Isoprenoid Precursor Biosynthesis Offers Potential Targets for Drug Discovery Against Diseases Caused by Apicomplexan Parasites

William      N. Hunter

Abstract

Two, simple, C5 compounds, dimethylally diphosphate and isopentenyl diphosphate, are the universal precursors of isoprenoids, a large family of natural products involved in numerous important biological processes. Two distinct biosynthetic pathways have evolved to supply these precursors. Humans use the mevalonate route whilst many species of bacteria including important pathogens, plant chloroplasts and apicomplexan parasites exploit the nonmevalonate pathway. The absence from humans, combined with genetic and chemical validation suggests that the nonmevalonate pathway holds the potential to support new drug discovery programmes targeting Gram-negative bacteria and the apicomplexan parasites responsible for causing serious human diseases, and also infections of veterinary importance. The non-mevalonate pathway relies on eight enzyme-catalyzed stages exploiting a range of cofactors and metal ions. A wealth of structural and mechanistic data, mainly derived from studies of bacterial enzymes, now exists for most components of the pathway and these will be described. Particular attention will be paid to how these data inform on the apicomplexan orthologues concentrating on the enzymes from Plasmodium spp. these cause malaria, one the most important parasitic diseases in the world today.

Keywords: Antimicrobial drug discovery, isoprenoid precursor biosynthesis, malaria, structure-based inhibitor discovery, toxoplasmosis, dimethylally diphosphate, isopentenyl diphosphate, mevalonate route, nonmevalonate pathway