Characterisation of ATP-dependent Mur ligases involved in the biogenesis of cell wall peptidoglycan in Mycobacterium tuberculosis
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...
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| creator | Munshi, Tulika Gupta, Antima Evangelopoulos, Dimitrios Guzman, Juan David Gibbons, Simon Keep, Nicholas H Bhakta, Sanjib |
| description | 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. |
| doi_str_mv | 10.1371/journal.pone.0060143 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0060143</identifier><identifier>PMID: 23555903</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine Triphosphate - metabolism ; Amino acids ; Analysis ; Antibacterial agents ; ATP ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Biology ; Biosynthesis ; Cations ; Cell division ; Cell Wall - metabolism ; Cell walls ; Chromatography, High Pressure Liquid ; Chromosomes ; Divalent cations ; Drug discovery ; Drug resistance ; E coli ; Enzymes ; Escherichia coli ; Health aspects ; Kinases ; Ligases ; Medicine ; Molecular biology ; Mycobacterium tuberculosis ; Mycobacterium tuberculosis - enzymology ; Mycobacterium tuberculosis - genetics ; Mycobacterium tuberculosis - metabolism ; Penicillin ; Peptide Synthases - genetics ; Peptide Synthases - metabolism ; Peptidoglycan - biosynthesis ; Peptidoglycans ; Pharmacy ; Phosphorylation ; Plasmids ; Protein Binding ; Protein Folding ; Protein kinase ; Protein kinases ; Protein Serine-Threonine Kinases - genetics ; Protein Serine-Threonine Kinases - metabolism ; Proteins ; Substrate inhibition ; Sugar ; Therapeutic applications ; Transcription ; Transcription (Genetics) ; Tuberculosis</subject><ispartof>PloS one, 2013-03, Vol.8 (3), p.e60143-e60143</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Munshi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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. 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| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adenosine Triphosphate - metabolism Amino acids Analysis Antibacterial agents ATP Bacterial Proteins - genetics Bacterial Proteins - metabolism Biology Biosynthesis Cations Cell division Cell Wall - metabolism Cell walls Chromatography, High Pressure Liquid Chromosomes Divalent cations Drug discovery Drug resistance E coli Enzymes Escherichia coli Health aspects Kinases Ligases Medicine Molecular biology Mycobacterium tuberculosis Mycobacterium tuberculosis - enzymology Mycobacterium tuberculosis - genetics Mycobacterium tuberculosis - metabolism Penicillin Peptide Synthases - genetics Peptide Synthases - metabolism Peptidoglycan - biosynthesis Peptidoglycans Pharmacy Phosphorylation Plasmids Protein Binding Protein Folding Protein kinase Protein kinases Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Proteins Substrate inhibition Sugar Therapeutic applications Transcription Transcription (Genetics) Tuberculosis |
| title | Characterisation of ATP-dependent Mur ligases involved in the biogenesis of cell wall peptidoglycan in Mycobacterium tuberculosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T22%3A58%3A46IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Characterisation%20of%20ATP-dependent%20Mur%20ligases%20involved%20in%20the%20biogenesis%20of%20cell%20wall%20peptidoglycan%20in%20Mycobacterium%20tuberculosis&rft.jtitle=PloS%20one&rft.au=Munshi,%20Tulika&rft.date=2013-03-21&rft.volume=8&rft.issue=3&rft.spage=e60143&rft.epage=e60143&rft.pages=e60143-e60143&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0060143&rft_dat=%3Cgale_plos_%3EA478173052%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1330893691&rft_id=info:pmid/23555903&rft_galeid=A478173052&rft_doaj_id=oai_doaj_org_article_e53b97656f6d45629eaee5ee1422a075&rfr_iscdi=true |