Nucleotide metabolism in Plasmodium falciparum: recent developments

Abstract

Plasmodium falciparum, the causative agent for the most lethal form of malaria, has developed resistance to almost all widely used antimalarials. Availability of the genome sequence with mRNA expression and proteome profiles permit identification of new therapeutic targets, opening up fresh possibilities for drug and vaccine development. Complete absence of the de novo purine biosynthetic pathway from the parasite genome makes all enzymes of the salvage pathway targets worthy of study for inhibitor design. Success of folate antagonists in antimalarial therapy provides impetus for detailed examination of other enzymes involved in pyrimidine biosynthesis. This review examines recent biochemical and structural data on enzymes of these two pathways. The salient features of the parasite purine nucleoside phosphorylase, hypoxanthine guanine phosphoribosyltransferase, adenylosuccinate synthetase and dihydrofolate reductase -thymidylate synthase are presented.