Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii

Xuefang Guo, Nuo Ji, Qinghong Guo, Mengting Wang, Huiyu Du, Jiajia Pan, Lihua Xiao, Nishith Gupta (), Yaoyu Feng () and Ningbo Xia ()
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Xuefang Guo: South China Agricultural University
Nuo Ji: South China Agricultural University
Qinghong Guo: South China Agricultural University
Mengting Wang: South China Agricultural University
Huiyu Du: South China Agricultural University
Jiajia Pan: South China Agricultural University
Lihua Xiao: South China Agricultural University
Nishith Gupta: Birla Institute of Technology and Science, Pilani (BITS-P)
Yaoyu Feng: South China Agricultural University
Ningbo Xia: South China Agricultural University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Ribose-5-phosphate (R5P) is a precursor for nucleic acid biogenesis; however, the importance and homeostasis of R5P in the intracellular parasite Toxoplasma gondii remain enigmatic. Here, we show that the cytoplasmic sedoheptulose-1,7-bisphosphatase (SBPase) is dispensable. Still, its co-deletion with transaldolase (TAL) impairs the double mutant’s growth and increases 13C-glucose-derived flux into pentose sugars via the transketolase (TKT) enzyme. Deletion of the latter protein affects the parasite’s fitness but is not lethal and is correlated with an increased carbon flux via the oxidative pentose phosphate pathway. Further, loss of TKT leads to a decline in 13C incorporation into glycolysis and the TCA cycle, resulting in a decrease in ATP levels and the inability of phosphoribosyl-pyrophosphate synthetase (PRPS) to convert R5P into 5′-phosphoribosyl-pyrophosphate and thereby contribute to the production of AMP and IMP. Likewise, PRPS is essential for the lytic cycle. Not least, we show that RuPE-mediated metabolic compensation is imperative for the survival of the ΔsbpaseΔtal strain. In conclusion, we demonstrate that multiple routes can flexibly supply R5P to enable parasite growth and identify catalysis by TKT and PRPS as critical enzymatic steps. Our work provides novel biological and therapeutic insights into the network design principles of intracellular parasitism in a clinically-relevant pathogen.

Date: 2024
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DOI: 10.1038/s41467-024-47097-8

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