Abstract:
BACKGROUND:Aminoacyl tRNA synthetases are central enzymes required for protein synthesis. These enzymes are the known drug targets in bacteria and fungi. Here, we for the first time report the functional characterization of threonyl tRNA synthetase (LdThrRS) of Leishmania donovani, a protozoan parasite, the primary causative agent of visceral leishmaniasis. METHODOLOGY:Recombinant LdThrRS (rLdThrRS) was expressed in E. coli and purified. The kinetic parameters for rLdThrRS were determined. The subcellular localization of LdThrRS was done by immunofluorescence analysis. Heterozygous mutants of LdThrRS were generated in Leishmania promastigotes. These genetically manipulated parasites were checked for their proliferation, virulence, aminoacylation activity and sensitivity to the known ThrRS inhibitor, borrelidin. An in silico generated structural model of L. donovani ThrRS was compared to that of human. CONCLUSIONS:Recombinant LdThrRS displayed aminoacylation activity, and the protein is possibly localized to both the cytosol and mitochondria. The comparison of the 3D-model of LdThrRS to human ThrRS displayed considerable similarity. Heterozygous parasites showed restrictive growth phenotype and had attenuated infectivity. These heterozygous parasites were more susceptible to inhibition by borrelidin. Several attempts to obtain ThrRS homozygous null mutants were not successful, indicating its essentiality for the Leishmania parasite. Borrelidin showed a strong affinity for LdThrRS (KD: 0.04 μM) and was effective in inhibiting the aminoacylation activity of the rLdThrRS (IC50: 0.06 μM). Borrelidin inhibited the promastigotes (IC50: 21 μM) stage of parasites. Our data shows that LdThrRS is essential for L. donovani survival and is likely to bind with small drug-like molecules with strong affinity, thus making it a potential target for drug discovery efforts.
journal_name
PLoS Negl Trop Disjournal_title
PLoS neglected tropical diseasesauthors
Chadha S,Vijayan R,Gupta S,Munde M,Gourinath S,Madhubala Rdoi
10.1371/journal.pntd.0006575subject
Has Abstractpub_date
2018-06-13 00:00:00pages
e0006575issue
6eissn
1935-2727issn
1935-2735pii
PNTD-D-18-00530journal_volume
12pub_type
杂志文章abstract::Benzimidazole anthelmintics have long been employed for the control of soil-transmitted helminth infections. Flubendazole (FBZ) was approved in 1980 for the treatment of gastrointestinal nematode infections in both veterinary and human medicine. It has also long been known that parenteral administration of FBZ can lea...
journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章,评审
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0007075
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:PLoS neglected tropical diseases
pub_type: 临床试验,杂志文章
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pub_type: 杂志文章
doi:10.1371/journal.pntd.0006261
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0004746
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pub_type: 杂志文章
doi:10.1371/journal.pntd.0008903
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章,评审
doi:10.1371/journal.pntd.0002020
更新日期:2013-01-01 00:00:00
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章,多中心研究,随机对照试验
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journal_title:PLoS neglected tropical diseases
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
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journal_title:PLoS neglected tropical diseases
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更新日期:2018-07-06 00:00:00
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0008217
更新日期:2020-04-13 00:00:00
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
doi:10.1371/journal.pntd.0006739
更新日期:2018-09-13 00:00:00
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
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更新日期:2019-03-18 00:00:00
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章,随机对照试验
doi:10.1371/journal.pntd.0002953
更新日期:2014-06-26 00:00:00
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journal_title:PLoS neglected tropical diseases
pub_type: 杂志文章
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