Insight into the molecular basis of substrate recognition by the wall teichoic acid glycosyltransferase TagA

Martinez, Orlando E.; Mahoney, Brendan J.; Goring, Andrew K.; Yi, Sung-Wook; Tran, Diana; Cascio, Duilio; Phillips, Martin; Muthana, Musleh M.; Chen, Xi; Jung, Michael E.; Loo, Joseph A.; Clubb, Robert T.

doi:10.1016/j.jbc.2021.101464

Cited by 4 publications

(2 citation statements)

References 79 publications

(193 reference statements)

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“…Similar results were reported for B. subtilis TagA, a teichoic acid glycosyltransferase. TagA binds both UDP- N -acetylmannosamine (UDP-ManNAc) and UDP-GlcNAc but is enzymatically active only with UDP-ManNAc [30]. This finding raises the question of how the efficiency of WTA rhamnosylation is ensured in bacteria since other TDP coupled sugars will compete for the TDP-rhamnose binding site, slowing the production of decorated WTA.…”

Section: Discussionmentioning

confidence: 99%

Molecular properties of RmlT, a wall teichoic acid rhamnosyltransferase that modulates virulence inListeria monocytogenes

Monteiro,

Cereija,

Pombinho

et al. 2024

Preprint

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Wall teichoic acids (WTA) from the major Gram-positive foodborne pathogenListeria monocytogenesare peptidoglycan-associated glycopolymers decorated by monosaccharides that, while not essential for bacterial growth, are required for bacterial virulence and resistance. Here we report the first structure and function of a bacterial WTA rhamnosyltransferase, RmlT, strictly required forL. monocytogenesWTA rhamnosylation. We demonstrated that RmlT transfers rhamnose from TDP-rhamnose to naked WTA, and that specificity towards TDP-rhamnose is kinetically determined. We solved the RmlT structure, identified key residues for its activity and showed that RmlT behaves as a dimer whose interface is important for its stability and function. We propose that RmlT undergoes a transition between an open and closed conformation, allowing RmlT to first bind WTA and then trapping it inside the tunnel formed by the catalytic, oligomerization and helical subdomains. Finally, we proved that mutation of a single residue in the RmlT active site leads to enzyme inactivation and decreased infectionin vivo, confirming WTA glycosyltransferases as promising targets for next-generation strategies against Gram-positive pathogens.

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Section: Discussionmentioning

confidence: 99%

Molecular properties of RmlT, a wall teichoic acid rhamnosyltransferase that modulates virulence inListeria monocytogenes

Monteiro,

Cereija,

Pombinho

et al. 2024

Preprint

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“…tagA-deficient strains are less toxic and sensitive to methicillin, imipenem, and ceftazidime (D'Elia et al, 2006a,b;Farha et al, 2015). Moreover, it has found that five residues (E210, W211, R214, R221, and R224) of the C-terminal in TagA are crucial to its catalysis (Martinez et al, 2022), suggesting the discovery of new antibiotics that could be achieved by disrupting the synthesis of important polymers. Similarly, the serine active sites of TagB and TagC were also discovered, which play an important role in bacterial adhesion, aggregation, invasion, and infection (Pokharel et al, 2020).…”

Section: Teichoic Acidmentioning

confidence: 99%

Breaking down the cell wall: Still an attractive antibacterial strategy

et al. 2022

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Since the advent of penicillin, humans have known about and explored the phenomenon of bacterial inhibition via antibiotics. However, with changes in the global environment and the abuse of antibiotics, resistance mechanisms have been selected in bacteria, presenting huge threats and challenges to the global medical and health system. Thus, the study and development of new antimicrobials is of unprecedented urgency and difficulty. Bacteria surround themselves with a cell wall to maintain cell rigidity and protect against environmental insults. Humans have taken advantage of antibiotics to target the bacterial cell wall, yielding some of the most widely used antibiotics to date. The cell wall is essential for bacterial growth and virulence but is absent from humans, remaining a high-priority target for antibiotic screening throughout the antibiotic era. Here, we review the extensively studied targets, i.e., MurA, MurB, MurC, MurD, MurE, MurF, Alr, Ddl, MurI, MurG, lipid A, and BamA in the cell wall, starting from the very beginning to the latest developments to elucidate antimicrobial screening. Furthermore, recent advances, including MraY and MsbA in peptidoglycan and lipopolysaccharide, and tagO, LtaS, LspA, Lgt, Lnt, Tol-Pal, MntC, and OspA in teichoic acid and lipoprotein, have also been profoundly discussed. The review further highlights that the application of new methods such as macromolecular labeling, compound libraries construction, and structure-based drug design will inspire researchers to screen ideal antibiotics.

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Molecular properties of the RmlT wall teichoic acid rhamnosyltransferase that modulates virulence in Listeria monocytogenes

Monteiro,

Cereija,

Pombinho

et al. 2025

Nat Commun

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Insight into the molecular basis of substrate recognition by the wall teichoic acid glycosyltransferase TagA

Cited by 4 publications

References 79 publications

Molecular properties of RmlT, a wall teichoic acid rhamnosyltransferase that modulates virulence inListeria monocytogenes

Molecular properties of RmlT, a wall teichoic acid rhamnosyltransferase that modulates virulence inListeria monocytogenes

Breaking down the cell wall: Still an attractive antibacterial strategy

Molecular properties of the RmlT wall teichoic acid rhamnosyltransferase that modulates virulence in Listeria monocytogenes

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