Journal of Bacteriology
The “magic spot” alarmones (pp)pGpp, previously implicated in Clostridioides difficile antibiotic survival, are synthesized by the RelA-SpoT homolog (RSH) of C. difficile (RSHCd) and RelQCd. These enzymes are transcriptionally activated by diverse environmental stresses. RSHCd has previously been reported to synthesize ppGpp, but in this study, we found that both clostridial enzymes exclusively synthesize pGpp. While direct synthesis of pGpp from a GMP substrate, and (p)ppGpp hydrolysis into pGpp by NUDIX hydrolases, have previously been reported, there is no precedent for a bacterium synthesizing pGpp exclusively. Hydrolysis of the 5′ phosphate or pyrophosphate from GDP or GTP substrates is necessary for activity by the clostridial enzymes, neither of which can utilize GMP as a substrate. Both enzymes are remarkably insensitive to the size of their metal ion cofactor, tolerating a broad array of metals that do not allow activity in (pp)pGpp synthetases from other organisms. It is clear that while C. difficile utilizes alarmone signaling, its mechanisms of alarmone synthesis are not directly homologous to those in more completely characterized organisms.
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Original Publication Citation
Poudel, A., Pokhrel, A., Oludiran, A., Coronado, E. J., Alleyne, K., Gilfus, M. M., Gurung, R. K., Adhikari, S. B., Purcell, E. B., & Federle, M. J. (2022). Unique features of alarmone metabolism in Clostridioides difficile. Journal of Bacteriology, 204(4), 1-18, Article e00575-21. https://doi.org/10.1128/jb.00575-21
Poudel, Asia; Pokhrel, Astha; Oludiran, Adenrele; Coronado, Estevan J.; Alleyne, Kwincy; Gilfus, Marrett M.; Gurung, Raj K.; Adhikari, Surya B.; and Purcell, Erin B., "Unique Features of Alarmone Metabolism in Clostridioides difficile" (2022). Chemistry & Biochemistry Faculty Publications. 242.