scholarly journals A novel heteromeric pantothenate kinase complex in apicomplexan parasites

2021 ◽  
Author(s):  
Erick T Tjhin ◽  
Vanessa M Howieson ◽  
Christina Spry ◽  
Giel G van Dooren ◽  
Kevin J Saliba

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.

2021 ◽  
Vol 17 (7) ◽  
pp. e1009797
Author(s):  
Erick T. Tjhin ◽  
Vanessa M. Howieson ◽  
Christina Spry ◽  
Giel G. van Dooren ◽  
Kevin J. Saliba

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.


Author(s):  
Chhaminder Kaur ◽  
Swati Patankar

During their complex life cycles, the Apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii employ several genetic switches to regulate their gene expression. One such switch is mediated at the level of translation through upstream Open Reading Frames (uORFs). As uORFs are found in the upstream regions of a majority of genes in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant proteins that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics, and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of genome-wide datasets will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response, and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.


Parasitology ◽  
2019 ◽  
Vol 146 (14) ◽  
pp. 1755-1766 ◽  
Author(s):  
Giulia Bandini ◽  
Andreia Albuquerque-Wendt ◽  
Jan Hegermann ◽  
John Samuelson ◽  
Françoise H. Routier

AbstractApicomplexan parasites are amongst the most prevalent and morbidity-causing pathogens worldwide. They are responsible for severe diseases in humans and livestock and are thus of great public health and economic importance. Until the sequencing of apicomplexan genomes at the beginning of this century, the occurrence of N- and O-glycoproteins in these parasites was much debated. The synthesis of rudimentary and divergent N-glycans due to lineage-specific gene loss is now well established and has been recently reviewed. Here, we will focus on recent studies that clarified classical O-glycosylation pathways and described new nucleocytosolic glycosylations in Toxoplasma gondii, the causative agents of toxoplasmosis. We will also review the glycosylation of proteins containing thrombospondin type 1 repeats by O-fucosylation and C-mannosylation, newly discovered in Toxoplasma and the malaria parasite Plasmodium falciparum. The functional significance of these post-translational modifications has only started to emerge, but the evidence points towards roles for these protein glycosylation pathways in tissue cyst wall rigidity and persistence in the host, oxygen sensing, and stability of proteins involved in host invasion.


2018 ◽  
Author(s):  
Johannes Felix Stortz ◽  
Mirko Singer ◽  
Jonathan M Wilkes ◽  
Markus Meissner ◽  
Sujaan Das

AbstractPathogenic obligate-intracellular apicomplexan parasites possess an essential chloroplast-like organelle called the apicoplast that undergoes division and segregation during replication. Parasite actin is essential during intracellular development, implicated in vesicular transport, parasite replication and apicoplast inheritance. However, the inability to visualise live actin dynamics in apicomplexan parasites limited functional characterisation of both filamentous-actin (F-actin) and actin regulatory factors. Apicomplexans possess at least two distinct formins, Formin-1 and Formin-2, predicted to serve as actin-nucleating factors, and previously implicated in regulating gliding motility and host cell invasion. Here, we expressed chromobodies and validated them as F-actin-binding sensors in Plasmodium falciparum and characterised the in vivo dynamics of the F-actin network. The F-actin network could be modulated chemically and disrupted by conditionally deleting the actin-1 gene. In a comparative approach, we demonstrate that Formin-2 is closely associated with apicoplasts and with the F-actin network in P. falciparum and Toxoplasma gondii. Consequently, disruption of Formin-2 resulted not only in an apicoplast segregation defect, but also in complete abrogation of F-actin dynamics in intracellular parasites. Together, our results strongly indicate that Formin-2-mediated filament formation is the common primary mechanism for F-actin nucleation during apicomplexan intracellular growth effecting apicoplast segregation.


2003 ◽  
pp. 167-170
Author(s):  
E. Maréchal ◽  
N. Azzouz ◽  
C. Mercier ◽  
C. Santos de Macedo ◽  
M. A. Block ◽  
...  

2015 ◽  
Vol 80 (11) ◽  
pp. 1339-1359 ◽  
Author(s):  
Dejan Opsenica ◽  
Jelena Radivojevic ◽  
Ivana Matic ◽  
Tijana Stajner ◽  
Slavica Knezevic-Usaj ◽  
...  

New cyclohexylidene 1,2,4,5-tetraoxanes with polar guanidine and urea based groups were synthesized and evaluated for antimalarial activity against chloroquine resistant and susceptible Plasmodium falciparum strains. Derivatives showed moderate nM range antimalarial activities and low cytotoxicity. N-phenyl-urea derivative 24 exhibited best resistant indices (RIW2 = 0.44, RITM91C235 = 0.80), and was not toxic against human normal peripheral blood mononuclear cells (IC50 > 200 ?M). Seven derivatives were tested in vitro against four human cancer cell lines and they demonstrated high selectivity toward leukemia K562 cells. One compound, derivative 21 with a primary amino-group, was the first tetraoxane tested in vivo against Toxoplasma gondii as another Apicomplexan parasite. Subcutaneous administration at a dose of 10 mg/kg/day for 8 days allowed survival of 20 % of infected mice, thus demonstrating the high potential of tetraoxanes for the treatment of Apicomplexan parasites.


mBio ◽  
2021 ◽  
Author(s):  
Julie M. J. Verhoef ◽  
Markus Meissner ◽  
Taco W. A. Kooij

Apicomplexan parasites, such as Toxoplasma gondii and Plasmodium falciparum , are the cause of many important human and veterinarian diseases. While T. gondii tachyzoites replicate through endodyogeny, during which two daughter cells are formed within the parental cell, P. falciparum replicates through schizogony, where up to 32 parasites are formed in a single infected red blood cell and even thousands of daughter cells during mosquito- or liver-stage development.


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