Folate metabolism is essential for DNA synthesis and a validated drug target in fast-growing cell populations, including tumors and malaria parasites. Genome data suggest that Plasmodium has retained its capacity to generate folates de novo. However, the metabolic plasticity of folate uptake and biosynthesis by the malaria parasite remains unresolved. Here, we demonstrate that Plasmodium uses an aminodeoxychorismate synthase and an aminodeoxychorismate lyase to promote the biogenesis of the central folate precursor para-aminobenzoate (pABA) in the cytoplasm. We show that the parasite depends on de novo folate synthesis only when dietary intake of pABA by the mammalian host is restricted and that only pABA, rather than fully formed folate, is taken up efficiently. This adaptation, which readily adjusts infection to highly variable pABA levels in the mammalian diet, is specific to blood stages and may have evolved to avoid folate competition between the parasite and its host.
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This work was supported in part by the Max Planck Society, Humboldt University, and by the Alliance Berlin Canberra “Crossing Boundaries: Molecular Interactions in Malaria”, which is co-funded by a grant from the Deutsche Forschungsgemeinschaft (DFG) for the International Research Training Group (IRTG) 2290 and the Australian National University. M.F. was supported by a fellowship from The World Academy of Sciences-Deutsche Forschungsgemeinschaft (TWAS-DFG).
Supplemental Information includes four figures and one table and can be found with this article online at https://doi.org/10.1016/j.celrep.2018.12.062.
Matz, Joachim Michael; Watanabe, Mutsumi; Falade, Mofolusho; Tohge, Takayuki; Hoefgen, Rainer; and Matuschewski, Kai, "Plasmodium Para-Aminobenzoate Synthesis and Salvage Resolve Avoidance of Folate Competition and Adaptation to Host Diet" (2019). Pharmaceutical Sciences Faculty Publications. 136.