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Enediyne antibiótico antitumoral maduropeptina biosíntesis con una C-metiltransferasa que actúa sobre un CoA atado a
Jianya Ling1, Geoffrey P Horsman, Sheng-Xiong Huang
1Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
Journal of the American Chemical Society
|August 20, 2010
Resumen
La biosíntesis del antibiótico maduropeptina (MDP, por sus siglas en inglés)
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Productos Naturales Química Productos Naturales
Sus antecedentes:
- La maduropeptina (MDP) es un antibiótico antitumoral enediyne producido por Actinomadura madurae.
- El cromóforo de MDP contiene una porción de ácido 3,6-dimetilsalicílico.
- La comprensión de la biosíntesis de MDP puede informar el desarrollo de nuevos fármacos contra el cáncer.
Objetivo del estudio:
- Para dilucidar la vía biosintética de la fracción de ácido 3,6-dimetilsalicílico de maduropeptina.
- Para caracterizar las funciones de las enzimas MdpB, MdpB1, MdpB2 y MdpB3 en esta vía.
- Para investigar la inusual lógica enzimática empleada en la biosíntesis del ácido aromático MDP.
Principales métodos:
- Análisis bioinformático del clúster de genes biosintéticos del MDP.
- Pruebas enzimáticas para determinar la especificidad del sustrato y los mecanismos de reacción.
- Caracterización bioquímica de las enzimas MdpB1 y MdpB2.
Principales resultados:
- La vía de biosíntesis del ácido aromático MDP presenta un orden inesperado de pasos enzimáticos.
- MdpB2 activa los análogos del ácido salicílico a través de la ligadura de CoA.
- MdpB1 metila únicamente C un ácido aromático atado a CoA, que precede a la activación catalizada por MdpB2.
Conclusiones:
- La biosíntesis de la fracción de ácido aromático del cromóforo MDP sigue una secuencia enzimática no convencional.
- La capacidad de MdpB1 para C-metilizar un sustrato atado a CoA es novedosa.
- La promiscuidad de la actividad de ligasa de CoA de MdpB2 ofrece potencial para la ingeniería de nuevos análogos de MDP.
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