Department of Bioengineering, University of California San Diego, La Jolla, CA 92093;
Department of Nanoengineering, University of California San Diego, La Jolla, CA 92093.
Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14368-14373. doi: 10.1073/pnas.1905039116. Epub 2019 Jul 3.
Catalysis using iron-sulfur clusters and transition metals can be traced back to the last universal common ancestor. The damage to metalloproteins caused by reactive oxygen species (ROS) can prevent cell growth and survival when unmanaged, thus eliciting an essential stress response that is universal and fundamental in biology. Here we develop a computable multiscale description of the ROS stress response in , called OxidizeME. We use OxidizeME to explain four key responses to oxidative stress: 1) ROS-induced auxotrophy for branched-chain, aromatic, and sulfurous amino acids; 2) nutrient-dependent sensitivity of growth rate to ROS; 3) ROS-specific differential gene expression separate from global growth-associated differential expression; and 4) coordinated expression of iron-sulfur cluster (ISC) and sulfur assimilation (SUF) systems for iron-sulfur cluster biosynthesis. These results show that we can now develop fundamental and quantitative genotype-phenotype relationships for stress responses on a genome-wide basis.
使用铁硫簇和过渡金属的催化作用可以追溯到最后一个普遍共同祖先。活性氧（ROS）对金属蛋白造成的损害如果得不到控制，会阻止细胞生长和存活，从而引发一种普遍存在且基本的生物学应激反应。在这里，我们开发了一种可计算的多尺度描述方法，用于研究，称为 OxidizeME。我们使用 OxidizeME 来解释四种对氧化应激的关键反应：1）ROS 诱导支链、芳香族和含硫氨基酸的营养缺陷型；2）营养依赖性 ROS 对生长速率的敏感性；3）ROS 特异性的差异基因表达与全局生长相关的差异表达分离；4）铁硫簇（ISC）和硫同化（SUF）系统的协调表达，用于铁硫簇生物合成。这些结果表明，我们现在可以在全基因组范围内为应激反应开发基本的、定量的基因型-表型关系。
