Fig. 5

Artemisinin resistance displays unique metabolic weaknesses. a Trycarboxylic acid cycle: Resistant parasites rely on generation of oxaloacetate from the conversion of fumarate to malate, using fumarate hydratase and malate dehydrogenase, in the mitochondria. Sensitive parasites can also import malate into the mitochondria and use an alternative enzyme (malate:quinone oxidoreductase) to convert malate to oxaloacetate. b Folate metabolism: Inhibition of the SHMT enzyme (left) and the glycine cleavage system (right) is lethal in resistant parasites. Sensitive parasites can use either of these enzyme complexes interchangeably to produce mthf and thf. c Cofactor synthesis: The import of thiamine and the conversion of thiamine to thiamine diphosphate via thiamine thiphosphokinase is essential in resistant parasites. Sensitive parasites can also synthesize thiamine diphosphate de novo. Arrows colored for flux via FVA and stars for essentiality. Gray background indicates cytosolic localization, yellow indicates mitochondrial localization. FVA, flux variability analysis. SHMT, serine hydroxylmethltransferase, mthf, methyltetrahydrofolate, thf, tetrahydrofolate