Essential role of pyrophosphate homeostasis mediated by the pyrophosphate-dependent phosphofructokinase in Toxoplasma gondii.

Abstract

Many biosynthetic pathways produce pyrophosphate (PPi) as a by-product, which is cytotoxic if accumulated at high levels. Pyrophosphatases play pivotal roles in PPi detoxification by converting PPi to inorganic phosphate. A number of apicomplexan parasites, including Toxoplasma gondii and Cryptosporidium parvum, express a PPi-dependent phosphofructokinase (PPi-PFK) that consumes PPi to power the phosphorylation of fructose-6-phosphate. However, the physiological roles of PPi-PFKs in these organisms are not known. Here, we report that Toxoplasma expresses both ATP- and PPi-dependent phosphofructokinases in the cytoplasm. Nonetheless, only PPi-PFK was indispensable for parasite growth, whereas the deletion of ATP-PFK did not affect parasite proliferation or virulence. The conditional depletion of PPi-PFK completely arrested parasite growth, but it did not affect the ATP level and only modestly reduced the flux of central carbon metabolism. However, PPi-PFK depletion caused a significant increase in cellular PPi and decreased the rates of nascent protein synthesis. The expression of a cytosolic pyrophosphatase in the PPi-PFK depletion mutant reduced its PPi level and increased the protein synthesis rate, therefore partially rescuing its growth. These results suggest that PPi-PFK has a major role in maintaining pyrophosphate homeostasis in T. gondii. This role may allow PPi-PFK to fine-tune the balance of catabolism and anabolism and maximize the utilization efficiency for carbon nutrients derived from host cells, increasing the success of parasitism. Moreover, PPi-PFK is essential for parasite propagation and virulence in vivo but it is not present in human hosts, making it a potential drug target to combat toxoplasmosis.

• Authors: Xuke Yang, Xiaoyan Yin, Jiaojiao Liu, Zhipeng Niu, Jichao Yang, Bang Shen
• Journal: PLoS pathogens (PLoS Pathog) Vol. 18 Issue 2 Pg. e1010293 (02 2022) ISSN: 1553-7374 [Electronic] United States
• PMID: 35104280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Diphosphates
• diphosphoric acid
• Adenosine Triphosphate
• Phosphotransferases
• pyrophosphate-fructose 6-phosphate 1-phosphotransferase

Topics

• Adenosine Triphosphate (metabolism)
• Carbohydrate Metabolism
• Diphosphates (metabolism)
• Homeostasis
• Mutation
• Phosphorylation
• Phosphotransferases (genetics, metabolism)
• Toxoplasma (genetics, metabolism)
• Toxoplasmosis (parasitology)