Inhibition of Helicobacter pylori Glu‐t<scp>RNAG</scp>ln amidotransferase by novel analogues of the putative transamidation intermediate

Pham, Van Hau; Maaroufi, Halim; Balg, Christian; Blais, Sébastien P.; Messier, Nancy; Roy, Paul H.; Otis, François; Voyer, Normand; Lapointe, Jacques; Chênevert, Robert

doi:10.1002/1873-3468.12380

Cited by 5 publications

(3 citation statements)

References 36 publications

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“…Small molecules targeting enzymatic inhibition of GatCAB have been discovered ( 35 , 36 ), but none have been validated against bacteria. Our work suggests that compounds that inhibit GatCAB could act not just by inhibiting enzyme synthesis but also by destabilizing GatCAB or Asn-transamidosome complex formation.…”

Section: Discussionmentioning

confidence: 99%

Clinically Relevant Mutations of Mycobacterial GatCAB Inform Regulation of Translational Fidelity

Cai

Yang

et al. 2021

mBio

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Most bacteria use a two-step indirect pathway to aminoacylate tRNA Gln and tRNA Asn , despite the fact that the indirect pathway consumes more energy and is error prone. We have previously shown that the higher protein synthesis errors from this indirect pathway in mycobacteria allow adaptation to hostile environments such as antibiotic treatment through generation of novel alternate proteins not coded by the genome.

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Section: Discussionmentioning

confidence: 99%

Clinically Relevant Mutations of Mycobacterial GatCAB Inform Regulation of Translational Fidelity

Cai

Yang

et al. 2021

mBio

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“…Small molecules targeting enzymatic inhibition of GatCAB have been discovered (37,38), but none have been validated against bacteria. Our work suggests that compounds that inhibit GatCAB could act not just by inhibiting enzyme synthesis, but also by destabilising GatCAB or Asn-transamidosome complex formation.…”

Section: Discussionmentioning

confidence: 99%

Clinically relevant mutations of mycobacterial GatCAB inform regulation of translational fidelity

Cai

Yang

et al. 2021

Preprint

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Most bacteria employ a two-step indirect tRNA aminoacylation pathway for the synthesis of aminoacylated tRNAGln and tRNAAsn. The heterotrimeric enzyme GatCAB performs a critical amidotransferase reaction in the second step of this pathway. We have previously demonstrated in mycobacteria that this two-step pathway is error-prone and translational errors contribute to adaptive phenotypes such as antibiotic tolerance. Furthermore, we identified clinical isolates of the globally important pathogen Mycobacterium tuberculosis with partial loss-of-function mutations in gatA, and demonstrated that these mutations result in high, specific rates of translational error and increased rifampicin tolerance. However, the mechanisms by which these clinically-derived mutations in gatA impact GatCAB function was unknown. Here, we describe biochemical and biophysical characterization of M. tuberculosis GatCAB, containing either wild-type gatA or one of two gatA mutants from clinical strains. We show that these mutations have minimal impact on enzymatic activity of GatCAB; however, they result in destabilization of the GatCAB complex as well as that of the ternary asparaginyl-transamidosome. Stabilizing complex formation with the solute trehalose increases specific translational fidelity of not only the mutant strains, but also of wild-type mycobacteria. Therefore, our data suggest that alteration of GatCAB stability may be a mechanism for modulation of translational fidelity.

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“…120 Given the importance of GatCAB in many human pathogens, the enzyme is a target of interest in the development of anti-microbial drugs. [139][140][141][142][143] The use of aminoacyl-tRNA analogs that act as competitive inhibitors of GatCAB transamidation is effective in reducing GatCAB activity. 142 Mitochondrial GatCAB is also a potential target for anti-cancer drugs.…”

Section: The Trna-dependent Amidotransferases: Gatcab and Gatdementioning

confidence: 99%

Evolution and variation in amide aminoacyl‐tRNA synthesis

Lewis,

Fallon,

Dittemore

et al. 2024

IUBMB Life

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The amide proteogenic amino acids, asparagine and glutamine, are two of the twenty amino acids used in translation by all known life. The aminoacyl‐tRNA synthetases for asparagine and glutamine, asparaginyl‐tRNA synthetase and glutaminyl tRNA synthetase, evolved after the split in the last universal common ancestor of modern organisms. Before that split, life used two‐step indirect pathways to synthesize asparagine and glutamine on their cognate tRNAs to form the aminoacyl‐tRNA used in translation. These two‐step pathways were retained throughout much of the bacterial and archaeal domains of life and eukaryotic organelles. The indirect routes use non‐discriminating aminoacyl‐tRNA synthetases (non‐discriminating aspartyl‐tRNA synthetase and non‐discriminating glutamyl‐tRNA synthetase) to misaminoacylate the tRNA. The misaminoacylated tRNA formed is then transamidated into the amide aminoacyl‐tRNA used in protein synthesis by tRNA‐dependent amidotransferases (GatCAB and GatDE). The enzymes and tRNAs involved assemble into complexes known as transamidosomes to help maintain translational fidelity. These pathways have evolved to meet the varied cellular needs across a diverse set of organisms, leading to significant variation. In certain bacteria, the indirect pathways may provide a means to adapt to cellular stress by reducing the fidelity of protein synthesis. The retention of these indirect pathways versus acquisition of asparaginyl‐tRNA synthetase and glutaminyl tRNA synthetase in lineages likely involves a complex interplay of the competing uses of glutamine and asparagine beyond translation, energetic costs, co‐evolution between enzymes and tRNA, and involvement in stress response that await further investigation.

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Inhibition of Helicobacter pylori Glu‐tRNA^G^ln amidotransferase by novel analogues of the putative transamidation intermediate

Cited by 5 publications

References 36 publications

Clinically Relevant Mutations of Mycobacterial GatCAB Inform Regulation of Translational Fidelity

Clinically Relevant Mutations of Mycobacterial GatCAB Inform Regulation of Translational Fidelity

Clinically relevant mutations of mycobacterial GatCAB inform regulation of translational fidelity

Evolution and variation in amide aminoacyl‐tRNA synthesis

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Inhibition of Helicobacter pylori Glu‐tRNAGln amidotransferase by novel analogues of the putative transamidation intermediate

Cited by 5 publications

References 36 publications

Clinically Relevant Mutations of Mycobacterial GatCAB Inform Regulation of Translational Fidelity

Clinically Relevant Mutations of Mycobacterial GatCAB Inform Regulation of Translational Fidelity

Clinically relevant mutations of mycobacterial GatCAB inform regulation of translational fidelity

Evolution and variation in amide aminoacyl‐tRNA synthesis

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Inhibition of Helicobacter pylori Glu‐tRNA^G^ln amidotransferase by novel analogues of the putative transamidation intermediate