Targeting Purine and Pyrimidine Metabolism in Human Apicomplexan Parasites

Abstract

Synthesis de novo, acquisition by salvage and interconversion of purines and pyrimidines represent the fundamental requirements for their eventual assembly into nucleic acids as nucleotides and the deployment of their derivatives in other biochemical pathways. A small number of drugs targeted to nucleotide metabolism, by virtue of their effect on folate biosynthesis and recycling, have been successfully used against apicomplexan parasites such as Plasmodium and Toxoplasma for many years, although resistance is now a major problem in the prevention and treatment of malaria. Many targets not involving folate metabolism have also been explored at the experimental level. However, the unravelling of the genome sequences of these eukaryotic unicellular organisms, together with increasingly sophisticated molecular analyses, opens up possibilities of introducing new drugs that could interfere with these processes. This review examines the status of established drugs of this type and the potential for further exploiting the vulnerability of apicomplexan human pathogens to inhibition of this key area of metabolism.

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

“…These recent advances have allowed development of bioassays based upon validated targets for drug screening, or targets still in the process of validation (for review see , Prabhu & Patravale, 2011, Sahu et al, 2008) : haem polymerization (O'Neill et al, 2006), pyrimidine, purine, folate (Hyde, 2007), lipid (Wengelnik et al, 2002), shikimate (McRobert et al, 2005), non-mevalonate (Wiesner & Jomaa, 2007) and other apicoplast metabolisms (Sato & Wilson, 2005), mitochondrial electron transport (Mather et al, 2007), redox homeostasis (Bauer et al, 2006), protein prenylation (Van Voorhis et al, 2007), proteases (Wegscheid-Gerlach et al, 2010), kinases (Doerig & Meijer, 2007)... Some of them are detailed below.…”

Erythrocytic Adenosine Monophosphate as an Alternative Purine Source in Plasmodium falciparum

“…falciparum is a purine auxotroph, salvaging host cell purines for synthesis of cofactors and nucleic acids (4,5). Purine nucleosides and nucleobases can be transported across the parasite plasma membrane by the PfNT1 2 transporter (Fig.…”

“…Hypoxanthine is the key precursor of other purines in Plasmodium metabolism and is commonly used as a nutritional supplement in malarial culture media. A key source of hypoxanthine in vivo is from the erythrocyte purine pool where ATP is in dynamic metabolic exchange with hypoxanthine via ADP, AMP, IMP, inosine, and adenosine (5). In human erythrocytes, adenosine is efficiently salvaged by adenosine kinase (hAK).…”

New Opportunities in the Structure-based Design of Anti-Protozoan Agents

“…Whilst higher eukaryotes use both pathways to significant levels, the picture is more complex amongst apicomplexan parasites. Plasmodium only uses the de novo pathway highlighting its essential function [7], whereas Cryptosporidium is deficient in de novo capabilities and relies on the salvage pathway [14]. Toxoplasma utilizes both pathways and inhibition of the de novo pathway leads to a reduction in acute virulence of the T. gondii parasite in mice, highlighting its potential as a point of chemotherapy [50].…”