ArticleProceedings of the National Academy of Sciences of the United States of America2023
Identification of a broadly conserved family of enzymes that hydrolyze (p)ppApp.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 13 citations in OpenAlex.
- Genomic, Evolutionary and Phenotypic Insights intoViruses · 2025Article
- Article
- Comparative study of adenosine 3'-pyrophosphokinase domains of MuF polymorphic toxins.FEBS open bio · 2025Article
- How to quantify magic spots - a brief overview of (p)ppGpp detection and quantitation methods.Frontiers in molecular biosciences · 2025Review
- Prokaryotic homeostasis - a solution to thrive and survive.Frontiers in molecular biosciences · 2025Review
- TGR5 deficiency in excitatory neurons ameliorates Alzheimer's pathology by regulating APP processing.Science advances · 2024Article
- Synthetase and Hydrolase Specificity Collectively Excludes 2'-Deoxyguanosine from Bacterial Alarmone.bioRxiv : the preprint server for biology · 2024Article
- Crosstalk between (p)ppGpp and other nucleotide second messengers.Current opinion in microbiology · 2023Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
Abstract
Bacteria produce a variety of nucleotide second messengers to adapt to their surroundings. Although chemically similar, the nucleotides guanosine penta- and tetraphosphate [(p)ppGpp] and adenosine penta- and tetraphosphate [(p)ppApp] have distinct functions in bacteria. (p)ppGpp mediates survival under nutrient-limiting conditions and its intracellular levels are regulated by synthetases and hydrolases belonging to the RelA-SpoT homolog (RSH) family of enzymes. By contrast, (p)ppApp is not known to be involved in nutrient stress responses and is synthesized by RSH-resembling toxins that inhibit the growth of bacterial cells. However, it remains unclear whether there exists a family of hydrolases that specifically act on (p)ppApp to reverse its toxic effects. Here, we present the structure and biochemical characterization of adenosine 3'-pyrophosphohydrolase 1 (Aph1), the founding member of a monofunctional (p)ppApp hydrolase family of enzymes. Our work reveals that Aph1 adopts a histidine-aspartate (HD)-domain fold characteristic of phosphohydrolase metalloenzymes and its activity mitigates the growth inhibitory effects of (p)ppApp-synthesizing toxins. Using an informatic approach, we identify over 2,000 putative (p)ppApp hydrolases that are widely distributed across bacterial phyla and found in diverse genomic contexts, and we demonstrate that 12 representative members hydrolyze ppApp. In addition, our in silico analyses reveal a unique molecular signature that is specific to (p)ppApp hydrolases, and we show that mutation of two residues within this signature broadens the specificity of Aph1 to promiscuously hydrolyze (p)ppGpp in vitro. Overall, our findings indicate that like (p)ppGpp hydrolases, (p)ppApp hydrolases are widespread in bacteria and may play important and underappreciated role(s) in bacterial physiology.
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Registered trials
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