A novel heteromeric pantothenate kinase complex in apicomplexan parasites

Coenzyme A is synthesised from pantothenate via five enzyme-mediated steps. The first step is catalysed by pantothenate kinase (PanK). All PanKs characterised to date form homodimers. Many organisms express multiple PanKs. In some cases, these PanKs are not functionally redundant, and some appear to...

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Published inPLoS pathogens Vol. 17; no. 7; p. e1009797
Main Authors Tjhin, Erick T, Howieson, Vanessa M, Spry, Christina, van Dooren, Giel G, Saliba, Kevin J
Format Journal Article
LanguageEnglish
Published San Francisco Public Library of Science 29.07.2021
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Abstract Coenzyme A is synthesised from pantothenate via five enzyme-mediated steps. The first step is catalysed by pantothenate kinase (PanK). All PanKs characterised to date form homodimers. Many organisms express multiple PanKs. In some cases, these PanKs are not functionally redundant, and some appear to be non-functional. Here, we investigate the PanKs in two pathogenic apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii. Each of these organisms express two PanK homologues (PanK1 and PanK2). We demonstrate that PfPanK1 and PfPanK2 associate, forming a single, functional PanK complex that includes the multi-functional protein, Pf14-3-3I. Similarly, we demonstrate that TgPanK1 and TgPanK2 form a single complex that possesses PanK activity. Both TgPanK1 and TgPanK2 are essential for T. gondii proliferation, specifically due to their PanK activity. Our study constitutes the first examples of heteromeric PanK complexes in nature and provides an explanation for the presence of multiple PanKs within certain organisms.
AbstractList Coenzyme A is synthesised from pantothenate via five enzyme-mediated steps. The first step is catalysed by pantothenate kinase (PanK). All PanKs characterised to date form homodimers. Many organisms express multiple PanKs. In some cases, these PanKs are not functionally redundant, and some appear to be non-functional. Here, we investigate the PanKs in two pathogenic apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii. Each of these organisms express two PanK homologues (PanK1 and PanK2). We demonstrate that PfPanK1 and PfPanK2 associate, forming a single, functional PanK complex that includes the multi-functional protein, Pf14-3-3I. Similarly, we demonstrate that TgPanK1 and TgPanK2 form a single complex that possesses PanK activity. Both TgPanK1 and TgPanK2 are essential for T. gondii proliferation, specifically due to their PanK activity. Our study constitutes the first examples of heteromeric PanK complexes in nature and provides an explanation for the presence of multiple PanKs within certain organisms.
Coenzyme A is synthesised from pantothenate via five enzyme-mediated steps. The first step is catalysed by pantothenate kinase (PanK). All PanKs characterised to date form homodimers. Many organisms express multiple PanKs. In some cases, these PanKs are not functionally redundant, and some appear to be non-functional. Here, we investigate the PanKs in two pathogenic apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii . Each of these organisms express two PanK homologues (PanK1 and PanK2). We demonstrate that Pf PanK1 and Pf PanK2 associate, forming a single, functional PanK complex that includes the multi-functional protein, Pf 14-3-3I. Similarly, we demonstrate that Tg PanK1 and Tg PanK2 form a single complex that possesses PanK activity. Both Tg PanK1 and Tg PanK2 are essential for T . gondii proliferation, specifically due to their PanK activity. Our study constitutes the first examples of heteromeric PanK complexes in nature and provides an explanation for the presence of multiple PanKs within certain organisms.
Coenzyme A is synthesised from pantothenate via five enzyme-mediated steps. The first step is catalysed by pantothenate kinase (PanK). All PanKs characterised to date form homodimers. Many organisms express multiple PanKs. In some cases, these PanKs are not functionally redundant, and some appear to be non-functional. Here, we investigate the PanKs in two pathogenic apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii . Each of these organisms express two PanK homologues (PanK1 and PanK2). We demonstrate that Pf PanK1 and Pf PanK2 associate, forming a single, functional PanK complex that includes the multi-functional protein, Pf 14-3-3I. Similarly, we demonstrate that Tg PanK1 and Tg PanK2 form a single complex that possesses PanK activity. Both Tg PanK1 and Tg PanK2 are essential for T . gondii proliferation, specifically due to their PanK activity. Our study constitutes the first examples of heteromeric PanK complexes in nature and provides an explanation for the presence of multiple PanKs within certain organisms. Apicomplexans are a phylum of obligate intracellular parasites that cause diseases in humans and other animals, inflicting considerable burdens on human societies. During their intracellular stage, these parasites must scavenge vitamins from their host organisms in order to survive and proliferate. One such vitamin is pantothenate (vitamin B 5 ), which parasites convert in a universal five-step pathway to the essential cofactor coenzyme A (CoA). The first reaction in the CoA biosynthesis pathway is catalysed by the enzyme pantothenate kinase (PanK). The genomes of humans and many other organisms, including apicomplexans, encode multiple PanK homologues, although in all studied examples, the functional PanK enzyme exists as a homodimer. In this study, we demonstrate that the two PanK homologues encoded in the genomes of the apicomplexans Plasmodium falciparum and Toxoplasma gondii , PanK1 and PanK2, exist as functional heteromeric complexes. We provide evidence that both PanK homologues contribute to the PanK activity in these parasites, and that both PanK1 and PanK2 are essential for the proliferation of T . gondii parasites specifically for their PanK activity. Our data describe the first known instances of heteromeric PanK complexes in nature and may explain why some organisms that express multiple PanKs harbour seemingly non-functional isoforms.
Audience Academic
Author van Dooren, Giel G
Howieson, Vanessa M
Saliba, Kevin J
Tjhin, Erick T
Spry, Christina
AuthorAffiliation 1 Research School of Biology, The Australian National University, Canberra, Australia
2 Medical School, The Australian National University, Canberra, Australia
Johns Hopkins Bloomberg School of Public Health, UNITED STATES
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Snippet Coenzyme A is synthesised from pantothenate via five enzyme-mediated steps. The first step is catalysed by pantothenate kinase (PanK). All PanKs characterised...
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StartPage e1009797
SubjectTerms Analysis
Biology and Life Sciences
Chemical properties
Coenzyme A
Coenzymes
Enzyme kinetics
Experiments
Genomes
Homology
Kinases
Medicine and Health Sciences
Mutation
Organisms
Pantothenate kinase
Parasites
Peptides
Phosphorylation
Plasmodium falciparum
Proteins
Research and Analysis Methods
Toxoplasma
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Title A novel heteromeric pantothenate kinase complex in apicomplexan parasites
URI https://www.proquest.com/docview/2561940726
https://search.proquest.com/docview/2557228762
https://pubmed.ncbi.nlm.nih.gov/PMC8366970
https://doaj.org/article/b157da0f67394e19927b74bd0e946384
http://dx.doi.org/10.1371/journal.ppat.1009797
Volume 17
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