Identification and functional characterization of a bacterial homologue of Zeta toxin in <i>Leishmania donovani</i>

Srivastav, Ajeet K.; Garg, Swati; Jain, Ravi; Ayana, Rajagopal; Kaushik, Himani; Garg, Lalit C.; Pati, Soumya; Singh, Shailja

doi:10.1002/1873-3468.13429

Cited by 11 publications

(14 citation statements)

References 33 publications

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“…The lytic phenotype generated by the overexpression of another E. coli toxin, EzeT, becomes more pronounced at temperatures below 30°C (Rocker and Meinhart 2015). Another zeta toxin, Ld_ζ1 domain of Leishmania donovani, also showed pronounced growth-inhibitory activity at lower temperatures (Srivastava et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of VapBC toxin–antitoxin system in Bosea sp. PAMC 26642 isolated from Arctic lichens

Jeon

Choi

Hwang

2021

RNA

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Toxin-antitoxin (TA) systems are genetic modules composed of a toxin interfering with cellular processes and its cognate antitoxin, which counteracts the activity of the toxin. TA modules are widespread in bacterial and archaeal genomes. It has been suggested that TA modules participate in the adaptation of prokaryotes to unfavorable conditions. The Bosea sp. PAMC 26642 used in this study was isolated from the Arctic lichen Stereocaulon sp.. There are twelve putative type II TA loci in the genome of Bosea sp. PAMC 26642. Of these, nine functional TA systems have been shown to be toxic in Escherichia coli. The toxin inhibits growth, but this inhibition is reversed when the cognate antitoxin genes are co-expressed, indicating that these putative TA loci were bona fide TA modules. Only the BoVapC (AXW83_01405) toxin, a homolog of VapC, showed growth inhibition specific to low temperatures, which was recovered by the co-expression of BoVapB (AXW83_01400). Microscopic observation and growth monitoring revealed that the BoVapC toxin had bacteriostatic effects on the growth of E. coli and induced morphological changes. Quantitative real time polymerase chain reaction and northern blotting analyses showed that the BoVapC toxin had a ribonuclease activity on the initiator tRNAfMet, implying that degradation of tRNAfMet might trigger growth arrest in E. coli. This is the first study to identify the function of TA systems in an Arctic bacterium.

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Section: Discussionmentioning

confidence: 99%

Identification and characterization of VapBC toxin–antitoxin system in Bosea sp. PAMC 26642 isolated from Arctic lichens

Jeon

Choi

Hwang

2021

RNA

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“…The toxin component of the TA module acts against cellular processes such as translation, and is neutralised by the antitoxin component in favourable conditions. Sharing similar functional domains and activity with the E. coli homologue (Srivastava et al , 2019) , L. donovani zeta toxin may therefore also be implicated in stress response and/or virulence (Rocker and Meinhart, 2015) .…”

Section: Genes Under Balancing Selection In the L Donovani Complexmentioning

confidence: 99%

“…The zeta domain is positioned at 744-861aa, with two non-synonymous variants resulting in the changes Leu747Thr and Ser752Phe, respectively, from the reference genome. The zeta toxin is part of the Type-II toxin-antitoxin (TA) module identified in prokaryotes, with homologues only recently discovered in Leishmania (Srivastava et al , 2019) . The toxin component of the TA module acts against cellular processes such as translation, and is neutralised by the antitoxin component in favourable conditions.…”

Section: Genes Under Balancing Selection In the L Donovani Complexmentioning

confidence: 99%

Multiple targets of balancing selection inLeishmania donovanicomplex parasites

Grace

Forrester

et al. 2021

Preprint

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The Leishmania donovani species complex are the causative agents of visceral leishmaniasis, which cause 20-40,000 fatalities a year. Here, we conduct a screen for balancing selection in this specie complex. We sequence 93 isolates of L. infantum from Brazil and used 387 publicly-available L. donovani and L. infantum genomes, to describe the global diversity of this species complex. We identify five genetically-distinct populations that are sufficiently represented by genomic data to search for signatures of selection. We show that multiple metrics identify genes with robust signatures of balancing selection. We produce a curated set of 19 genes with robust signatures, including zeta toxin, nodulin-like and flagellum attachment proteins. Candidate genes were generally not shared between populations, consistent with divergent rather than long-term balancing selection in these species. This study highlights the extent of genetic divergence between L. donovani complex parasites and provides candidate genes for further study.

