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Epoxide hidrolase Lsd19 para la formación de poliéteres en la biosíntesis del lasalocida A: evidencia experimental
Yoshihiro Shichijo1, Akira Migita, Hiroki Oguri
1Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan.
Journal of the American Chemical Society
|August 20, 2008
Resumen
Los investigadores identificaron la enzima Lsd19, crucial para la formación de productos naturales de poliéter como el lasalocid. Este estudio proporciona la primera evidencia experimental de la apertura de epóxido enzimático en la biosíntesis de poliéteres, revelando un mecanismo de ciclización 6-endo-tet.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biosíntesis de Productos Naturales de Productos Naturales
- Enzimología Enzimología.
Sus antecedentes:
- Los metabolitos de poliéter son productos naturales vitales con estructuras complejas.
- La comprensión de los mecanismos enzimáticos detrás de la construcción del esqueleto de poliéter sigue siendo un desafío significativo en la química orgánica.
- Se han carecido de datos experimentales sobre la formación enzimática de poliéteres.
Objetivo del estudio:
- Para dilucidar la vía enzimática de la biosíntesis del producto natural poliéter.
- Identificar y caracterizar la enzima responsable de las etapas clave de ciclización en la formación de lasalocid.
- Proporcionar la primera evidencia experimental de la apertura enzimática del epoxido en la biosíntesis de poliéteres.
Principales métodos:
- La clonación y la sobreexpresión del gen putativo de la epoxida hidrolasa lsd19 del clúster de genes biosintéticos de lasalocid en Escherichia coli.
- Purificación de la enzima Lsd19.
- Los ensayos de conversión enzimática utilizan un sustrato propuesto, bisepoxyprelasalocid, y su análogo sintetizado.
- Tratamiento químico del bispoxido con ácido tricloroacético para la comparación.
Principales resultados:
- La enzima Lsd19 purificada convirtió con éxito el bispoxiprelasalocid en lasalocid A a través de un modo de ciclización 6-endo-tet.
- Un análogo sintetizado también fue convertido a su derivado por Lsd19, confirmando su actividad catalítica.
- El tratamiento químico produjo isolasalocid A a través de una ciclización de 5-exo-tet, destacando el mecanismo específico de la enzima.
- Este estudio proporciona evidencia inequívoca para el bispoxiprelasalocid como un intermediario biosintético.
Conclusiones:
- La enzima Lsd19 cataliza las formaciones secuenciales de éter cíclico en la biosíntesis del lasalocida.
- Lsd19 facilita una ciclización energéticamente desfavorecida de 6-endo-tet, un hallazgo novedoso en la formación de poliéteres.
- Este trabajo representa la primera demostración de reacciones enzimáticas de apertura de epoxido que conducen a un producto natural de poliéter.
- Los hallazgos ofrecen una visión crítica de la biosíntesis de productos naturales complejos de poliéter.
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