The conserved nucleotide diadenosine tetraphosphate (Ap4A) is induced under various stresses, including heat. In a non-biased screen, we identified a critical role of Ap4A in inhibiting a central step in purine metabolism and heat resistance. We clarify the molecular mechanism of Ap4A action on the inosine-5′-monophosphate dehydrogenase (IMPDH) enzyme, showing Ap4A as a bona fide nucleotide second messenger.
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References
Lee, P. C., Bochner, B. R. & Ames, B. N. AppppA, heat-shock stress, and cell oxidation. Proc. Natl Acad. Sci. USA 80, 7496–7500 (1983). A classic review article describing the early discovery of Ap4A as a potential alarmone.
Fernández-Justel, D., Peláez, R., Revuelta, J. L. & Buey, R. M. The Bateman domain of IMP dehydrogenase is a binding target for dinucleoside polyphosphates. J. Biol. Chem. 294, 14768–14775 (2019). An earlier study that corroborates the finding of IMPDH as a binding target of Ap4A in the fungus Ashbya gossypii.
Yang, J. et al. The nucleotide pGpp acts as a third alarmone in Bacillus, with functions distinct from those of (p)ppGpp. Nat. Commun. 11, 5388 (2020). This paper reports the Bacillus anthracis open reading frame overexpression library used in this systematic screen, and the DRaCALA method that identified IMPDH as an Ap4A target.
Hedstrom, L. IMP dehydrogenase: structure, mechanism, and inhibition. Chem. Rev. 109, 2903–2928 (2009). A review article that gives an overview of IMPDH.
Kriel, A. et al. Direct regulation of GTP homeostasis by (p)ppGpp: a critical component of viability and stress resistance. Mol. Cell 48, 231–241 (2012). This paper reports direct enzymatic inhibition of purine synthesis enzymes by another bona fide alarmone, (p)ppGpp.
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This is a summary of: Giammarinaro, P. I. et al. Diadenosine tetraphosphate regulates biosynthesis of GTP in Bacillus subtilis. Nat. Microbiol. https://doi.org/10.1038/s41564-022-01193-x (2022).
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A conserved alarmone as a direct regulator of purine metabolism. Nat Microbiol 7, 1331–1332 (2022). https://doi.org/10.1038/s41564-022-01194-w
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DOI: https://doi.org/10.1038/s41564-022-01194-w
