Unique Features of Alarmone Metabolism in Clostridioides difficile

Authors

Asia Poudel, Old Dominion UniversityFollow
Astha Pokhrel, Old Dominion UniversityFollow
Adenrele Oludiran, Old Dominion UniversityFollow
Estevan J. Coronado, Old Dominion University
Kwincy Alleyne, Old Dominion UniversityFollow
Marrett M. Gilfus, Old Dominion University
Raj K. Gurung, Old Dominion UniversityFollow
Surya B. Adhikari, Old Dominion UniversityFollow
Erin B. Purcell, Old Dominion UniversityFollow

Document Type

Article

Publication Date

2022

DOI

10.1128/jb.00575-21

Publication Title

Journal of Bacteriology

Volume

204

Issue

4

Pages

e00575-21 (1-18)

Abstract

The “magic spot” alarmones (pp)pGpp, previously implicated in Clostridioides difficile antibiotic survival, are synthesized by the RelA-SpoT homolog (RSH) of C. difficile (RSH_Cd) and RelQ_Cd. These enzymes are transcriptionally activated by diverse environmental stresses. RSH_Cd 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.

Rights

© 2022 American Society for Microbiology.

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Data Availability

Article states: The data that support the findings of this study are available from the corresponding author upon reasonable request.

Comments

Supplemental material available as attachment.

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

ORCID

0000-0002-8736-0433 (Purcell)

Repository Citation

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.
https://digitalcommons.odu.edu/chemistry_fac_pubs/242