Purine and Pyrimidine Metabolism in Leishmania

Abstract

Purines and pyrimidines are indispensable to all life, performing many vital functions for cells: ATP serves as the universal currency of cellular energy, cAMP and cGMP are key second messenger molecules, purine and pyrimidine nucleotides are precursors for activated forms of both carbohydrates and lipids, nucleotide derivatives of vitamins are essential cofactors in metabolic processes, and nucleoside triphosphates are the immediate precursors for DNA and RNA synthesis. Unlike their mammalian and insect hosts, Leishmania lack the metabolic machinery to make purine nucleotides de novo and must rely on their host for preformed purines. The obligatory nature of purine salvage offers, therefore, a plethora of potential targets for drug targeting, and the pathway has consequently been the focus of considerable scientific investigation. In contrast, Leishmania are prototrophic for pyrimidines and also express a small complement of pyrimidine salvage enzymes. Because the pyrimidine nucleotide biosynthetic pathways of Leishmania and humans are similar, pyrimidine metabolism in Leishmania has generally been considered less amenable to therapeutic manipulation than the purine salvage pathway. However, evidence garnered from a variety of parasitic protozoa suggests that the selective inhibition of pyrimidine biosynthetic enzymes offers a rational therapeutic paradigm. In this chapter, we present an overview of the purine and pyrimidine pathways in Leishmania, make comparisons to the equivalent pathways in their mammalian host, and explore how these pathways might be amenable to selective therapeutic targeting.

Isotopomer Profiling of Leishmania mexicana Promastigotes Reveals Important Roles for Succinate Fermentation and Aspartate Uptake in Tricarboxylic Acid Cycle (TCA) Anaplerosis, Glutamate Synthesis, and Growth

“…Glutamate is the precursor for other amino acids, such as proline and glutamine, that are both internalized at low rates under standard culture conditions. Glutamine is also required for pyrimidine and hexosamine biosynthesis (44,52), as well as the synthesis of the major thiols of these parasites, glutathione and trypanothione (53,54). Trypanothione participates in many anabolic and redox processes and can be conjugated to other metabolites necessitating continuous synthesis (53,54).…”

Antiviral screening identifies adenosine analogs targeting the endogenous dsRNALeishmaniaRNA virus 1 (LRV1) pathogenicity factor

“…Following uptake and activation to the triphosphate form, these analogs primarily target viral replication, with different classes acting preferentially against viral DNA or RNA polymerases (RDRP) or reverse transcriptases, as well as cellular metabolism. A second rationale was that Leishmania are purine auxotrophs, with highly active and multiply redundant pathways for uptake and activation of nucleobases and nucleosides (31). Indeed, a great deal of prior effort has been devoted to the development of antileishmanial purine analogs; however, whereas the nucleobase allopurinol is commonly used as a veterinary agent, it has proven more difficult to find agents of sufficient potency and selectivity against Leishmania to be used widely against human leishmaniasis (32).…”

Estudo do mecanismo e inibição da enzima diidroorotato desidrogenase de Leishmania major

“…Por exemplo, AMP desempenha um papel fundamental na transformação de energia; cAMP e cGMP são importantes compostos que atuam como segundos mensageiros; ATP, ADP e AMP funcionam como reguladores alostéricos; formas ativadas de carboidratos e lipídios têm nucleotídeos de purinas e pirimidinas como precursores e nucleotídeos trifosfatos são precursores imediatos para macromoléculas de informação na célula [36].…”

“…Isso obviamente faz com que a via de salvação de purinas seja crucial e consequentemente, repleta de alvos atrativos para o planejamento de fármacos [36]. Entretanto, ainda que a natureza obrigatória da via de salvação de purina torne esta uma rota crítica no metabolismo de Leishmania, nenhuma quimioterapia baseada em purina foi desenvolvida para parasitas cinetoplastídeos.…”

“…Por outro lado, Leishmania pode sintetizar pirimidina de novo e ainda expressa um conteúdo de enzimas da via de salvação [36]. Embora o metabolismo de pirimidinas em…”