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Un homólogo de la transglutaminasa como catalizador de condensación en las líneas de ensamblaje de antibióticos

Pascal D Fortin¹, Christopher T Walsh, Nathan A Magarvey

¹Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.

|July 27, 2007

Resumen

Una enzima recién descubierta, AdmF, actúa como una transglutaminasa (TGase) para formar el primer enlace amídico en la biosíntesis de antibióticos andrímidos. Este hallazgo abre caminos para la ingeniería de nuevos antibióticos y el descubrimiento de nuevas vías de biosíntesis.

Área de la Ciencia:

Bioquímica y Biología Molecular.
Biosíntesis de Productos Naturales de Productos Naturales
El descubrimiento de los antibióticos.

Sus antecedentes:

La resistencia a los antibióticos requiere nuevos antibióticos con mecanismos únicos de acción.
Andrimid es un potente inhibidor de pseudopéptido de la biosíntesis de ácidos grasos bacterianos.
El grupo de genes andrímido (adm) ha sido aislado y expresado en Escherichia coli para su posterior estudio.

Objetivo del estudio:

Para identificar la enzima responsable de la formación inicial de enlaces amídicos en la biosíntesis de andrímidos.
Para caracterizar la función de esta nueva enzima dentro de la línea de ensamblaje de andrímido.
Explorar el potencial de los homólogos de la transglutaminasa (TGase) en la biosíntesis de productos naturales.

Principales métodos:

Análisis bioinformático del clúster de genes de la andrímida (adm).
Expresión heteróloga del grupo de adm en Escherichia coli.
Caracterización bioquímica de la enzima identificada, AdmF.

Principales resultados:

El análisis bioinformático reveló una falta de sintasas de amida canónicas en el clúster adm.
AdmF, un homólogo de la transglutaminasa (TGase), fue identificado como la enzima que cataliza la primera formación de enlaces amídicos (enlace N-acil-beta-péptido).
AdmF funciona como una amida sintasa independiente, que une sustratos unidos a proteínas en la línea de ensamblaje de antibióticos.

Conclusiones:

AdmF representa una enzima biosintética recién descubierta, un homólogo de TGase, reclutado para el ensamblaje de antibióticos.
Este estudio informa la primera instancia de una enzima similar a la TGasa en la biosíntesis de antibióticos.
La minería del genoma para los homólogos de TGasa puede descubrir nuevas vías biosintéticas de productos naturales y nuevos antibióticos potenciales.

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