Unicellular organisms have evolved collections of mechanisms that allow them to tolerate stress conditions and environmental challenges. Nutrient starvation triggers in bacteria a stringent metabolic response that is regulated by alarmones, small intracellular signal molecules such as guanosine tetraphosphate (ppGpp). Discovered more than half a century ago, these alarmones are so peculiar, that they were originally named as ‘magic spots’. In most bacteria, the turnover of the alarmones is controlled by bi-functional enzymes called Rel and the influence of the alarmones themselves on Rel has a strong impact on the stringent response. In a collaborative effort, the group of Abel Garcia-Pino (WELBIO investigator - ULB) together with the group of Jelle Hendrix (Hasselt University and KULeuven) and the group of Vasili Hauryliuk (Umeå University) discovered the elusive molecular bases of the allosteric regulation of Rel by ‘magic spots’.
Using the thermophilic bacterium T. thermophilus as a model for the stringent response, they took a combined structural, biochemical and biophysical approach to unravel the system. Taking advantage of the slow catalysis by this thermophilic Rel at low temperatures, they could ‘catch’ the enzyme right at the act of synthesis or degradation of the alarmone, and capture the dynamics of the mechanism at a single molecule level. It turned out that the ‘magic spot’ controls the opposing activities of Rel by priming the enzyme for destruction, when bound in the degradation site, and at the same time switches off the active site in charge of making the alarmone. Conversely, binding of substrates to the site responsible for the synthesis of the ‘magic spot’ activates this function while switching off the domain responsible for its degradation. This simple but elegant mechanism ensures that almost by ‘magic’, bacteria avoid wasting energy in futile cycles of catalysis.
Source and illustration : Université libre de Bruxelles
Référence : Tamman, H., Van Nerom, K., Takada, H., Vandenberk, N., Scholl, D., Polikanov, Y., … Garcia-Pino, A. (2020). A nucleotide-switch mechanism mediates opposing catalytic activities of Rel enzymes. Nature Chemical Biology. https://doi.org/10.1038/s41589-020-0520-2