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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\n                    <jats:italic>Toxoplasma gondii<\/jats:italic>\n                    , a widespread intracellular pathogen and a model protozoan organism. Herein, we show that\n                    <jats:italic>T<\/jats:italic>\n                    .\n                    <jats:italic>gondii<\/jats:italic>\n                    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\n                    <jats:italic>T<\/jats:italic>\n                    .\n                    <jats:italic>gondii<\/jats:italic>\n                    . Our data show that of the seven PPP proteins, the two glucose-6-phosphate dehydrogenases (\n                    <jats:italic>Tg<\/jats:italic>\n                    G6PDH1,\n                    <jats:italic>Tg<\/jats:italic>\n                    G6PDH2), one of the two 6-phosphogluconate dehydrogenases (\n                    <jats:italic>Tg<\/jats:italic>\n                    6PGDH1), ribulose-5-phosphate epimerase (\n                    <jats:italic>Tg<\/jats:italic>\n                    RuPE) and transaldolase (\n                    <jats:italic>Tg<\/jats:italic>\n                    TAL) are dispensable\n                    <jats:italic>in vitro<\/jats:italic>\n                    as well as\n                    <jats:italic>in vivo<\/jats:italic>\n                    , disclosing substantial metabolic plasticity in\n                    <jats:italic>T<\/jats:italic>\n                    .\n                    <jats:italic>gondii<\/jats:italic>\n                    . Among these,\n                    <jats:italic>Tg<\/jats:italic>\n                    G6PDH2 plays a vital role in defense against oxidative stress by the pathogen. Further, we show that\n                    <jats:italic>Tg<\/jats:italic>\n                    6PGDH2 and ribulose-5-phosphate isomerase (\n                    <jats:italic>Tg<\/jats:italic>\n                    RPI) are critical for tachyzoite growth. The depletion of\n                    <jats:italic>Tg<\/jats:italic>\n                    RPI 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\n                    <jats:italic>T<\/jats:italic>\n                    .\n                    <jats:italic>gondii<\/jats:italic>\n                    while unraveling metabolic flexibility and antiparasitic targets.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1010864","type":"journal-article","created":{"date-parts":[[2022,9,19]],"date-time":"2022-09-19T13:41:12Z","timestamp":1663594872000},"page":"e1010864","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":30,"title":["Metabolic flexibilities and vulnerabilities in the pentose phosphate pathway of the zoonotic pathogen Toxoplasma gondii"],"prefix":"10.1371","volume":"18","author":[{"given":"Ningbo","family":"Xia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishith","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nuo","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0103-271X","authenticated-orcid":true,"given":"Bang","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8532-2727","authenticated-orcid":true,"given":"Lihua","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8380-1246","authenticated-orcid":true,"given":"Yaoyu","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,9,19]]},"reference":[{"key":"ppat.1010864.ref001","doi-asserted-by":"crossref","unstructured":"David S. 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