Trypanosoma cruzi genome encodes a pteridine reductase 2 protein.

Abstract

Pteridine metabolism in Trypanosoma cruzi is poorly understood. The term ‘pteridine’ is used collectively for two classes of structurally-related compounds, folates and biopterins, which differ only in the nature of the side chain attached to the C6 atom of the pterin ring. Both folate and biopterin, in their reduced (tetrahydro) forms, serve as essential cofactors in a number of critical metabolic steps in many organisms [1]. While some microorganisms and parasites such as Plasmodium can synthesize folate, mammals and trypanosomatid parasites lack this ability. On the other hand, mammalian cells can synthesize tetrahydrobiopterin de novo from GTP, while these parasites cannot synthesize biopterin either [2–4]. In order to meet the need for these essential nutrients, folate and biopterin are transported from the host into the parasite, and are subsequently reduced to their respective dihydro and tetrahydro forms by parasitic dihydrofolate reductase (DHFR) and pteridine reductase (PTR1) enzymes [1,2]. DHFR is one of the best characterized enzymes. Structure function relationships in DHFR from a variety of sources have been studied in detail and a number of inhibitors targeting DHFR has been successfully used in cancer chemotherapy and against some infectious pathogens including malaria parasite [1,5,6]. On the other hand, much of our current knowledge about pteridine reductase 1 (PTR1) is derived from research in Leishmania [7–12]. The Leishmania gene encoding PTR1 enzyme was found to be responsible for resistance to the classical antifolate drug methotrexate (MTX). The enzyme belongs to the family of short-chain dehydrogenases/reductases (SDR). Biochemical studies showed that it had broad substrate specificity and was able to reduce both folates and biopterins using NADPH as cofactor. PTR1 is considerably less sensitive (at