Metabolic flexibilities and vulnerabilities in the pentose phosphate pathway of the zoonotic pathogen Toxoplasma gondii

PLoS Pathog. 2022 Sep 19;18(9):e1010864. doi: 10.1371/journal.ppat.1010864. eCollection 2022 Sep.

Abstract

Metabolic pathways underpin the growth and virulence of intracellular parasites and are therefore promising antiparasitic targets. The pentose phosphate pathway (PPP) is vital in most organisms, providing a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) and ribose sugar for nucleotide synthesis; however, it has not yet been studied in Toxoplasma gondii, a widespread intracellular pathogen and a model protozoan organism. Herein, we show that T. gondii has a functional PPP distributed in the cytoplasm and nucleus of its acutely-infectious tachyzoite stage. We produced eight parasite mutants disrupting seven enzymes of the PPP in T. gondii. Our data show that of the seven PPP proteins, the two glucose-6-phosphate dehydrogenases (TgG6PDH1, TgG6PDH2), one of the two 6-phosphogluconate dehydrogenases (Tg6PGDH1), ribulose-5-phosphate epimerase (TgRuPE) and transaldolase (TgTAL) are dispensable in vitro as well as in vivo, disclosing substantial metabolic plasticity in T. gondii. Among these, TgG6PDH2 plays a vital role in defense against oxidative stress by the pathogen. Further, we show that Tg6PGDH2 and ribulose-5-phosphate isomerase (TgRPI) are critical for tachyzoite growth. The depletion of TgRPI impairs the flux of glucose in central carbon pathways, and causes decreased expression of ribosomal, microneme and rhoptry proteins. In summary, our results demonstrate the physiological need of the PPP in T. gondii while unraveling metabolic flexibility and antiparasitic targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiparasitic Agents
  • Carbon / metabolism
  • Glucose / metabolism
  • Glucose-6-Phosphate / metabolism
  • Isomerases / metabolism
  • NADP / metabolism
  • Pentose Phosphate Pathway* / physiology
  • Phosphates / metabolism
  • Racemases and Epimerases / metabolism
  • Ribose
  • Toxoplasma* / metabolism
  • Transaldolase / metabolism

Substances

  • Antiparasitic Agents
  • Phosphates
  • NADP
  • Glucose-6-Phosphate
  • Ribose
  • Carbon
  • Transaldolase
  • Isomerases
  • Racemases and Epimerases
  • Glucose

Grants and funding

This work was supported by the National Natural Science Foundation of China (32002305 to NX), Laboratory for Lingnan Modern Agriculture Project (NT2021007 to YF), Natural Science Foundation of Guangdong Province (2022A1515011104 to NX), Scholar Mobility Program sponsored by the Sino-German Center for Research Promotion (M-0074 to NG), Science and Technology Program of Guangzhou, China (202201010500 to NX), 111 Project (D20008 to LX), and Innovation Team Project of Guangdong University (2019KCXTD001 to YF). The funders had no role in the study design, data collection and analysis, preparation of the manuscript, or decision to submit the work for publication.