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Essential residues for the enzyme activity of ATP-dependent MurE ligase from Mycobacterium tuberculosis.

Basavannacharya C, Moody PR, Munshi T, Cronin N, Keep NH, Bhakta S
Protein Cell 1 1011-22 (2010)
Cited: 20 times
EuropePMC logo PMID: 21153518

Abstract

The emergence of total drug-resistant tuberculosis (TDRTB) has made the discovery of new therapies for tuberculosis urgent. The cytoplasmic enzymes of peptidoglycan biosynthesis have generated renewed interest as attractive targets for the development of new anti-mycobacterials. One of the cytoplasmic enzymes, uridine diphosphate (UDP)-MurNAc-tripeptide ligase (MurE), catalyses the addition of meso-diaminopimelic acid (m-DAP) into peptidoglycan in Mycobacterium tuberculosis coupled to the hydrolysis of ATP. Mutants of M. tuberculosis MurE were generated by replacing K157, E220, D392, R451 with alanine and N449 with aspartate, and truncating the first 24 amino acid residues at the N-terminus of the enzyme. Analysis of the specific activity of these proteins suggested that apart from the 24 N-terminal residues, the other mutated residues are essential for catalysis. Variations in K(m) values for one or more substrates were observed for all mutants, except the N-terminal truncation mutant, indicating that these residues are involved in binding substrates and form part of the active site structure. These mutant proteins were also tested for their specificity for a wide range of substrates. Interestingly, the mutations K157A, E220A and D392A showed hydrolysis of ATP uncoupled from catalysis. The ATP hydrolysis rate was enhanced by at least partial occupation of the uridine nucleotide dipeptide binding site. This study provides an insight into the residues essential for the catalytic activity and substrate binding of the ATP-dependent MurE ligase. Since ATP-dependent MurE ligase is a novel drug target, the understanding of its function may lead to development of novel inhibitors against resistant forms of M. tuberculosis.

Reviews - 2xja mentioned but not cited (3)

  1. Cell wall peptidoglycan in Mycobacterium tuberculosis: An Achilles' heel for the TB-causing pathogen. Maitra A, Munshi T, Healy J, Martin LT, Vollmer W, Keep NH, Bhakta S. FEMS Microbiol Rev 43 548-575 (2019)
  2. Structural and functional features of enzymes of Mycobacterium tuberculosis peptidoglycan biosynthesis as targets for drug development. Moraes GL, Gomes GC, Monteiro de Sousa PR, Alves CN, Govender T, Kruger HG, Maguire GE, Lamichhane G, Lameira J. Tuberculosis (Edinb) 95 95-111 (2015)
  3. Anti-Tuberculosis Mur Inhibitors: Structural Insights and the Way Ahead for Development of Novel Agents. Mehta K, Khambete M, Abhyankar A, Omri A. Pharmaceuticals (Basel) 16 377 (2023)

Articles - 2xja mentioned but not cited (2)

  1. Structure based virtual screening to identify inhibitors against MurE Enzyme of Mycobacterium tuberculosis using AutoDock Vina. Singh S, Bajpai U, Lynn AM. Bioinformation 10 697-702 (2014)
  2. Characterization of the MurT/GatD complex in Mycobacterium tuberculosis towards validating a novel anti-tubercular drug target. Maitra A, Nukala S, Dickman R, Martin LT, Munshi T, Gupta A, Shepherd AJ, Arnvig KB, Tabor AB, Keep NH, Bhakta S. JAC Antimicrob Resist 3 dlab028 (2021)


Reviews citing this publication (1)

  1. The Mycobacterial Cell Wall--Peptidoglycan and Arabinogalactan. Alderwick LJ, Harrison J, Lloyd GS, Birch HL. Cold Spring Harb Perspect Med 5 a021113 (2015)

Articles citing this publication (14)

