Fresh insights into the pyrimidine metabolism in the trypanosomatids

Abstract

The trypanosomatid parasites continue their killing spree resulting in significant annual mortality due to the lack of effective treatments and the prominence of these diseases in poorer countries. These dimorphic parasites thrive unchecked in the host system, outsmarting the immune mechanisms. An understanding of biology of these parasitic forms will help in the management and elimination of these fatal diseases. Investigation of various metabolic pathways in these parasites has shed light in the understanding of the unique biology of the trypansomatids. An understanding of these pathways have helped in tracing the soft targets in the metabolic pathways, which could be used as effective drug targets which would further impact the therupeutic implications. Pyrimidine pathway is a vital metabolic pathway which yields in the formation of pyrimidines, which are then integrated in nucleic acids (DNA and RNA) in sugars (UDP sugars) and lipids (CDP lipids). A wealth of data and information has been generated in the past decades by in-depth analyses of pyrimidine pathway in the trypanosomatid parasites, which can aid in the identification of anomalies between the parasitic and host counterpart which could be further harnessed to develop therapeutic interventions for the treatment of parasitic diseases. This review presents an updated and comprehensive detailing of the pyrimidine metabolism in the trypansomatids, their uniqueness and their distinctions, and its possible outcomes that would aid in the eradication of these parasitic diseases.

Keywords: Crithidia; Leishmania; Pyrimidine; Trypanosoma; Trypanosomatids.

Fig. 1

Schematic representation of various transporters involved in the pyrimidine transport in trypanosomatids. a Pyrimidine transport in Trypanosoma. b Pyrimidine transport in Leishmania and Crithidia. Abbreviation: TbBFs, Trypansosoma blood stream forms

Fig. 2

Schematic representation of the oligomeric states of the various enzymes involved in the pyrimidine metabolism of the trypanosomatids. a Enzymes involved in the de novo pyrimidine biosynthesis pathway. b Enzymes involved in salvage pathway for pyrimidines. The bracketed abbreviations are depicting the techniques employed for the estimation of oligomeric state of an enzyme. PDB ID is also mentioned if the crytstal structure of the given enzyme has been solved. Abbreviations: CPSII, carbamoyl-phosphate synthase; ATCase, aspartate carbamoyl transferase; DHOase, dihydroorotase; DHODH, dihydroorotate dehydrogenase; UMPS, uridine monophosphate synthetase; UKase, uridine kinase; UPase, uridine phosphorylase; UPRT, uracil phospho ribosyl transferase; NDPK, nucleoside-diphosphate kinase; dUTPase, deoxyuridine-triphosphatase; DHFR-TS, dihydrofolate reductase-thymidylate synthase; TK, thymidine kinase. Tc, Trypanosoma cruzi; Tb, Trypanosoma brucei; Ld, Leishmania donovani; Lm, Leishmania major; Cl, Crithidia luciliae; GFC, gel filtration chromatography; DLS, dynamic light scattering; CLS, cross linking Studies; ACS, analytical centrifugation studies; GEMMA, gas phase electrophoretic mobility macromolecule/nanoparticle analysis