Functional Consequence of Covalent Reaction of Phosphoenolpyruvate with UDP-N-acetylglucosamine 1-Carboxyvinyltransferase (MurA)

Zhu, J.; Yang, Yan; Han, Huijong; Betzi, S.; Olesen, Sanne H.; Marsilio, Frank; Schönbrunn, E.

doi:10.1074/jbc.m112.342725

Cited by 58 publications

(75 citation statements)

References 31 publications

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“…Recent studies have shown that MurA forms dormant complexes with UDP-N-acetylmuramic acid (UDP-MurNAc), which is the product of MurB, the second enzyme partici-pating in peptidoglycan synthesis. This supports the idea that Cys115 provides tight product regulation and protection, which are absent from species containing aspartic acid in this position (30).…”

supporting

confidence: 81%

“…A previous study reported that the product of the MurB enzyme UDP-MurNAc of E. cloacae binds tightly to MurA, creating a dormant complex. Therefore, UDP-MurNAc could act as a negative feedback regulator of MurA when it is present in excess (30). Because the murB sequences of Hungary 19A and D39 differ, we tested whether murB switch mutants of strains D39 (GenBank accession no.…”

Section: Resultsmentioning

confidence: 99%

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Heteroresistance to Fosfomycin Is Predominant in Streptococcus pneumoniae and Depends on the murA1 Gene

Engel

Gutiérrez-Fernández

Flückiger

et al. 2013

Antimicrob Agents Chemother

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dFosfomycin targets the first step of peptidoglycan biosynthesis in Streptococcus pneumoniae catalyzed by UDP-N-acetylglucosamine enolpyruvyltransferase (MurA1). We investigated whether heteroresistance to fosfomycin occurs in S. pneumoniae. We found that of 11 strains tested, all but 1 (Hungary 19A ) displayed heteroresistance and that deletion of murA1 abolished heteroresistance. Hungary 19A differs from the other strains by a single amino acid substitution in MurA1 (Ala 364 Thr). To test whether this substitution is responsible for the lack of heteroresistance, it was introduced into strain D39. The heteroresistance phenotype of strain D39 was not changed. Furthermore, no relevant structural differences between the MurA1 crystal structures of heteroresistant strain D39 and nonheteroresistant strain Hungary 19A were found. Our results reveal that heteroresistance to fosfomycin is the predominant phenotype of S. pneumoniae and that MurA1 is required for heteroresistance to fosfomycin but is not the only factor involved. The findings provide a caveat for any future use of fosfomycin in the treatment of pneumococcal infections.

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supporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

Heteroresistance to Fosfomycin Is Predominant in Streptococcus pneumoniae and Depends on the murA1 Gene

Engel

Gutiérrez-Fernández

Flückiger

et al. 2013

Antimicrob Agents Chemother

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“…Recent work (Zhu et al 2012) indicates that, in the cell, the activity of MurA is subject to regulation by the binding of UDP-NAc-muramic acid (UDP-MurNAc), the product of the MurB enzyme, to MurA. In the presence of bound UDP-MurNAc, PEP covalently attaches to C115, leading to the formation of a "locked" dormant tertiary complex (MurA:PEP-UDPMurNAc), which is the predominant form of cellular MurA.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Fosfomycin: Mechanism and Resistance

Silver¹

2017

Cold Spring Harb Perspect Med

241

169

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“…The assay developed by Zhu and colleagues (2012) [49] revealed that the cysteine and aspartate side chains adopt similar positions and conformations in the PEP binding site through a general acid-–base mechanism with rapid and reversible binding of PEP. The results of this study imply that the cysteine or aspartate residue at position 115 of E. coli (residue 117 in M. tuberculosis ) performs the role of a general acid in the protonation of C-3 of PEP during the reaction.…”

Section: Methodsmentioning

confidence: 99%

“…Superposition of the calculated MurA protein of M. tuberculosis (blue) and H. influenzae (green – 3SWE) [49]. Catalytic residues are shown.…”

Section: Figurementioning

confidence: 99%

Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development

et al. 2015

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SUMMARY Tuberculosis (TB) is the second leading cause of human mortality from infectious diseases worldwide. The WHO reported 1.3 million deaths and 8.6 million new cases of TB in 2012. Mycobacterium tuberculosis (M. tuberculosis), the infectious bacteria that causes TB, is encapsulated by a thick and robust cell wall. The innermost segment of the cell wall is comprised of peptidoglycan, a layer that is required for survival and growth of the pathogen. Enzymes that catalyse biosynthesis of the peptidoglycan are essential and are therefore attractive targets for discovery of novel antibiotics as humans lack similar enzymes making it possible to selectively target bacteria only. In this paper, we have reviewed the structures and functions of enzymes GlmS, GlmM, GlmU, MurA, MurB, MurC, MurD, MurE and MurF from M. tuberculosis that are involved in peptidoglycan biosynthesis. In addition, we report homology modelled 3D structures of those key enzymes from M. tuberculosis of which the structures are still unknown. We demonstrated that natural substrates can be successfully docked into the active sites of the GlmS and GlmU respectively. It is therefore expected that the models and the data provided herein will facilitate translational research to develop new drugs to treat TB.

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Functional Consequence of Covalent Reaction of Phosphoenolpyruvate with UDP-N-acetylglucosamine 1-Carboxyvinyltransferase (MurA)

Cited by 58 publications

References 31 publications

Heteroresistance to Fosfomycin Is Predominant in Streptococcus pneumoniae and Depends on the murA1 Gene

Heteroresistance to Fosfomycin Is Predominant in Streptococcus pneumoniae and Depends on the murA1 Gene

Fosfomycin: Mechanism and Resistance

Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development

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