Metabolomics in systems microbiology

Abstract

Due to the importance of microbes as model organisms, biotechnology tools, and contributors to mammalian and ecosystem metabolism, there has been longstanding interest in measuring their metabolite levels. Current metabolomic methods, involving mass spectrometry-based measurement of cell extracts, enable routine quantitation of most central metabolites. Metabolomics alone, however, is inadequate to understand cellular metabolic activity: Flux measurement and proteomic, genetic, and biochemical approaches with a metabolomics bent are all needed. Here we highlight examples where these integrated methods have contributed to discovery of metabolic pathways, regulatory interactions, and homeostasis mechanisms. We also indicate enduring challenges concerning unstable and low abundance compounds, subcellular compartmentalization, and quantitative amalgamation of different data types.Systems biology aims to explain physiological processes in terms of the concerted actions of numerous biochemicals. Microbial metabolism would seem to provide a promising arena for achieving this aim. Balanced growth in diverse environments a hallmark of microbial physiology is a metabolic capability. Microbes are relatively simple. Model microbes are also easy to grow and genetically tractable. The connections between metabolites, catalyzed by enzymatic transformations, are well mapped.Consistent with this promise, microbial metabolism has been among the fastest areas of systems biology to develop. A key driver in this regard has been the constraints-based computational approach of flux balance analysis (FBA). A remarkable finding has been that E. coli (although not most other microbes) often maximizes growth per unit of carbon source consumed: Fluxes are optimally efficient [1]. This raises key questions: What regulatory mechanisms lead to flux optimality? How are these mechanisms different in organisms that have different metabolic objectives? How do these mechanisms coordinate appropriate responses to changing nutrient availability?Metabolomics, defined broadly as the systems biology of metabolism, aims to address these questions. Metabolomics, defined more narrowly as comprehensive metabolite measurement, provides a critical tool for doing so. Figure 1 provides a schematic overview of microbial metabolomics and its integration with other experimental approaches. Metabolomics and genomics provide complementary tools for identifying metabolites and

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