingolipid biosynthetic pathways had blocks at points where heme and diiron enzymes function, and most of these enzymes were expressed without their iron cofactors. Iron-deficient cells exhibited dramatic depletion of iron enzyme activity, but as most iron-dependent enzymes were expressed in vast excess, loss of activity during iron deficiency did not consistently disrupt metabolism. Amino acid homeostasis was robust, but iron deficiency impaired lipid synthesis, altering the properties and functions of cellular membranes.