Functional Metabolomics Describes the Yeast Biosynthetic Regulome

Genome-metabolism interactions enable cell growth. To probe the extent of these interactions and delineate their functional contributions, we quantified the Saccharomyces amino acid metabolome and its response to systematic gene deletion. Over one-third of coding genes, in particular those important for chromatin dynamics, translation, and transport, contribute to biosynthetic metabolism. Specific amino acid signatures characterize genes of similar function. This enabled us to exploit functional metabolomics to connect metabolic regulators to their effectors, as exemplified by TORC1, whose inhibition in exponentially growing cells is shown to match an interruption in endomembrane transport. Providing orthogonal information compared to physical and genetic interaction networks, metabolomic signatures cluster more than half of the so far uncharacterized yeast genes and provide functional annotation for them. A major part of coding genes is therefore participating in gene-metabolism interactions that expose the metabolism regulatory network and enable access to an underexplored space in gene function.

基因组与代谢的相互作用支撑细胞生长。为探究此类相互作用的覆盖范围并阐明其功能贡献，本研究对酿酒酵母（Saccharomyces）的氨基酸代谢组及其对系统性基因敲除的响应进行了定量分析。超过三分之一的编码基因，尤其是参与染色质动态调控、蛋白质翻译及物质转运的基因，参与生物合成代谢过程。特定的氨基酸特征谱可用于表征功能相似的基因。这一发现使得我们能够借助功能代谢组学将代谢调控因子与其效应因子关联起来，以TORC1为例：在指数生长期细胞中抑制TORC1，可观察到内膜系统转运过程受阻，与该关联相吻合。相较于物理相互作用与遗传相互作用网络，代谢组特征谱提供了正交信息，可将超过半数迄今尚未注释的酵母基因进行聚类，并为这些基因提供功能注释。因此，大部分编码基因均参与基因组-代谢相互作用，此类作用可揭示代谢调控网络，并为探索基因功能中未被充分发掘的领域提供途径。