Identification of enzymes that have helminth-specific active sites and are required for Rhodoquinone-dependent metabolism as targets for new anthelmintics.
Soil transmitted helminths (STHs) are major human pathogens that infect over a billion people. Resistance to current anthelmintics is rising and new drugs are needed. Here we combine multiple approaches to find druggable targets in the anaerobic metabolic pathways STHs need to survive in their mamma...
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Online Access: | https://doi.org/10.1371/journal.pntd.0009991 https://doaj.org/article/4c6646960b5242a4b5fbec3f2473cff7 |
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ftdoajarticles:oai:doaj.org/article:4c6646960b5242a4b5fbec3f2473cff7 2023-05-15T15:04:35+02:00 Identification of enzymes that have helminth-specific active sites and are required for Rhodoquinone-dependent metabolism as targets for new anthelmintics. Margot J Lautens June H Tan Xènia Serrat Samantha Del Borrello Michael R Schertzberg Andrew G Fraser 2021-11-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009991 https://doaj.org/article/4c6646960b5242a4b5fbec3f2473cff7 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009991 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009991 https://doaj.org/article/4c6646960b5242a4b5fbec3f2473cff7 PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009991 (2021) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2021 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009991 2022-12-31T11:01:39Z Soil transmitted helminths (STHs) are major human pathogens that infect over a billion people. Resistance to current anthelmintics is rising and new drugs are needed. Here we combine multiple approaches to find druggable targets in the anaerobic metabolic pathways STHs need to survive in their mammalian host. These require rhodoquinone (RQ), an electron carrier used by STHs and not their hosts. We identified 25 genes predicted to act in RQ-dependent metabolism including sensing hypoxia and RQ synthesis and found 9 are required. Since all 9 have mammalian orthologues, we used comparative genomics and structural modeling to identify those with active sites that differ between host and parasite. Together, we found 4 genes that are required for RQ-dependent metabolism and have different active sites. Finding these high confidence targets can open up in silico screens to identify species selective inhibitors of these enzymes as new anthelmintics. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 15 11 e0009991 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Margot J Lautens June H Tan Xènia Serrat Samantha Del Borrello Michael R Schertzberg Andrew G Fraser Identification of enzymes that have helminth-specific active sites and are required for Rhodoquinone-dependent metabolism as targets for new anthelmintics. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Soil transmitted helminths (STHs) are major human pathogens that infect over a billion people. Resistance to current anthelmintics is rising and new drugs are needed. Here we combine multiple approaches to find druggable targets in the anaerobic metabolic pathways STHs need to survive in their mammalian host. These require rhodoquinone (RQ), an electron carrier used by STHs and not their hosts. We identified 25 genes predicted to act in RQ-dependent metabolism including sensing hypoxia and RQ synthesis and found 9 are required. Since all 9 have mammalian orthologues, we used comparative genomics and structural modeling to identify those with active sites that differ between host and parasite. Together, we found 4 genes that are required for RQ-dependent metabolism and have different active sites. Finding these high confidence targets can open up in silico screens to identify species selective inhibitors of these enzymes as new anthelmintics. |
format |
Article in Journal/Newspaper |
author |
Margot J Lautens June H Tan Xènia Serrat Samantha Del Borrello Michael R Schertzberg Andrew G Fraser |
author_facet |
Margot J Lautens June H Tan Xènia Serrat Samantha Del Borrello Michael R Schertzberg Andrew G Fraser |
author_sort |
Margot J Lautens |
title |
Identification of enzymes that have helminth-specific active sites and are required for Rhodoquinone-dependent metabolism as targets for new anthelmintics. |
title_short |
Identification of enzymes that have helminth-specific active sites and are required for Rhodoquinone-dependent metabolism as targets for new anthelmintics. |
title_full |
Identification of enzymes that have helminth-specific active sites and are required for Rhodoquinone-dependent metabolism as targets for new anthelmintics. |
title_fullStr |
Identification of enzymes that have helminth-specific active sites and are required for Rhodoquinone-dependent metabolism as targets for new anthelmintics. |
title_full_unstemmed |
Identification of enzymes that have helminth-specific active sites and are required for Rhodoquinone-dependent metabolism as targets for new anthelmintics. |
title_sort |
identification of enzymes that have helminth-specific active sites and are required for rhodoquinone-dependent metabolism as targets for new anthelmintics. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2021 |
url |
https://doi.org/10.1371/journal.pntd.0009991 https://doaj.org/article/4c6646960b5242a4b5fbec3f2473cff7 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009991 (2021) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009991 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009991 https://doaj.org/article/4c6646960b5242a4b5fbec3f2473cff7 |
op_doi |
https://doi.org/10.1371/journal.pntd.0009991 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
15 |
container_issue |
11 |
container_start_page |
e0009991 |
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1766336325970034688 |