Abstract
SummaryGenome-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.
Highlights
Metabolic alterations play a key role in cancer, metabolic disease, pathogen infections, microbial communities, caloric restriction, and driving the aging process
We find that functional metabolomics provides orthogonal information in comparison to existing functional genomic data, in particular compared to physical and genetic interaction networks, and is found to be a rich resource to annotate so far uncharacterized genes
Gene Deletions that Impact the Biosynthetic Metabolome 4,913 gene-deletion strains that are viable in the absence of amino acid supplements (Figure S1A; Mulleder et al, 2012) were cultivated in synthetic minimal medium and grown to exponential phase, and their amino acid profile was determined by a precise, targeted analysis (Figure 1A)
Summary
Metabolic alterations play a key role in cancer, metabolic disease, pathogen infections, microbial communities, caloric restriction, and driving the aging process. Metabolism received limited attention in the context of gene regulatory networks, and many experiments in yeast and other organisms have been conducted under supplemented growth conditions that render large parts of biosynthetic metabolism artificially dispensable (Gibney et al, 2013; Mulleder et al, 2012). For these reasons, the genome-scale picture of the regulation of biosynthesis and the interactions between genome and metabolome is so far incomplete. By picturing the metabolic impact of transcription and signaling that operates predominantly at the chromatin level or via homeostatic feedback by metabolism-dependent systems, the ribosome, or protein transport, we achieve global insight into the regulation and homeostasis of metabolism during cell growth
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