ArticleProtein science : a publication of the Protein Society2022
Diversity of mechanisms to control bacterial GTP homeostasis by the mutually exclusive binding of adenine and guanine nucleotides to IMP dehydrogenase.
Article in Protein science : a publication of the Protein Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Substrate cooperativity shapes competitive inhibitor responses in mycobacterial inosine 5'-monophosphate dehydrogenase.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Structural basis for allosteric regulation of mycobacterial guanosine 5´-monophosphate reductase by ATP and GTP.Nature communications · 2026Article
- Article
- The Leptospira interrogans proteome's response to zinc highlights the potential involvement of this metal in translational-machinery and virulence.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2024Article
- Deciphering the allosteric regulation of mycobacterial inosine-5'-monophosphate dehydrogenase.Nature communications · 2024Article
- Specific Mutations Reverse Regulatory Effects of Adenosine Phosphates and Increase Their Binding Stoichiometry in CBS Domain-Containing Pyrophosphatase.International journal of molecular sciences · 2024Article
- A journey into the regulatory secrets of theFrontiers in pharmacology · 2024Review
- The Structure and Nucleotide-Binding Characteristics of Regulated Cystathionine β-Synthase Domain-Containing Pyrophosphatase without One Catalytic Domain.International journal of molecular sciences · 2023Article
- Crosstalk between (p)ppGpp and other nucleotide second messengers.Current opinion in microbiology · 2023Review
- Tale of Twin Bifunctional Second Messenger (p)ppGpp Synthetases and Their Function in Mycobacteria.ACS omega · 2023Review
- Insight into the role of the Bateman domain at the molecular and physiological levels through engineered IMP dehydrogenases.Protein science : a publication of the Protein Society · 2023Article
- The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases.Protein science : a publication of the Protein Society · 2022Review
- Diversity of mechanisms to control bacterial GTP homeostasis by the mutually exclusive binding of adenine and guanine nucleotides to IMP dehydrogenase.Protein science : a publication of the Protein Society · 2022Article
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8 authors.
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Abstract
IMP dehydrogenase(IMPDH) is an essential enzyme that catalyzes the rate-limiting step in the guanine nucleotide pathway. In eukaryotic cells, GTP binding to the regulatory domain allosterically controls the activity of IMPDH by a mechanism that is fine-tuned by post-translational modifications and enzyme polymerization. Nonetheless, the mechanisms of regulation of IMPDH in bacterial cells remain unclear. Using biochemical, structural, and evolutionary analyses, we demonstrate that, in most bacterial phyla, (p)ppGpp compete with ATP to allosterically modulate IMPDH activity by binding to a, previously unrecognized, conserved high affinity pocket within the regulatory domain. This pocket was lost during the evolution of Proteobacteria, making their IMPDHs insensitive to these alarmones. Instead, most proteobacterial IMPDHs evolved to be directly modulated by the balance between ATP and GTP that compete for the same allosteric binding site. Altogether, we demonstrate that the activity of bacterial IMPDHs is allosterically modulated by a universally conserved nucleotide-controlled conformational switch that has divergently evolved to adapt to the specific particularities of each organism. These results reconcile the reported data on the crosstalk between (p)ppGpp signaling and the guanine nucleotide biosynthetic pathway and reinforce the essential role of IMPDH allosteric regulation on bacterial GTP homeostasis.
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