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La liberación de policetida mediada por la aciltransferasa de una megasintasa fúngica
Xinkai Xie1, Michael J Meehan, Wei Xu
1Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, California 90095, USA.
Journal of the American Chemical Society
|June 18, 2009
Resumen
Los investigadores aclararon cómo la enzima fúngica LovF libera su producto utilizando la aciltransferasa LovD. Este mecanismo de liberación mediado por aciltransferasa mejora la eficiencia catalítica para producir lovastatina, un medicamento para bajar el colesterol.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- La micología de la micología.
Sus antecedentes:
- LovF, una poliquetida sintasa altamente reductora (HR-PKS) de Aspergillus terreus, sintetiza una cadena lateral clave para la producción de lovastatina.
- La lovastatina es un producto natural con propiedades reductoras del colesterol, derivado de la cadena lateral alfa-S-metilbutirato sintetizada por LovF.
Objetivo del estudio:
- Para expresar y reconstituir las actividades enzimáticas de LovF in vitro.
- Investigar y confirmar el mecanismo de descarga de productos de diketida desde el dominio LovF ACP.
- Para caracterizar la interacción entre LovF y la aciltransferasa LovD y su papel en la transferencia de productos.
Principales métodos:
- Expresión de la enzima LovF en su totalidad.
- Reconstitución in vitro de las actividades de la megasintasa.
- Estudios de interacción proteína-proteína entre LovF y LovD.
- Cinética de las enzimas para determinar la eficiencia catalítica.
Principales resultados:
- El producto de la ditetida se descarga eficientemente del dominio LovF ACP por la aciltransferasa LovD. disociada.
- Este es el primer caso reportado de liberación mediada por aciltransferasa de productos policetídicos de PKS de hongos.
- LovD interactúa principalmente con el dominio ACP de LovF, lo que lleva a una mejora de ~ 1 x 10 6 veces en la eficiencia catalítica en comparación con la N-acetilcisteamina.
Conclusiones:
- El estudio revela un nuevo mecanismo de descarga mediado por aciltransferasa para el fungo HR-PKS.
- Este mecanismo mejora significativamente la eficiencia de la transferencia de productos de policetida.
- Estos hallazgos ofrecen nuevos conocimientos sobre los mecanismos funcionales de las enzimas fúngicas HR-PKS.
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