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Biosíntesis bacteriana y maduración de los agentes anticancerígenos de la didemnina
Ying Xu1, Roland D Kersten, Sang-Jip Nam
1KAUST Global Collaborative Research, Division of Life Science, School of Science, Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
Journal of the American Chemical Society
|March 31, 2012
Resumen
Los tunicados marinos producen compuestos anticancerígenos, pero el suministro es limitado. Estas dideminas son en realidad hechas por bacterias, ofreciendo un nuevo camino para la producción y el desarrollo de fármacos.
Área de la Ciencia:
- Productos naturales del mar productos naturales del mar.
- Biosíntesis bacteriana de la biosíntesis bacteriana.
- Descubrimiento de fármacos.
Sus antecedentes:
- La didemnina B, un producto natural marino de Trididemnum solidum, fue el primer fármaco marino en ensayos clínicos en humanos.
- El suministro limitado y la estructura compleja de las didemninas obstaculizan el desarrollo de fármacos, lo que afecta a los ensayos clínicos de aplidina (dehidrodidemnin B).
Objetivo del estudio:
- Identificar la fuente de las didemninas y dilucidar su vía biosintética.
- Para hacer frente a las limitaciones de suministro de agentes anticancerígenos a base de didemnin.
Principales métodos:
- Secuenciación del genoma completo de Tistrella mobilis.
- Análisis del grupo de genes biosintéticos didemnin putativo (did).
- Espectrometría de masas de imágenes para observar la conversión de precursores.
Principales resultados:
- Las didemninas son productos bacterianos sintetizados por las α-proteobacterias marinas Tistrella mobilis y Tistrella bauzanensis.
- El clúster de genes biosintéticos de didemnin (did) fue identificado en un megaplasmido en T. mobilis.
- Las didemninas X e Y se sintetizan primero, luego se convierten extracelularmente en didemnin B a través de un nuevo mecanismo de post-ensamblaje.
Conclusiones:
- El origen bacteriano de los didemninos resuelve los problemas de suministro de estos productos naturales marinos.
- Discovery facilita la ingeniería genética para nuevos análogos de didemnin.
- Este hallazgo abre nuevas vías para el desarrollo de terapias basadas en didemnin.
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