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“…Recently, Srivastava et al, 28 have reported that the unicellular eukaryote Leishmania donovani possesses orthologs Zeta‐Toxin (Ld_ζ1) which is structurally and functionally similar to the bacterial‐Zeta‐Toxin (BzT). L. donovani harbors similar ATP and UNAG binding pockets like prokaryotic bacteria and triggers cell death 28 . Therefore, Zeta‐Toxin mediated cell death can act as a novel anti‐eukaryotic and anti‐prokaryotic chemotherapeutics.…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20][25][26][27] The Zeta Toxin of A. baumannii shares high homology with Gram-positive (S. pyogenes and S. pneumoniae) and Gram-negative (N. gonorrhoeae) pathogens. 18 Recently, Srivastava et al, 28 have reported that the unicellular eukaryote Leishmania donovani possesses orthologs Zeta-Toxin (Ld_ζ1) which is structurally and functionally similar to the bacterial-Zeta-Toxin (BzT).…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulation of Toxin‐Antitoxin (TA) system in Acinetobacter baumannii to explore the novel mechanism for inhibition of cell wall biosynthesis: Zeta Toxin as an effective therapeutic target

Karthika

Ramachandran

Jeyarajpandian³

et al. 2021

J of Cellular Biochemistry

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The majority of bacteria and archaea contains Toxin‐Antitoxin system (TA) that codes for the stable Toxin and unstable Antitoxin components forming a complex. The Antitoxin inhibits the catalytic activities of the Toxin. In general, the Antitoxin will be degraded by the proteases leading to the Toxin activation that subsequently targets essential cellular processes, including transcription, translation, replication, cell division, and cell wall biosynthesis. The Zeta Toxin‐Epsilon Antitoxin system in ESKAPE pathogen stabilizes the resistance plasmid and promotes pathogenicity. The known TA system in Acinetobacter baumannii are known to be involved in the replication and translation, however, the mechanism of Zeta Toxin‐Epsilon Antitoxin in cell wall biosynthesis remains unknown. In the present study, molecular docking and molecular dynamic (MD) simulations were employed to demonstrate whether Zeta Toxin can impair cell wall synthesis in A. baumannii. Further, the degradation mechanism of Antitoxin in the presence and absence of adenosine triphosphate (ATP) molecules are explained through MD simulation. The result reveals that the cleavage of Antitoxin could be possible with the presence of ATP by displaying its response from 20 ns, whereas the Zeta Toxin/Epsilon was unstable after 90 ns. The obtained results demonstrate that Zeta Toxin is “temporarily favorable” for ATP to undergo phosphorylation at UNAG kinase through the substrate tunneling process. The study further evidenced that phosphorylated UNAG prevents the binding of MurA, the enzyme that catalyzes the initial step of bacterial peptidoglycan biosynthesis. Therefore, the present study explores the binding mechanism of Zeta Toxin/Epsilon Antitoxin, which could be beneficial for preventing cell wall biosynthesis as well as for unveiling the alternative treatment options to antibiotics.

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Identification and functional characterization of a bacterial homologue of Zeta toxin in Leishmania donovani

Cited by 11 publications

References 33 publications

Identification and characterization of VapBC toxin–antitoxin system in Bosea sp. PAMC 26642 isolated from Arctic lichens

Identification and characterization of VapBC toxin–antitoxin system in Bosea sp. PAMC 26642 isolated from Arctic lichens

Multiple targets of balancing selection inLeishmania donovanicomplex parasites

Molecular dynamics simulation of Toxin‐Antitoxin (TA) system in Acinetobacter baumannii to explore the novel mechanism for inhibition of cell wall biosynthesis: Zeta Toxin as an effective therapeutic target

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