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Metabolic plasticity, essentiality and therapeutic potential of ribose-5-phosphate synthesis in Toxoplasma gondii.
Guo, Xuefang; Ji, Nuo; Guo, Qinghong; Wang, Mengting; Du, Huiyu; Pan, Jiajia; Xiao, Lihua; Gupta, Nishith; Feng, Yaoyu; Xia, Ningbo.
Afiliação
  • Guo X; State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China.
  • Ji N; Guangdong Laboratory for Lingnan Modern Agriculture, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • Guo Q; State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China.
  • Wang M; Guangdong Laboratory for Lingnan Modern Agriculture, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • Du H; State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China.
  • Pan J; Guangdong Laboratory for Lingnan Modern Agriculture, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • Xiao L; State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China.
  • Gupta N; Guangdong Laboratory for Lingnan Modern Agriculture, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
  • Feng Y; State Key Laboratory for Animal Disease Control and Prevention, South China Agricultural University, Guangzhou, China.
  • Xia N; Guangdong Laboratory for Lingnan Modern Agriculture, Center for Emerging and Zoonotic Diseases, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
Nat Commun ; 15(1): 2999, 2024 Apr 08.
Article em En | MEDLINE | ID: mdl-38589375
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Toxoplasma Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Toxoplasma Idioma: En Ano de publicação: 2024 Tipo de documento: Article