Functional interrogation of Plasmodium genus metabolism identifies species- and stage-specific differences in nutrient essentiality and drug targeting
Fig 6
Species-specific models provide mechanistic explanation for differences in drug response between human- and rodent-infecting malaria species.
(a) The core and pan metabolic content of 5 malaria species was identified based on the respective species-specific reconstructions. The core content, illustrated by the intersection of the Venn diagram, is shared by all species. The pan content represents the union of the content across all of the multi-species reconstructions. (b) 14 metabolic reactions differed in their presence across the 5 reconstructed Plasmodium species. (c) Thiamine pyrophosphokinase (TPK) and (d) Choline kinase (CK) were predicted by the models to be essential for the growth of the rodent-infecting species (P. berghei) while their deletion had no effect on the growth of human and non-human primate species. Differential essentiality of TPK is due to absence of phosphomethylpyrimidine kinase and thiamine-phosphate pyrophosphorylase the rodent-infecting species. In the case of CK, the differential essentiality is due to the absence of phosphoethanolamine N-methyltransferase. (See Table A in S1 Tables for reactions abbreviations and gene-protein-reaction associations). (e) Pantothenate metabolism showed differences in essentiality between stage- and species-specific models. Tables indicate percentage in growth reduction compared to the WT upon deletion of the respective gene. ‘X’ indicates absence of a reaction from the respective reconstruction, ‘—‘ indicates no effect on growth upon deletion of the corresponding reaction and ‘%’ indicates the growth reduction percentage resulting from deletion of the corresponding gene. T: trophozoite, GII: early gametocyte stage, GV: late gametocyte stage, Ook: ookinete. See S3 Fig for the high resolution version of the figure.