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Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets

The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct...

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Autores principales: de Vries, Laura E., Lunghi, Matteo, Krishnan, Aarti, Kooij, Taco W. A., Soldati-Favre, Dominique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717973/
https://www.ncbi.nlm.nih.gov/pubmed/34969059
http://dx.doi.org/10.1371/journal.ppat.1010124
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author de Vries, Laura E.
Lunghi, Matteo
Krishnan, Aarti
Kooij, Taco W. A.
Soldati-Favre, Dominique
author_facet de Vries, Laura E.
Lunghi, Matteo
Krishnan, Aarti
Kooij, Taco W. A.
Soldati-Favre, Dominique
author_sort de Vries, Laura E.
collection PubMed
description The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct adaptations to the differences in nutritional availabilities, either relying on biosynthetic pathways or by salvaging metabolites from their host. Pantothenate (Pan, vitamin B5) is the precursor for the synthesis of an essential cofactor, coenzyme A (CoA), but among the apicomplexans, only the coccidian subgroup has the ability to synthesize Pan. While the pathway to synthesize CoA from Pan is largely conserved across all branches of life, there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA from Pan. Impeding the scavenge of Pan and synthesis of Pan and CoA have been long recognized as potential targets for antimicrobial drug development, but in order to fully exploit these critical pathways, it is important to understand such differences. Recently, a potent class of pantothenamides (PanAms), Pan analogs, which target CoA-utilizing enzymes, has entered antimalarial preclinical development. The potential of PanAms to target multiple downstream pathways make them a promising compound class as broad antiparasitic drugs against other apicomplexans. In this review, we summarize the recent advances in understanding the Pan and CoA biosynthesis pathways, and the suitability of these pathways as drug targets in Apicomplexa, with a particular focus on the cyst-forming coccidian, Toxoplasma gondii, and the haemosporidian, Plasmodium falciparum.
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spelling pubmed-87179732021-12-31 Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets de Vries, Laura E. Lunghi, Matteo Krishnan, Aarti Kooij, Taco W. A. Soldati-Favre, Dominique PLoS Pathog Review The Apicomplexa phylum comprises thousands of distinct intracellular parasite species, including coccidians, haemosporidians, piroplasms, and cryptosporidia. These parasites are characterized by complex and divergent life cycles occupying a variety of host niches. Consequently, they exhibit distinct adaptations to the differences in nutritional availabilities, either relying on biosynthetic pathways or by salvaging metabolites from their host. Pantothenate (Pan, vitamin B5) is the precursor for the synthesis of an essential cofactor, coenzyme A (CoA), but among the apicomplexans, only the coccidian subgroup has the ability to synthesize Pan. While the pathway to synthesize CoA from Pan is largely conserved across all branches of life, there are differences in the redundancy of enzymes and possible alternative pathways to generate CoA from Pan. Impeding the scavenge of Pan and synthesis of Pan and CoA have been long recognized as potential targets for antimicrobial drug development, but in order to fully exploit these critical pathways, it is important to understand such differences. Recently, a potent class of pantothenamides (PanAms), Pan analogs, which target CoA-utilizing enzymes, has entered antimalarial preclinical development. The potential of PanAms to target multiple downstream pathways make them a promising compound class as broad antiparasitic drugs against other apicomplexans. In this review, we summarize the recent advances in understanding the Pan and CoA biosynthesis pathways, and the suitability of these pathways as drug targets in Apicomplexa, with a particular focus on the cyst-forming coccidian, Toxoplasma gondii, and the haemosporidian, Plasmodium falciparum. Public Library of Science 2021-12-30 /pmc/articles/PMC8717973/ /pubmed/34969059 http://dx.doi.org/10.1371/journal.ppat.1010124 Text en © 2021 de Vries et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Review
de Vries, Laura E.
Lunghi, Matteo
Krishnan, Aarti
Kooij, Taco W. A.
Soldati-Favre, Dominique
Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets
title Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets
title_full Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets
title_fullStr Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets
title_full_unstemmed Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets
title_short Pantothenate and CoA biosynthesis in Apicomplexa and their promise as antiparasitic drug targets
title_sort pantothenate and coa biosynthesis in apicomplexa and their promise as antiparasitic drug targets
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8717973/
https://www.ncbi.nlm.nih.gov/pubmed/34969059
http://dx.doi.org/10.1371/journal.ppat.1010124
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