ABSTRACT
BACKGROUND An increasing amount of research has led to the positioning of nucleoside diphosphate kinases (NDPK/NDK) as key metabolic enzymes among all organisms. They contribute to the maintenance the intracellular di- and tri- phosphate nucleoside homeostasis, but they also are involved in widely diverse processes such as gene regulation, apoptosis, signal transduction and many other regulatory roles. OBJETIVE Examine in depth the NDPKs of trypanosomatid parasites responsible for devastating human diseases (e.g., Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp.) which deserve special attention. METHODS The earliest and latest advances in the topic were explored, focusing on trypanosomatid NDPK features, multifunctionality and suitability as molecular drug targets. FINDINGS Trypanosomatid NDPKs appear to play functions different from their host counterparts. Evidences indicate that they would perform key roles in the parasite metabolism such as nucleotide homeostasis, drug resistance, DNA damage responses and gene regulation, as well as host-parasite interactions, infection, virulence and immune evasion, placing them as attractive pharmacological targets. MAIN CONCLUSIONS NDPKs are very interesting multifunctional enzymes. In the present review, the potential of trypanosomatid NDPKs was highlighted, raising awareness of their value not only with respect to parasite biology but also as molecular targets.
ABSTRACT
La vía TOR ("Target Of Rapamycin") de mamíferos es una red proteica de regulación para una amplia gama de procesos involucrados en el crecimiento y la diferenciación celular, constituyendo un interruptor funcional entre el metabolismo anabólico y catabólico de la célula. El Trypanosoma cruzi, agente etiológico de la enfermedad de Chagas, tiene un ciclo de vida muy complejo con diferentes estadios morfológicos en varios hospedadores. Este ciclo de vida implica que los parásitos enfrentan grandes fluctuaciones en el medio extracelular que deben ser detectadas y a las cuales deben responder adaptando su metabolismo. Un candidato a ser el mediador entre los receptores/sensores del medio y la respuesta adaptativa celular es la vía TOR. En este trabajo integramos los datos bibliográficos de la vía TOR de organismos tripanosomátidos con un análisis in silico (simulación computacional de procesos o estructuras biológicas) del genoma del parásito. Se proponen además posibles efectores y procesos regulados por esta ruta metabólica. Teniendo en cuenta que existe muy poca información sobre los mecanismos de transducción de señales en tripanosomátidos, consideramos que el mapa presentado en este trabajo puede ser una referencia para futuros trabajos experimentales.
The mammalian TOR pathway ("Target Of Rapamycin") is a regulatory protein network involved in a wide range of processes including cell growth and differentiation, providing a functional switch between anabolic and catabolic cell metabolism. Trypanosoma cruzi, the etiologic agent of Chagas disease, has a complex life cycle with different morphological stages in various hosts. This life cycle implies that parasites have to deal with fluctuations in the extracellular medium that should be detected and counteracted adapting their metabolism. A candidate to be the mediator between the receptors / sensors of the environment and cellular adaptive response is the TOR pathway. In this paper we integrate the bibliographic data of the TOR pathway in trypanosomatids by in silico analysis (computer simulation of biological structures and processes) of the parasite's genome. Possible effectors and processes regulated by this metabolic pathway are also proposed. Given that the information on the mechanisms of signal transduction in trypanosomatids is scarce, we consider the model presented in this work may be a reference for future experimental work.