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Síntesis quimioenzimática de micociclosina fluorada habilitada por la reacción de acoplamiento de biarilo catalizada

Shuo-Han Li¹, Xue Zhang², Ze-Long Mei¹

¹Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300072, China.

Journal of the American Chemical Society

|July 10, 2024

Resumen

Los investigadores diseñaron una enzima del citocromo P450 para crear nuevos productos naturales fluorados. Este enfoque híbrido permite la síntesis de derivados de micociclosina sustituidos por flúor con beneficios farmacológicos potenciales.

Área de la Ciencia:

La bioquímica
Química orgánica
Química medicinal

Sus antecedentes:

La incorporación de flúor mejora las propiedades farmacológicas del producto natural.
El acoplamiento oxidativo enzimático es clave para la síntesis de biarilo.
La síntesis de productos naturales fluorados mediante este método está poco explorada.

Objetivo del estudio:

Ingeniería del citocromo P450 (MtCYP121) para la síntesis de nuevos productos naturales fluorados.
Desarrollar una vía quimioenzimática para los derivados de micociclosina sustituidos por flúor.
Investigar el mecanismo de la ingeniería MtCYP121 en la formación de enlaces C-C.

Principales métodos:

Ingeniería de las proteínas del citocromo P450 de Mycobacterium tuberculosis (MtCYP121).
Síntesis quimioenzimática que incluye tirosina fenol liasa y MtCYP121.
Estudios mecánicos computacionales para elucidar las vías de reacción.

Principales resultados:

Se han sintetizado con éxito derivados de micociclosina sustituidos por flúor nuevos en la naturaleza.
Elucidado un mecanismo de reacción que involucra la abstracción de átomos de hidrógeno y el acoplamiento intramolecular.
Se ha demostrado que la sustitución de flúor afecta la eficiencia del acoplamiento de biarilo debido a las conformaciones de unión.

Conclusiones:

El MtCYP121 de ingeniería es eficaz para sintetizar productos naturales fluorados.
El enfoque quimioenzimático híbrido proporciona acceso a macrociclos fluorados complejos.
La comprensión de las interacciones de unión al sustrato es crucial para optimizar las reacciones enzimáticas de acoplamiento C-C.

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