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Función y estructura de las halogenasas iterativas de MalA/MalA' para la funcionalización C-H en etapa tardía de los

Amy E Fraley, Marc Garcia-Borràs¹, Ashootosh Tripathi

¹Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.

Journal of the American Chemical Society

|August 5, 2017

Resumen

Este estudio identifica dos enzimas fúngicas, MalA y MalA.

Área de la Ciencia:

La bioquímica
Micología
Química de los productos naturales

Sus antecedentes:

La malbranqueamida es un alcaloide indólico fúngico diclorado único.
Su estructura presenta un núcleo de biciclo[2.2.2]diazaoctano, con átomos de cloro que mejoran la actividad biológica.
La halogenación es un paso clave en su biosíntesis.

Objetivo del estudio:

Caracterizar las halogenasas dependientes de la flavina responsables de la biosíntesis de la malbranqueamida.
Investigar el mecanismo enzimático de la fase tardía de la halogenación.
Explorar la creación de nuevos análogos de la malbranqueamida.

Principales métodos:

Pruebas enzimáticas para caracterizar MalA y MalA' de cepas de hongos.
Síntesis quimioenzimática para generar análogos de bromo-cloro-malbranqueamida.
Estudios estructurales y computacionales de MalA' en complejo con sustratos.

Principales resultados:

MalA y MalA' fueron identificados como halogenasas dependientes de la flavina que catalizan la diclorinación iterativa y la monobrominación.
Se sintetizaron dos nuevos análogos de bromo-cloro-malbranqueamida.
MalA' representa una nueva clase de halogenasas dependientes de la flavina que se unen al zinc con un mecanismo de reacción único.

Conclusiones:

El estudio aclara el mecanismo enzimático detrás de la halogenación de la malbranqueamida.
Las halogenasas identificadas proporcionan información sobre la biosíntesis de productos naturales y la evolución de las enzimas.
Los hallazgos abren caminos para el desarrollo de nuevos productos naturales halogenados análogos.

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