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Enzimas de hierro heterodímero no hemo en la biosíntesis de meroterpenoides de hongos
Xinyang Li1, Takayoshi Awakawa1,2, Takahiro Mori1,2,3
1Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Journal of the American Chemical Society
|December 9, 2021
Resumen
El hongo marino Talaromyces purpureogenus produce meroterpenoides hexacíclicos inusuales llamados talaromiólidos. Los investigadores aclararon su grupo de genes biosintéticos (tlxA-J) y descubrieron nuevos heterodímeros de enzimas de hierro no hemo (NHI) que catalizan las etapas oxidativas clave.
Área de la Ciencia:
- La bioquímica
- Química de los productos naturales
- Biología molecular
Sus antecedentes:
- Los talaromiolidos son meroterpenoides hexacíclicos complejos aislados del hongo marino Talaromyces purpureogenus.
- Estos compuestos presentan subestructuras únicas de (3R) -6-hidroximeleína y 4,5-seco-drimano.
Objetivo del estudio:
- Identificar y caracterizar el grupo de genes biosintéticos responsables de la producción de talaromiólidos.
- Elucidar los mecanismos enzimáticos subyacentes a la formación del complejo andamio de talaromiólidos.
- Investigar las nuevas funciones catalíticas de los heterodimeros de enzimas de hierro no hemo (NHI) en la biosíntesis de metabolitos secundarios.
Principales métodos:
- Expresión heteróloga del grupo de genes biosintéticos putativos (tlxA-J) en Aspergillus.
- Pruebas enzimáticas in vitro para determinar las actividades catalíticas de enzimas individuales y combinadas.
- La inactivación del gen basado en CRISPR-Cas9 para confirmar las funciones genéticas.
- Análisis estructural de rayos X y mutagénesis dirigida al sitio para comprender las relaciones estructura-función de la enzima.
Principales resultados:
- Se identificó y caracterizó funcionalmente el clúster de genes biosintéticos tlxA-J.
- Se encontró que un heterodímero de las enzimas NHI, TlxJ-TlxI, cataliza tres pasos oxidativos, incluida una reacción retro-aldol crucial que facilita la formación del esqueleto de 4,5-secodrimano.
- Otro heterodímero NHI, TlxA-TlxC, y TlxB participaron en las etapas posteriores de hidroxilación y acetilación para obtener productos finales.
- El análisis estructural proporcionó información sobre la formación y el mecanismo catalítico del heterodímero TlxJ-TlxI.
Conclusiones:
- Este estudio revela la vía biosintética completa de los talaromiolidos, destacando las funciones cruciales de los heterodímeros de la enzima NHI.
- Es el primer informe que demuestra que dos proteínas NHI forman un heterodímero funcional para la catálisis en la biosíntesis de metabolitos secundarios.
- Se estableció una nueva metodología para crear estructuras funcionales de oxigenasa en la biosíntesis de metabolitos secundarios.
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