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Reprogramación racional de la regioselectividad de la O-metilación para la adaptación biosintética combinatoria de
Xiaojing Wang1,2,3, Chen Wang1,2, Lixin Duan2,4
1Biotechnology Research Institute , Chinese Academy of Agricultural Sciences , 12 Zhongguancun South Street , Beijing 100081 , P.R. China.
Journal of the American Chemical Society
|February 16, 2019
Resumen
Desarrollamos métodos biosintéticos y biocatalíticos eficientes utilizando O-metiltransferasas (OMT) diseñadas para crear nuevos productos naturales O-metilados. Estas enzimas diseñadas ofrecen regioselectividad ajustable para el descubrimiento y desarrollo de fármacos.
Área de la Ciencia:
- Biocatálisis y ingeniería metabólica
- Descubrimiento de fármacos de productos naturales
- Ingeniería de enzimas
Sus antecedentes:
- La O-metilación tiene un impacto significativo en las propiedades farmacocinéticas y farmacodinámicas (PK/PD) de los productos naturales de molécula pequeña.
- Los biocatalizadores eficientes de O-metiltransferasa (OMT) con promiscuidad de sustrato y regioselectividad sintonizable son cruciales para el descubrimiento y desarrollo de fármacos.
- Se necesitan métodos de producción escalables y sostenibles para la síntesis catalizada por OMT.
Objetivo del estudio:
- Establecer plataformas biosintéticas y biocatalíticas totales eficientes para la producción de policetidos O-metilados no naturales.
- Demostrar la reprogramación de la regioselectividad OMT a través de la ingeniería guiada por la estructura.
- Investigar la relación entre la regioselectividad de ingeniería y la plasticidad del sustrato.
Principales métodos:
- Utilizó un par de OMT de hongos con especificidad de región ortogonal.
- Ingeniería racional de cavidades activas guiadas por la estructura para modificar la regioselectividad de las enzimas.
- Se han desarrollado plataformas totales de producción biosintética y biocatalítica.
Principales resultados:
- Se han producido con éxito policetidos de lactona benzenodiol metilados no naturales.
- Demostró que los OMT diseñados exhiben regioselectividad reprogramada.
- Caracterizó la interacción entre la regioselectividad de ingeniería y la plasticidad del sustrato.
Conclusiones:
- Los OMT diseñados proporcionan una herramienta poderosa para generar diversas sustancias químicas para el descubrimiento de fármacos.
- Estas plataformas biocatalíticas facilitan la optimización de la PK/PD de los andamios bioactivos.
- Los hallazgos sirven de guía para la adaptación biosintética combinatoria de productos no naturales.
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