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Bases estructurales del reconocimiento y transporte de antifolatos por PCFT
Joanne L Parker1, Justin C Deme2,3,4, Gabriel Kuteyi5
1Department of Biochemistry, University of Oxford, Oxford, UK. joanne.parker@bioch.ox.ac.uk.
Nature
|May 27, 2021
Resumen
Este estudio revela la estructura del transportador de folato acoplado a protones (PCFT), explicando cómo reconoce los folatos y los fármacos antifolato como el pemetrexed. Estos hallazgos ofrecen información sobre el transporte de folato regulado por pH y la administración de fármacos.
Área de la Ciencia:
- La bioquímica
- Biología estructural
- La medicina molecular
Sus antecedentes:
- Los folatos (vitamina B9) son esenciales para el metabolismo celular, incluida la síntesis de ácido nucleico y aminoácidos.
- La deficiencia de folato puede conducir a trastornos del desarrollo, inmunológicos y neurológicos.
- Los mamíferos requieren folato en la dieta, dependiendo de sistemas de transporte especializados como el transportador de folato acoplado a protones (PCFT).
Objetivo del estudio:
- Para aclarar el mecanismo molecular de reconocimiento de folato por PCFT.
- Comprender cómo interactúa la PCFT con los fármacos antifolatos utilizados en la quimioterapia contra el cáncer.
- Proporcionar información estructural sobre la función de transporte regulada por el pH de la PCFT.
Principales métodos:
- Para determinar la estructura de la PCFT se utilizó la criomicroscopia electrónica (cryo-EM).
- Se obtuvieron estructuras para PCFT en estado libre de sustrato y en complejo con pemetrexed.
- El análisis se centró en la base estructural del reconocimiento y el transporte de antifolatos.
Principales resultados:
- El estudio presenta las estructuras cryo-EM de PCFT, revelando su arquitectura molecular.
- Se obtuvo información estructural detallada para la PCFT unida al fármaco antifolado pemetrexed.
- Los resultados proporcionan una base estructural para comprender cómo PCFT reconoce sus sustratos.
Conclusiones:
- Las estructuras determinadas ofrecen una comprensión mecanicista del reconocimiento de antifolatos por PCFT.
- Se obtuvieron conocimientos sobre el mecanismo de transporte de PCFT regulado por el pH.
- Esta investigación proporciona una base para el desarrollo de nuevas terapias basadas en antifolatos.
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