The isoprenoid-precursor dependence of Plasmodium spp.

Abstract

Due to the increase in resistance of Plasmodium spp. against available antimalarials, there is a need for new, effective and innovative drugs. The non-mevalonate pathway for the biosynthesis of the universal isoprenoid precursors, which is absent in humans, is suggested as an attractive source of targets for such drugs with a novel mode of action. The biological importance of this pathway to Plasmodium spp. is proven by the efficacy of the clinical candidate fosmidomycin, which inhibits the biosynthesis of isoprenoid precursors; it is, however, less clear which isoprenoid end products are essential for parasite survival. In this Highlight, we identify protein prenylation, isoprene-containing quinone production, N-linked glycosylation as well as carotenoid and vitamin-E biosynthesis as probably essential isoprenoid-dependent physiological processes in Plasmodium. Inhibition of any of these processes blocks parasite development. Furthermore, both protein prenylation of SNARE proteins and a protein tyrosine phosphatase as well as tRNA prenylation have been identified as isoprene-dependent processes for which the physiological role in Plasmodium remains unclear. Therefore, the biosynthetic route to the isoprenoid precursors presents attractive drug targets for the development of antimalarials with novel modes of action.