ArticleNature chemical biology2020
Structural basis for antibiotic action of the B
Article in Nature chemical biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 25 citations in OpenAlex.
- Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds.Biochemistry · 2026Article
- Covalent Docking to the Active Sites of Thiamine Diphosphate-Dependent Enzymes.Molecules (Basel, Switzerland) · 2025Article
- Triazole-Based Thiamine Analogues as Inhibitors of Thiamine Pyrophosphate-Dependent Enzymes: 1,3-Dicarboxylate for Metal Binding.ACS omega · 2024Article
- Phosphomethylpyrimidine Synthase (ThiC): Trapping of Five Intermediates Provides Mechanistic Insights on a Complex Radical Cascade Reaction in Thiamin Biosynthesis.ACS central science · 2024Article
- Structural determination and kinetic analysis of the transketolase from Vibrio vulnificus reveal unexpected cooperative behavior.Protein science : a publication of the Protein Society · 2024Article
- Characterization of anBiochemistry · 2024Article
- Inhibition of Thiamine Diphosphate-Dependent Enzymes by Triazole-Based Thiamine Analogues.ACS medicinal chemistry letters · 2023Article
- Simulations of Pathogenic E1α Variants: Allostery and Impact on Pyruvate Dehydrogenase Complex-E1 Structure and Function.Journal of chemical information and modeling · 2022Article
- Article
- Low barrier hydrogen bonds in protein structure and function.Biochimica et biophysica acta. Proteins and proteomics · 2021Review
- Conformational Dynamics Contribute to Substrate Selectivity and Catalysis in Human Kynureninase.ACS chemical biology · 2020Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The natural antivitamin 2'-methoxy-thiamine (MTh) is implicated in the suppression of microbial growth. However, its mode of action and enzyme-selective inhibition mechanism have remained elusive. Intriguingly, MTh inhibits some thiamine diphosphate (ThDP) enzymes, while being coenzymatically active in others. Here we report the strong inhibition of Escherichia coli transketolase activity by MTh and unravel its mode of action and the structural basis thereof. The unique 2'-methoxy group of MTh diphosphate (MThDP) clashes with a canonical glutamate required for cofactor activation in ThDP-dependent enzymes. This glutamate is forced into a stable, anticatalytic low-barrier hydrogen bond with a neighboring glutamate, disrupting cofactor activation. Molecular dynamics simulations of transketolases and other ThDP enzymes identify active-site flexibility and the topology of the cofactor-binding locale as key determinants for enzyme-selective inhibition. Human enzymes either retain enzymatic activity with MThDP or preferentially bind authentic ThDP over MThDP, while core bacterial metabolic enzymes are inhibited, demonstrating therapeutic potential.
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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.