Biochemistry and metabolism of Toxoplasma gondii: purine and pyrimidine acquisition in Toxoplasma gondii and other Apicomplexa

Fox, Barbara A.; Bzik, David J.

doi:10.1016/b978-0-12-815041-2.00009-8

Cited by 10 publications

(18 citation statements)

References 314 publications

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“…Figures modified from Pesi, et al . (62) and Fox & Bzik (47). cN-II: cytosolic 5′-nucleotidase II; PNP: purine nucleoside phosphorylase; HPRT: hypoxanthine guanine phosphoribosyl transferase; XO: xanthine oxidase; ADA, Adenosine deaminase; ADE, adenine deaminase; ADSL, adenylosucccinate lyase; ADSS, adenylosuccinate synthetase; AMPD, AMP deaminase; GMPS, GMP synthetase; HXGPRT, hypoxanthine_xanthine_guanine phosphoribosyltransferase; IMPDH, inosine 50-monophosphate dehydrogenase; PNP, purine nucleoside phosphorylase; PRPP, 5-phosphoribosyl-1-pyrophosphate.…”

Section: Resultsmentioning

confidence: 99%

“…T. gondii is an obligate intracellular parasite that cannot replicate outside of its host cell. They may exist in extracellular forms, but only for a short time without any replication (47). T. gondii needs to scavenge many metabolites from their host to replicate.…”

Section: Discussionmentioning

confidence: 99%

“…T. gondii needs to scavenge many metabolites from their host to replicate. Nucleotides are essential to different cellular functions that involve DNA and RNA synthesis, chemical energy (ATP), nucleotide-based enzyme cofactors (NAD, FAD), and secondary messengers (cAMP) (47, 48). Most apicomplexans can produce pyrimidines de novo but none of them can produce purines (49).…”

Section: Discussionmentioning

confidence: 99%

“…The cell membranes are a barrier to nucleotides transport, but nucleosides can pass in either direction(52). In T. gondii, three purine transporters have been characterized so far, TgAT1, TgAT2, and TgNT1 (47). The identification of host enzymes used by the parasite in purine salvage is essential for designing better drugs against parasites.…”

Section: Discussionmentioning

confidence: 99%

“…The study of purine metabolism in apicomplexan parasites is not clear due to the challenge of completely separating the parasite from the host cell. The capture, transport, and salvage pathways necessary for purine acquisition have long been viewed as a significant Achilles heel of the parasite that may be targeted for chemotherapy (47). Current treatment strategies in human infections caused by T. gondii or P. falciparum are based on targeting parasite enzymes and blocking the accumulation of nucleotides.…”

Section: Discussionmentioning

confidence: 99%

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Kiss and spit metabolomics highlights the role of the host cN-II enzyme on purine metabolism during pathogen infection

Gallego-López

Olson

Perdomo

et al. 2022

Preprint

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Intracellular pathogens are auxotrophic for many metabolites and must rely on the host. While this reliance is well established, how pathogens manipulate host metabolism to their benefit is not understood. For intracellular pathogens, distinguishing the origin of the metabolite as host- or pathogen-derived is challenging. The obligate intracellular parasite Toxoplasma gondii alters the host cell by a pre-invasion process known as “kiss and spit”, where the contents of the parasite rhoptry organelles are secreted into the host cytoplasm before invasion occurs. This separation of microbe from the host offers a rare opportunity to demonstrate pathogen manipulation of the host. Using mass spectrometry-based metabolomics, we determined that kiss and spit changed host metabolites in nucleotide synthesis, the pentose phosphate pathway, glycolysis, and amino acid synthesis. An increase in 2,3-bisphosphoglycerate (2,3-BPG) abundance led us to hypothesize that high levels of host 2,3-BPG contribute to the activation of host cytosolic nucleosidase II (cN-II) to alter purine availability. Treatment with the cN-II inhibitor fludarabine and a cell line with a cN-II genetic knockout reduced T. gondii growth. Our results demonstrate that T. gondii rhoptry contents discharged during kiss and spit remodel host metabolism. They also suggest that T. gondii manipulates the host cN-II enzyme to acquire its necessary purine metabolites.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Kiss and spit metabolomics highlights the role of the host cN-II enzyme on purine metabolism during pathogen infection

Gallego-López

Olson

Perdomo

et al. 2022

Preprint

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Metabolic drug targets of the cytosine metabolism pathways in the dromedary camel (Camelus dromedarius) and blood parasite Trypanosoma evansi

Kandeel

Al‐Taher

2020

Trop Anim Health Prod

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Host metabolic pathways essential for malaria and related hemoparasites in the infection of nucleated cells

Maurizio,

Masid,

Woods

et al. 2023

Preprint

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SUMMARYApicomplexan parasite diseases, including malaria (Plasmodium) and theileriosis (Theileria), pose a significant threat to global health and the socioeconomic well-being of low-income countries. Despite recent advances, the common host metabolic proteins essential for these highly auxotrophic pathogens remain elusive. Here, we present a comprehensive investigation integrating a metabolic model ofP. falciparumparasites in hepatocytes and a genome-wide CRISPR screen targetingTheileriaschizont-infected macrophages. We reveal unifying host metabolic enzymes critical for the intracellular survival of these related hematozoa. We show that pathways such as host purine and heme biosynthesis are essential for bothTheileriasurvival andPlasmodiumliver development, while genes involved in glutathione and polyamine biosynthesis are predicted to be essential forPlasmodiumonly under certain metabolic conditions. Our work highlights the importance of host porphyrins for the viability of liver-stagePlasmodium. Shared parasite vulnerabilities provide a resource for exploring alternative therapeutic approaches to combat these crippling diseases.

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Biochemistry and metabolism of Toxoplasma gondii: purine and pyrimidine acquisition in Toxoplasma gondii and other Apicomplexa

Cited by 10 publications

References 314 publications

Kiss and spit metabolomics highlights the role of the host cN-II enzyme on purine metabolism during pathogen infection

Kiss and spit metabolomics highlights the role of the host cN-II enzyme on purine metabolism during pathogen infection

Metabolic drug targets of the cytosine metabolism pathways in the dromedary camel (Camelus dromedarius) and blood parasite Trypanosoma evansi

Host metabolic pathways essential for malaria and related hemoparasites in the infection of nucleated cells

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