MurD enzymes from different bacteria: Evaluation of inhibitors

Barreteau, Hélène; Sosič, Izidor; Turk, Samo; Humljan, Jan; Tomašič, Tihomir; Zidar, Nace; Hervé, Mireille; Boniface, Audrey; Mašič, Lucíja Peterlin; Kikelj, D.; Mengin‐Lecreulx, Dominique; Blanot, Didier

doi:10.1016/j.bcp.2012.06.006

Cited by 20 publications

(17 citation statements)

References 33 publications

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“…Furthermore, these proteins were highly sensitive to pH, showing optimal activity at alkaline pH 8.0–8.5, as also seen earlier in the cases of MurD [31] and MurE [15], [41], [42]. We further showed that a concentration of UDP sugar higher than 0.2 mM led to significant inhibition of the ligation activity.…”

Section: Discussionsupporting

confidence: 87%

“…MurD on the other hand exhibited higher K M values for UDP-MurNAc-L-Ala whereas ATP and D-Glu values were comparable to those obtained for E. coli MurD [28]. However, kinetic analysis of M. tuberculosis MurD by Barreteau et al [31] showed higher K M values, which might be attributed to the difference in assay methods used for analysis. Similarly the K M values for ATP and UDP-MurNAc-L-Ala-γ-D-Glu-m-DAP were obtained for MurF, but were much lower than those published for either Staphylococcus aureus or E. coli MurF [11], [32].…”

Section: Resultsmentioning

confidence: 96%

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Characterisation of ATP-Dependent Mur Ligases Involved in the Biogenesis of Cell Wall Peptidoglycan in Mycobacterium tuberculosis

et al. 2013

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ATP-dependent Mur ligases (Mur synthetases) play essential roles in the biosynthesis of cell wall peptidoglycan (PG) as they catalyze the ligation of key amino acid residues to the stem peptide at the expense of ATP hydrolysis, thus representing potential targets for antibacterial drug discovery. In this study we characterized the division/cell wall (dcw) operon and identified a promoter driving the co-transcription of mur synthetases along with key cell division genes such as ftsQ and ftsW. Furthermore, we have extended our previous investigations of MurE to MurC, MurD and MurF synthetases from Mycobacterium tuberculosis. Functional analyses of the pure recombinant enzymes revealed that the presence of divalent cations is an absolute requirement for their activities. We also observed that higher concentrations of ATP and UDP-sugar substrates were inhibitory for the activities of all Mur synthetases suggesting stringent control of the cytoplasmic steps of the peptidoglycan biosynthetic pathway. In line with the previous findings on the regulation of mycobacterial MurD and corynebacterial MurC synthetases via phosphorylation, we found that all of the Mur synthetases interacted with the Ser/Thr protein kinases, PknA and PknB. In addition, we critically analyzed the interaction network of all of the Mur synthetases with proteins involved in cell division and cell wall PG biosynthesis to re-evaluate the importance of these key enzymes as novel therapeutic targets in anti-tubercular drug discovery.

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 96%

Characterisation of ATP-Dependent Mur Ligases Involved in the Biogenesis of Cell Wall Peptidoglycan in Mycobacterium tuberculosis

et al. 2013

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“…However, the overall similarity is small. Considering this, it was not quite surprising that compounds that had been designed as inhibitors of MurD from E. coli turned out to be weaker inhibitors of other MurD orthologs (52). For example, compounds 15, 16, 20 (Scheme 6) and 22, 24, 25, 26 (Scheme 7) either inhibited MurD enzymes from S. aureus, S. pneumoniae, B. burgdorferi and M. tuberculosis in the 0.1-1 mmol/l range or were not inhibitors at all.…”

Section: Scheme 5 5-benzylidenerhodanines Containing D-glutamic Acidmentioning

confidence: 95%

“…For example, compounds 15, 16, 20 (Scheme 6) and 22, 24, 25, 26 (Scheme 7) either inhibited MurD enzymes from S. aureus, S. pneumoniae, B. burgdorferi and M. tuberculosis in the 0.1-1 mmol/l range or were not inhibitors at all. This divergent result could be explained by differences in amino acid sequences and topologies of the active sites of the MurD ligases in question (52).…”

Section: Scheme 5 5-benzylidenerhodanines Containing D-glutamic Acidmentioning

confidence: 97%

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MurD enzymes: some recent developments

Šink

Barreteau

Patin

et al. 2013

BioMolecular Concepts

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The synthesis of the peptide stem of bacterial peptidoglycan involves four enzymes, the Mur ligases (MurC, D, E and F). Among them, MurD is responsible for the ATP-dependent addition of d-glutamic acid to UDP-MurNAc-l-Ala, a reaction which involves acyl-phosphate and tetrahedral intermediates. Like most enzymes of peptidoglycan biosynthesis, MurD constitutes an attractive target for the design and synthesis of new antibacterial agents. Escherichia coli MurD has been the first Mur ligase for which the tridimensional (3D) structure was solved. Thereafter, several co-crystal structures with different ligands or inhibitors were released. In the present review, we will deal with work performed on substrate specificity, reaction mechanism and 3D structure of E. coli MurD. Then, a part of the review will be devoted to recent work on MurD orthologs from species other than E. coli and to cellular organization of Mur ligases and in vivo regulation of the MurD activity. Finally, we will review the different classes of MurD inhibitors that have been designed and assayed to date with the hope of obtaining new antibacterial compounds.

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Structure-based virtual screening to identify inhibitors against Staphylococcus aureus MurD enzyme

Azam

Jupudi

2019

Struct Chem

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MurD enzymes from different bacteria: Evaluation of inhibitors

Cited by 20 publications

References 33 publications

Characterisation of ATP-Dependent Mur Ligases Involved in the Biogenesis of Cell Wall Peptidoglycan in Mycobacterium tuberculosis

Characterisation of ATP-Dependent Mur Ligases Involved in the Biogenesis of Cell Wall Peptidoglycan in Mycobacterium tuberculosis

MurD enzymes: some recent developments

Structure-based virtual screening to identify inhibitors against Staphylococcus aureus MurD enzyme

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