Diadenosine tetraphosphate regulates biosynthesis of GTP in Bacillus subtilis.
Journal
Nature microbiology
ISSN: 2058-5276
Titre abrégé: Nat Microbiol
Pays: England
ID NLM: 101674869
Informations de publication
Date de publication:
09 2022
09 2022
Historique:
received:
11
06
2021
accepted:
29
06
2022
pubmed:
12
8
2022
medline:
31
8
2022
entrez:
11
8
2022
Statut:
ppublish
Résumé
Diadenosine tetraphosphate (Ap4A) is a putative second messenger molecule that is conserved from bacteria to humans. 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, which suggests that these mutants have a dysregulated purine, and in particular GTP, metabolome and phenotypic analysis, which shows increased sensitivity of B. subtilis IMPDH mutant strains to heat compared with wild-type strains. Our study identifies a central role for IMPDH in remodelling metabolism and heat resistance, and provides evidence that Ap4A can function as an alarmone.
Identifiants
pubmed: 35953658
doi: 10.1038/s41564-022-01193-x
pii: 10.1038/s41564-022-01193-x
pmc: PMC10439310
mid: NIHMS1919768
doi:
Substances chimiques
Dinucleoside Phosphates
0
diadenosine tetraphosphate
5542-28-9
Guanosine Triphosphate
86-01-1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1442-1452Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM127088
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
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