  1. Characterisation of ATP-dependent Mur ligases involved in the biogenesis of cell wall peptidoglycan in Mycobacterium tuberculosis. Munshi T, Gupta A, Evangelopoulos D, Guzman JD, Gibbons S, Keep NH, Bhakta S. PLoS One 8 e60143 (2013)
  2. MreB and MurG as scaffolds for the cytoplasmic steps of peptidoglycan biosynthesis. Favini-Stabile S, Contreras-Martel C, Thielens N, Dessen A. Environ Microbiol 15 3218-3228 (2013)
  3. An antibacterial from Hypericum acmosepalum inhibits ATP-dependent MurE ligase from Mycobacterium tuberculosis. Osman K, Evangelopoulos D, Basavannacharya C, Gupta A, McHugh TD, Bhakta S, Gibbons S. Int J Antimicrob Agents 39 124-129 (2012)
  4. Interaction of N-methyl-2-alkenyl-4-quinolones with ATP-dependent MurE ligase of Mycobacterium tuberculosis: antibacterial activity, molecular docking and inhibition kinetics. Guzman JD, Wube A, Evangelopoulos D, Gupta A, Hüfner A, Basavannacharya C, Rahman MM, Thomaschitz C, Bauer R, McHugh TD, Nobeli I, Prieto JM, Gibbons S, Bucar F, Bhakta S. J Antimicrob Chemother 66 1766-1772 (2011)
  5. Structure of the essential peptidoglycan amidotransferase MurT/GatD complex from Streptococcus pneumoniae. Morlot C, Straume D, Peters K, Hegnar OA, Simon N, Villard AM, Contreras-Martel C, Leisico F, Breukink E, Gravier-Pelletier C, Le Corre L, Vollmer W, Pietrancosta N, Håvarstein LS, Zapun A. Nat Commun 9 3180 (2018)
  6. Specificity determinants for lysine incorporation in Staphylococcus aureus peptidoglycan as revealed by the structure of a MurE enzyme ternary complex. Ruane KM, Lloyd AJ, Fülöp V, Dowson CG, Barreteau H, Boniface A, Dementin S, Blanot D, Mengin-Lecreulx D, Gobec S, Dessen A, Roper DI. J Biol Chem 288 33439-33448 (2013)
  7. Comparative modeling of UDP-N-acetylmuramoyl-glycyl-D-glutamate-2, 6-diaminopimelate ligase from Mycobacterium leprae and analysis of its binding features through molecular docking studies. Shanmugam A, Natarajan J. J Mol Model 18 115-125 (2012)
  8. Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase. Guzman JD, Pesnot T, Barrera DA, Davies HM, McMahon E, Evangelopoulos D, Mortazavi PN, Munshi T, Maitra A, Lamming ED, Angell R, Gershater MC, Redmond JM, Needham D, Ward JM, Cuca LE, Hailes HC, Bhakta S. J Antimicrob Chemother 70 1691-1703 (2015)
  9. Development of a one-pot assay for screening and identification of Mur pathway inhibitors in Mycobacterium tuberculosis. Eniyan K, Kumar A, Rayasam GV, Perdih A, Bajpai U. Sci Rep 6 35134 (2016)
  10. Congress Early diagnosis and effective treatment regimens are the keys to tackle antimicrobial resistance in tuberculosis (TB): A report from Euroscicon's international TB Summit 2016. Maitra A, Kamil TK, Shaik M, Danquah CA, Chrzastek A, Bhakta S. Virulence 8 1005-1024 (2017)
  11. Mutations in MurE, the essential UDP-N-acetylmuramoylalanyl-D-glutamate 2,6-diaminopimelate ligase of Corynebacterium glutamicum: effect on L-lysine formation and analysis of systemic consequences. Hochheim J, Kranz A, Krumbach K, Sokolowsky S, Eggeling L, Noack S, Bocola M, Bott M, Marienhagen J. Biotechnol Lett 39 283-288 (2017)
  12. Congress Mycobacterium tuberculosis... Can we beat it? Report from a Euroscicon conference 2013. Maitra A, Bhakta S. Virulence 4 499-503 (2013)
  13. Diaminopimelic Acid Metabolism by Pseudomonadota in the Ocean. Zheng LY, Liu NH, Zhong S, Yu Y, Zhang XY, Qin QL, Song XY, Zhang YZ, Fu H, Wang M, McMinn A, Chen XL, Li PY. Microbiol Spectr 10 e0069122 (2022)
  14. Putative hexameric glycosyltransferase functional unit revealed by the crystal structure of Acinetobacter baumannii MurG. Jung KH, Kwon S, Kim CM, Lee JH, Park HH. IUCrJ 8 574-583 (2021)


Related citations provided by authors (1)

  1. ATP-dependent MurE ligase in Mycobacterium tuberculosis: biochemical and structural characterisation.. Basavannacharya C, Robertson G, Munshi T, Keep NH, Bhakta S Tuberculosis (Edinb) 90 16-24 (2010)

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