Conservation of metabolic regulation by phosphorylation and non-covalent small-molecule interactions

Here, we review extant observations of protein phosphorylation and small-molecule interactions in metabolism and ask which of their specific regulatory functions are conserved in Escherichia coli and Homo sapiens. While the number of phosphosites is dramatically higher in humans, the number of metabolite-protein interactions remains largely constant. Moreover, we found the regulatory logic of metabolite-protein interactions, and in many cases also the effector molecules, to be conserved. Post-translational regulation through phosphorylation does not appear to replace this regulation in human but rather seems to add additional opportunities for fine-tuning and more complex responses. The abundance of metabolite-protein interactions in metabolism, their conserved cross-species abundance, and the apparent conservation of regulatory logic across enormous phylogenetic distance demonstrate their relevance for maintaining cellular homeostasis in these ancient biological processes.