ArticlePLoS pathogens2019
Inhibition of the Staphylococcus aureus c-di-AMP cyclase DacA by direct interaction with the phosphoglucosamine mutase GlmM.
Article in PLoS pathogens, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
35 citing papers in PubMed, 62 citations in OpenAlex.
- Cyclic di-AMP signaling and regulation inmSphere · 2026Review
- TheInfection and immunity · 2026Article
- Post-translational modifications of GlmR integrate metabolic and stress signals to maintain cell envelope homeostasis in Bacillus subtilis.PLoS genetics · 2026Article
- Staying in the loop to make ends meet: roles and regulation of GlmR inbioRxiv : the preprint server for biology · 2025Article
- The second messenger signaling molecule cyclic di-AMP drives developmental cycle progression ineLife · 2025Article
- Genome-wide analysis ofJournal of bacteriology · 2025Article
- Membrane-embedded CdaA is required for efficient synthesis of second messenger cyclic di-AMP.Communications biology · 2024Article
- Article
- Characterization of c-di-AMP signaling in the periodontal pathobiont, Treponema denticola.Molecular oral microbiology · 2024Article
- Depletion of essential mycobacterial gene glmM reduces pathogen survival and induces host-protective immune responses against tuberculosis.Communications biology · 2024Article
- Reducing Peptidoglycan Crosslinking by Chemical Modulator Reverts β-lactam Resistance in Methicillin-Resistant Staphylococcus aureus.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Bacterial cell volume regulation and the importance of cyclic di-AMP.Microbiology and molecular biology reviews : MMBR · 2024Review
- Tetracyclic homoisoflavanoid (+)-brazilin: a natural product inhibits c-di-AMP-producing enzyme andMicrobiology spectrum · 2024Article
- Bacteriophages avoid autoimmunity from cognate immune systems as an intrinsic part of their life cycles.Nature microbiology · 2024Article
- Coordinated regulation of osmotic imbalance by c-di-AMP shapes ß-lactam tolerance in Group BmicroLife · 2024Article
- Synthesis and degradation of the cyclic dinucleotide messenger c-di-AMP in the hyperthermophilic archaeon Pyrococcus yayanosii.Protein science : a publication of the Protein Society · 2023Article
- All DACs in a Row: Domain Architectures of Bacterial and Archaeal Diadenylate Cyclases.Journal of bacteriology · 2023Review
- C-di-AMP Is a Second Messenger inMicroorganisms · 2023Article
- Cyclic di-AMP, a multifaceted regulator of central metabolism and osmolyte homeostasis inmicroLife · 2023Review
- The many roles of cyclic di-AMP to control the physiology ofmicroLife · 2023Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
c-di-AMP is an important second messenger molecule that plays a pivotal role in regulating fundamental cellular processes, including osmotic and cell wall homeostasis in many Gram-positive organisms. In the opportunistic human pathogen Staphylococcus aureus, c-di-AMP is produced by the membrane-anchored DacA enzyme. Inactivation of this enzyme leads to a growth arrest under standard laboratory growth conditions and a re-sensitization of methicillin-resistant S. aureus (MRSA) strains to ß-lactam antibiotics. The gene coding for DacA is part of the conserved three-gene dacA/ybbR/glmM operon that also encodes the proposed DacA regulator YbbR and the essential phosphoglucosamine mutase GlmM, which is required for the production of glucosamine-1-phosphate, an early intermediate of peptidoglycan synthesis. These three proteins are thought to form a complex in vivo and, in this manner, help to fine-tune the cellular c-di-AMP levels. To further characterize this important regulatory complex, we conducted a comprehensive structural and functional analysis of the S. aureus DacA and GlmM enzymes by determining the structures of the S. aureus GlmM enzyme and the catalytic domain of DacA. Both proteins were found to be dimers in solution as well as in the crystal structures. Further site-directed mutagenesis, structural and enzymatic studies showed that multiple DacA dimers need to interact for enzymatic activity. We also show that DacA and GlmM form a stable complex in vitro and that S. aureus GlmM, but not Escherichia coli or Pseudomonas aeruginosa GlmM, acts as a strong inhibitor of DacA function without the requirement of any additional cellular factor. Based on Small Angle X-ray Scattering (SAXS) data, a model of the complex revealed that GlmM likely inhibits DacA by masking the active site of the cyclase and preventing higher oligomer formation. Together these results provide an important mechanistic insight into how c-di-AMP production can be regulated in the cell.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.