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Title: Diadenosine-tetraphosphate regulates biosynthesis of GTP in Bacillus subtilis
Diadenosine tetraphosphate (Ap4A) is a putative second messenger molecule that is conserved from bacteria to man. Nevertheless, its physiological role, and the underlying molecular mechanisms, are poorly characterized. We investigated the molecular mechanism by which Ap4A regulates inosine-5’-monophosphate dehydrogenase (IMPDH, a key branching point enzyme for the biosynthesis of adenosine or guanosine nucleotides) in Bacillus subtilis. We solved the crystal structure of BsIMPDH bound to Ap4A at a resolution of 2.45 Å to show that Ap4A binds to the interface between two IMPDH subunits, acting as the glue that switches active IMPDH tetramers into less active octamers. Guided by these insights, we engineered mutant strains of B. subtilis that bypass Ap4A-dependent IMPDH regulation without perturbing intracellular Ap4A pools themselves. We used metabolomics suggesting that these mutants have a dysregulated purine, and in particular GTP, metabolome and phenotypic analysis showing increased sensitivity of B. subtilis IMPDH mutant strains to heat compared with wild-type. Our study identifies a central role for IMPDH in remodelling metabolism and heat resistance, and provides evidence that Ap4A can function as an alarmone.  more » « less
Award ID(s):
1715710
PAR ID:
10345311
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ;
Editor(s):
Emma Overmaat
Date Published:
Journal Name:
Nature microbiology
ISSN:
2058-5276
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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