Metabolites as global regulators: A new view of protein regulation

Small metabolites represent the group of non-polymer compounds that a cell continually synthesizes, acquires, and utilizes from its surroundings. In any living cell, small metabolites outnumber proteins by at least one order of magnitude, creating a plethora of non-inherited molecular interactions. Recent systematic examination disclosed that 20% of proteins bind to at least one hydrophobic metabolite, suggesting that a large fraction of the proteome may bind metabolites. These interactions can modify protein activities and abundance. Regulation of protein function by metabolites may provide benefits for cells to adapt to ever-changing environmental conditions. The construction of a global small metaboliteprotein interactome will provide new insights into functional genomes and small-molecule drug development. The inherited and acquired biomolecules have to work in concert to keep life from collapsing out of the state of dynamic equilibrium in accordance with the second law of thermodynamics [1]. The underlying regulatory mechanisms are traditionally thought to be biochemical reactions where protein enzymes control the abundance and flux of metabolites in feedback and feedforward loops. However, given the fact that most proteins are surrounded by an excessive number of metabolites, it is reasonable to postulate that protein functions can also be modulated by interacting with metabolites that are not their substrates or products. In fact, several classic examples exist in which metabolites regulate protein functions in a nonenzymatic manner, including transcription co-factors, hormone signals or neurotransmitters. A recent study has also noted ‘‘strongly bound impurities’’ in commercial protein samples [2], suggesting undisclosed metaboliteprotein interactions. However, the extent to which such types of regulators exist in cells has not been systematically examined until recently. In this paper, we attempt to review recent advances in querying metaboliteprotein interactions, and speculate on its potential impact in systems biology and drug development. Throughout this paper we use small metabolites to denote non-polymer natural compounds found in cells, and small molecules to denote both small metabolites and synthetic pharmaceutical chemicals.