ArticleThe Journal of biological chemistry2012
Structural and functional characterization of VanG D-Ala:D-Ser ligase associated with vancomycin resistance in Enterococcus faecalis.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
- Catalytic loop closure governs substrate selectivity in the rhizocticin biosynthetic ligases RhiM and RhiC.The Journal of biological chemistry · 2026Article
- Overexpression, Purification, and Biochemical Characterization of the vanC2 d-Ala-d-Ser Ligase fromACS omega · 2025Article
- Phylogenetic Analysis of the Genes in D-Ala-D-Lactate Synthesizing Glycopeptide Resistance Operons: The Different Origins of Functional and Regulatory Genes.Antibiotics (Basel, Switzerland) · 2024Article
- VanG- and D-Ala-D-Ser-dependent peptidoglycan synthesis and vancomycin resistance in Clostridioides difficile.Molecular microbiology · 2022Article
- Consequences of Substitution Model Selection on Protein Ancestral Sequence Reconstruction.Molecular biology and evolution · 2022Article
- Regulation of Resistance in Vancomycin-Resistant Enterococci: The VanRS Two-Component System.Microorganisms · 2021Review
- Novel vancomycin resistance gene cluster inEuro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin · 2021Article
- Integron gene cassettes harboring novel variants of D-alanine-D-alanine ligase confer high-level resistance to D-cycloserine.Scientific reports · 2020Article
- New Antimicrobial Bioactivity against Multidrug-Resistant Gram-Positive Bacteria of Kinase Inhibitor IMD0354.Antibiotics (Basel, Switzerland) · 2020Article
- Molecular mechanisms of vancomycin resistance.Protein science : a publication of the Protein Society · 2020Review
- Peptidoglycan O-acetylation increases in response to vancomycin treatment in vancomycin-resistant Enterococcus faecalis.Scientific reports · 2017Article
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- Resistance to antibiotics targeted to the bacterial cell wall.Protein science : a publication of the Protein Society · 2014Review
- Vancomycin Insights: An Update on Mechanism, Activity, Toxicity, Resistance, and Novel Drug Delivery Systems.Iranian journal of pharmaceutical research : IJPRReview
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
d-Alanyl:d-lactate (d-Ala:d-Lac) and d-alanyl:d-serine ligases are key enzymes in vancomycin resistance of Gram-positive cocci. They catalyze a critical step in the synthesis of modified peptidoglycan precursors that are low binding affinity targets for vancomycin. The structure of the d-Ala:d-Lac ligase VanA led to the understanding of the molecular basis for its specificity, but that of d-Ala:d-Ser ligases had not been determined. We have investigated the enzymatic kinetics of the d-Ala:d-Ser ligase VanG from Enterococcus faecalis and solved its crystal structure in complex with ADP. The overall structure of VanG is similar to that of VanA but has significant differences mainly in the N-terminal and central domains. Based on reported mutagenesis data and comparison of the VanG and VanA structures, we show that residues Asp-243, Phe-252, and Arg-324 are molecular determinants for d-Ser selectivity. These residues are conserved in both enzymes and explain why VanA also displays d-Ala:d-Ser ligase activity, albeit with low catalytic efficiency in comparison with VanG. These observations suggest that d-Ala:d-Lac and d-Ala:d-Ser enzymes have evolved from a common ancestral d-Ala:d-X ligase. The crystal structure of VanG showed an unusual interaction between two dimers involving residues of the omega loop that are deeply anchored in the active site. We constructed an octapeptide mimicking the omega loop and found that it selectively inhibits VanG and VanA but not Staphylococcus aureus d-Ala:d-Ala ligase. This study provides additional insight into the molecular evolution of d-Ala:d-X ligases and could contribute to the development of new structure-based inhibitors of vancomycin resistance enzymes.
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