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Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway

Parasitic helminths infect over a billion humans. To survive in the low oxygen environment of their hosts, these parasites use unusual anaerobic metabolism — this requires rhodoquinone (RQ), an electron carrier that is made by very few animal species. Crucially RQ is not made or used by any parasiti...

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Autores principales: Del Borrello, Samantha, Lautens, Margot, Dolan, Kathleen, Tan, June H, Davie, Taylor, Schertzberg, Michael R, Spensley, Mark A, Caudy, Amy A, Fraser, Andrew G
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656428/
https://www.ncbi.nlm.nih.gov/pubmed/31232688
http://dx.doi.org/10.7554/eLife.48165
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author Del Borrello, Samantha
Lautens, Margot
Dolan, Kathleen
Tan, June H
Davie, Taylor
Schertzberg, Michael R
Spensley, Mark A
Caudy, Amy A
Fraser, Andrew G
author_facet Del Borrello, Samantha
Lautens, Margot
Dolan, Kathleen
Tan, June H
Davie, Taylor
Schertzberg, Michael R
Spensley, Mark A
Caudy, Amy A
Fraser, Andrew G
author_sort Del Borrello, Samantha
collection PubMed
description Parasitic helminths infect over a billion humans. To survive in the low oxygen environment of their hosts, these parasites use unusual anaerobic metabolism — this requires rhodoquinone (RQ), an electron carrier that is made by very few animal species. Crucially RQ is not made or used by any parasitic hosts and RQ synthesis is thus an ideal target for anthelmintics. However, little is known about how RQ is made and no drugs are known to block RQ synthesis. C. elegans makes RQ and can use RQ-dependent metabolic pathways — here, we use C. elegans genetics to show that tryptophan degradation via the kynurenine pathway is required to generate the key amine-containing precursors for RQ synthesis. We show that C. elegans requires RQ for survival in hypoxic conditions and, finally, we establish a high throughput assay for drugs that block RQ-dependent metabolism. This may drive the development of a new class of anthelmintic drugs. This study is a key first step in understanding how RQ is made in parasitic helminths.
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spelling pubmed-66564282019-07-25 Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway Del Borrello, Samantha Lautens, Margot Dolan, Kathleen Tan, June H Davie, Taylor Schertzberg, Michael R Spensley, Mark A Caudy, Amy A Fraser, Andrew G eLife Biochemistry and Chemical Biology Parasitic helminths infect over a billion humans. To survive in the low oxygen environment of their hosts, these parasites use unusual anaerobic metabolism — this requires rhodoquinone (RQ), an electron carrier that is made by very few animal species. Crucially RQ is not made or used by any parasitic hosts and RQ synthesis is thus an ideal target for anthelmintics. However, little is known about how RQ is made and no drugs are known to block RQ synthesis. C. elegans makes RQ and can use RQ-dependent metabolic pathways — here, we use C. elegans genetics to show that tryptophan degradation via the kynurenine pathway is required to generate the key amine-containing precursors for RQ synthesis. We show that C. elegans requires RQ for survival in hypoxic conditions and, finally, we establish a high throughput assay for drugs that block RQ-dependent metabolism. This may drive the development of a new class of anthelmintic drugs. This study is a key first step in understanding how RQ is made in parasitic helminths. eLife Sciences Publications, Ltd 2019-06-24 /pmc/articles/PMC6656428/ /pubmed/31232688 http://dx.doi.org/10.7554/eLife.48165 Text en © 2019, Del Borrello et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry and Chemical Biology
Del Borrello, Samantha
Lautens, Margot
Dolan, Kathleen
Tan, June H
Davie, Taylor
Schertzberg, Michael R
Spensley, Mark A
Caudy, Amy A
Fraser, Andrew G
Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway
title Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway
title_full Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway
title_fullStr Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway
title_full_unstemmed Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway
title_short Rhodoquinone biosynthesis in C. elegans requires precursors generated by the kynurenine pathway
title_sort rhodoquinone biosynthesis in c. elegans requires precursors generated by the kynurenine pathway
topic Biochemistry and Chemical Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656428/
https://www.ncbi.nlm.nih.gov/pubmed/31232688
http://dx.doi.org/10.7554/eLife.48165
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