Genomic analyses of aminoacyl tRNA synthetases from human-infecting helminths
Abstract Background Helminth infections affect ~ 60% of the human population that lives in tropical and subtropical regions worldwide. These infections result in diseases like schistosomiasis, lymphatic filariasis, river blindness and echinococcosis. Here we provide a comprehensive computational ana...
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | BMC Genomics |
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| Online Access: | http://link.springer.com/article/10.1186/s12864-019-5679-0 |
| _version_ | 1818499822356791296 |
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| author | Preeti Goel Suhel Parvez Amit Sharma |
| author_facet | Preeti Goel Suhel Parvez Amit Sharma |
| author_sort | Preeti Goel |
| collection | DOAJ |
| description | Abstract Background Helminth infections affect ~ 60% of the human population that lives in tropical and subtropical regions worldwide. These infections result in diseases like schistosomiasis, lymphatic filariasis, river blindness and echinococcosis. Here we provide a comprehensive computational analysis of the aminoacyl tRNA synthetase (aaRS) enzyme family from 27 human-infecting helminths. Our analyses support the idea that several helminth aaRSs can be targeted for drug repurposing or for development of new drugs. For experimental validation, we focused on Onchocerciasis (also known as “river blindness”), a filarial vector-borne disease that is prevalent in Africa and Latin America. We show that halofuginone (HF) can act as a potent inhibitor of Onchocerca volvulus prolyl tRNA synthetase (OvPRS). Results The conserved enzyme family of aaRSs has been validated as druggable targets in numerous eukaryotic parasites. We thus embarked on assessing aaRSs from the genomes of 27 helminths that cause infections in humans. In order to delineate the distribution of aaRSs per genome we utilized Hidden Markov Models of aaRS catalytic domains to identify all orthologues. We note that Fasciola hepatica genome encodes the highest number of aaRS-like proteins (69) whereas Taenia asiatica has the lowest count (32). The number of genes for any particular aaRS-like protein varies from 1 to 8 in these 27 studied helminths. Sequence alignments of helminth-encoded lysyl, prolyl, leucyl and threonyl tRNA synthetases suggest that various known aaRS inhibitors like Cladosporin, Halofuginone, Benzoborale and Borrelidin may be of utility against helminths. The recombinantly expressed Onchocerca volvulus PRS was used as proof of concept for targeting aaRS with drug-like molecules like HF. Conclusions Systematic analysis of unique subdomains within helminth aaRSs reveals the presence of a number of non-canonical domains like PAC3, Utp-14, Pex2_Pex12 fused to catalytic domains in the predicted helminth aaRSs. We have established a platform for biochemical validation of a large number of helminth aaRSs that can be targeted using available inhibitors to jump-start drug repurposing against human helminths. |
| first_indexed | 2024-12-10T20:34:48Z |
| format | Article |
| id | doaj.art-8c3e9df4044846aa81f405f9f7ade4b9 |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-12-10T20:34:48Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-8c3e9df4044846aa81f405f9f7ade4b92022-12-22T01:34:35ZengBMCBMC Genomics1471-21642019-05-0120111210.1186/s12864-019-5679-0Genomic analyses of aminoacyl tRNA synthetases from human-infecting helminthsPreeti Goel0Suhel Parvez1Amit Sharma2Structural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB)Department of Toxicology, School of Chemical and Life Sciences, Jamia HamdardStructural Parasitology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB)Abstract Background Helminth infections affect ~ 60% of the human population that lives in tropical and subtropical regions worldwide. These infections result in diseases like schistosomiasis, lymphatic filariasis, river blindness and echinococcosis. Here we provide a comprehensive computational analysis of the aminoacyl tRNA synthetase (aaRS) enzyme family from 27 human-infecting helminths. Our analyses support the idea that several helminth aaRSs can be targeted for drug repurposing or for development of new drugs. For experimental validation, we focused on Onchocerciasis (also known as “river blindness”), a filarial vector-borne disease that is prevalent in Africa and Latin America. We show that halofuginone (HF) can act as a potent inhibitor of Onchocerca volvulus prolyl tRNA synthetase (OvPRS). Results The conserved enzyme family of aaRSs has been validated as druggable targets in numerous eukaryotic parasites. We thus embarked on assessing aaRSs from the genomes of 27 helminths that cause infections in humans. In order to delineate the distribution of aaRSs per genome we utilized Hidden Markov Models of aaRS catalytic domains to identify all orthologues. We note that Fasciola hepatica genome encodes the highest number of aaRS-like proteins (69) whereas Taenia asiatica has the lowest count (32). The number of genes for any particular aaRS-like protein varies from 1 to 8 in these 27 studied helminths. Sequence alignments of helminth-encoded lysyl, prolyl, leucyl and threonyl tRNA synthetases suggest that various known aaRS inhibitors like Cladosporin, Halofuginone, Benzoborale and Borrelidin may be of utility against helminths. The recombinantly expressed Onchocerca volvulus PRS was used as proof of concept for targeting aaRS with drug-like molecules like HF. Conclusions Systematic analysis of unique subdomains within helminth aaRSs reveals the presence of a number of non-canonical domains like PAC3, Utp-14, Pex2_Pex12 fused to catalytic domains in the predicted helminth aaRSs. We have established a platform for biochemical validation of a large number of helminth aaRSs that can be targeted using available inhibitors to jump-start drug repurposing against human helminths.http://link.springer.com/article/10.1186/s12864-019-5679-0Aminoacyl tRNA synthetasesCladosporinHalofuginoneHelminthInhibitors |
| spellingShingle | Preeti Goel Suhel Parvez Amit Sharma Genomic analyses of aminoacyl tRNA synthetases from human-infecting helminths BMC Genomics Aminoacyl tRNA synthetases Cladosporin Halofuginone Helminth Inhibitors |
| title | Genomic analyses of aminoacyl tRNA synthetases from human-infecting helminths |
| title_full | Genomic analyses of aminoacyl tRNA synthetases from human-infecting helminths |
| title_fullStr | Genomic analyses of aminoacyl tRNA synthetases from human-infecting helminths |
| title_full_unstemmed | Genomic analyses of aminoacyl tRNA synthetases from human-infecting helminths |
| title_short | Genomic analyses of aminoacyl tRNA synthetases from human-infecting helminths |
| title_sort | genomic analyses of aminoacyl trna synthetases from human infecting helminths |
| topic | Aminoacyl tRNA synthetases Cladosporin Halofuginone Helminth Inhibitors |
| url | http://link.springer.com/article/10.1186/s12864-019-5679-0 |
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