Plasmodium Para-Aminobenzoate Synthesis and Salvage Resolve Avoidance of Folate Competition and Adaptation to Host Diet

Matz, Joachim M.; Watanabe, Mutsumi; Falade, Mofolusho O.; Tohge, Takayuki; Hoefgen, Rainer; Matuschewski, Kai

doi:10.1016/j.celrep.2018.12.062

Cited by 21 publications

(26 citation statements)

References 40 publications

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“…These results Removal of PABA from diet rapidly decreases parasitemia in P. yoelii infected weanlings. The requirement for PABA in Plasmodium growth is well documented 32 . Our studies with milk-based diet and PABA-deficient diet clearly demonstrated that challenging of weanlings that are already on PABA-deficient diet prevents the establishment of infection to a high degree.…”

Section: Resultsmentioning

confidence: 99%

Neonatal mice resist Plasmodium yoelii infection until exposed to para-aminobenzoic acid containing diet after weaning

Parra

Yang

Weitner

et al. 2021

Sci Rep

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We developed a newborn (NB) mouse Plasmodium yoelii NL infection model to study malaria in early age. Surprisingly, the onset of parasitemia in P. yoelii challenged NB mice was delayed compared to adults and coincided with the weaning date when weanlings switched from maternal milk to normal chow diet. Also, compared to adult mice, parasitemia resolved much later (48 days vs 20 days post challenge) and the peak parasitemia was twice as high in weanlings. Concurrently, weanlings’ germinal center reaction was delayed and diminished compared to adult mice. Maternal milk is deficient in para-aminobenzoic acid (PABA), which is required for de novo folate synthesis by Plasmodium. Suggesting a possible role for the protection afforded by PABA-deficient maternal milk, mice fed with a PABA-deficient diet after the weaning continued to control parasitemia. Despite the reduced parasitemia, these mice developed robust T follicular helper (Tfh) responses and were protected from a second P. yoelii challenge. The NB malaria model provides mechanistic insight into the human infant malaria manifestations where a diet solely based on breast-feeding reduces the incidence of severe malaria in infants. NB mice experiments also support further studies to investigate dietary PABA restriction in the management of severe malaria in infants.

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Section: Resultsmentioning

confidence: 99%

Neonatal mice resist Plasmodium yoelii infection until exposed to para-aminobenzoic acid containing diet after weaning

Parra

Yang

Weitner

et al. 2021

Sci Rep

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“…Future studies would have to unravel the molecular mechanisms of resistance and enable future development of alternative strategies targeting the crucial biosynthesis and scavenge pathways (89). In recent in vivo experiments, the contributions of para-amino benzoic acid (pABA), a precursor for folate synthesis, were also re-examined (90,91). pABA is synthesized with the action of two enzymes, aminodeoxychorismate synthase and aminodeoxychorismate lyase.…”

Section: Vitamin Bmentioning

confidence: 99%

“…The two genes were knocked out in the rodent malaria parasite P. berghei, and the deletions were shown to be dispensable for parasite propagation in mice fed with a conventional diet. However, in mice fed with milk (lacking pABA), the mutants displayed a severe growth phenotype, abolished with the supplementation of pABA (90,91). In the liver stage, the lack of aminodeoxychorismate synthase was dispensable, suggesting an active salvage, given the folate-rich environment of the liver.…”

Section: Vitamin Bmentioning

confidence: 99%

Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

Krishnan¹,

Kloehn²,

Lunghi³

et al. 2019

J. Biol. Chem.

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The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile metabolic capabilities reflecting their capacity to survive and grow in different hosts and varying niches. Determined by nutrient availability, they either use their biosynthesis machineries or largely depend on their host for metabolite acquisition. Because vitamins cannot be synthesized by the mammalian host, the enzymes required for their synthesis in apicomplexan parasites represent a large repertoire of potential therapeutic targets. Here, we review recent advances in metabolic reconstruction and functional studies coupled to metabolomics that unravel the interplay between biosynthesis and salvage of vitamins and cofactors in apicomplexans. A particular emphasis is placed on Toxoplasma gondii, during both its acute and latent stages of infection.

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“…falciparum IspD inhibitor MMV008138 48,49 as well as new antibacterial inhibitors 50 . However, due to the potential role of chorismate as a precursor in de novo folate biosynthesis and the complexity of folate metabolism in the malaria parasite where the contribution of the de novo biosynthesis and salvage pathways is starting to be elucidated 51,52 , the use of reversal of growth inhibition will likely result in the selection of competitive antifolates even when chorismate is used as a metabolic suppressor of growth inhibition 25 . Thus, the use of in vitro enzymatic reactions as screening platforms using recombinant proteins of selected targets may be a better approach to identify or rationally design non-competitive or uncompetitive antifolates in order to circumvent the challenge of high plasma concentrations of pABA 53 .…”

Section: Resultsmentioning

confidence: 99%

Metabolic dependency of chorismate in Plasmodium falciparum suggests an alternative source for the ubiquinone biosynthesis precursor

Valenciano

Fernández-Murga

Merino

et al. 2019

Sci Rep

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The shikimate pathway, a metabolic pathway absent in humans, is responsible for the production of chorismate, a branch point metabolite. In the malaria parasite, chorismate is postulated to be a direct precursor in the synthesis of p-aminobenzoic acid (folate biosynthesis), p-hydroxybenzoic acid (ubiquinone biosynthesis), menaquinone, and aromatic amino acids. While the potential value of the shikimate pathway as a drug target is debatable, the metabolic dependency of chorismate in P. falciparum remains unclear. Current evidence suggests that the main role of chorismate is folate biosynthesis despite ubiquinone biosynthesis being active and essential in the malaria parasite. Our goal in the present work was to expand our knowledge of the ubiquinone head group biosynthesis and its potential metabolic dependency on chorismate in P. falciparum. We systematically assessed the development of both asexual and sexual stages of P. falciparum in a defined medium in the absence of an exogenous supply of chorismate end-products and present biochemical evidence suggesting that the benzoquinone ring of ubiquinones in this parasite may be synthesized through a yet unidentified route.

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Plasmodium Para-Aminobenzoate Synthesis and Salvage Resolve Avoidance of Folate Competition and Adaptation to Host Diet

Cited by 21 publications

References 40 publications

Neonatal mice resist Plasmodium yoelii infection until exposed to para-aminobenzoic acid containing diet after weaning

Neonatal mice resist Plasmodium yoelii infection until exposed to para-aminobenzoic acid containing diet after weaning

Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

Metabolic dependency of chorismate in Plasmodium falciparum suggests an alternative source for the ubiquinone biosynthesis precursor

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