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Modo de unión tricovalente inesperado de los ácidos borónicos dentro del sitio activo de una proteína que se une a la
Astrid Zervosen1, Raphael Herman, Frédéric Kerff
1Centre de Recherches du Cyclotron, Université de Liège, B-4000 Sart Tilman, Liège, Belgium.
Journal of the American Chemical Society
|May 18, 2011
Resumen
Los ácidos borónicos forman inesperadamente aductos tricovalentes con la proteína R39 que se une a la penicilina, revelando un nuevo mecanismo de inhibición de la enzima. Este descubrimiento ofrece nuevos conocimientos sobre la inhibición de la serina amidohidrolasa y el diseño de fármacos.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- La inhibición de la enzima inhibición de la enzima.
Sus antecedentes:
- Los ácidos borónicos son inhibidores conocidos de las serina amidohidrolasas, generalmente formando adductos tetraédricos que imitan el estado de transición de la enzima.
- Las proteínas que se unen a la penicilina (PBP), como la DD-peptidasa de Actinomadura sp. R39, son objetivos cruciales en la investigación antibacteriana.
Objetivo del estudio:
- Para aclarar la base estructural de la inhibición de la DD-peptidasa R39 por los nuevos ácidos amidometilborónicos.
- Investigar la formación de adductos inhibidores de enzimas y sus implicaciones para los mecanismos catalíticos.
Principales métodos:
- Se utilizó la cristalografía de rayos X para resolver las estructuras de la DD-peptidasa R39 compleja con cuatro ácidos amidometilborónicos y un éster de pinacol de ácido borónico.
- Se realizaron estudios cinéticos para analizar la reacción entre la DD-peptidasa R39 y el ácido 2,6-dimetoxibenzamidometilborónico.
Principales resultados:
- El estudio identificó los primeros adductos inhibidores de enzimas tricovalentes cristalográficamente observados, donde el boro interactúa con tres residuos del sitio activo (Ser49, Ser298, Lys410).
- En algunos casos, se observaron aductos tricovalentes y monocovalentes dentro de la misma estructura cristalina, lo que sugiere un proceso de unión dinámico.
- Se observaron cinéticas bifásicas, aunque no directamente correlacionadas con la formación de complejos tricovalentes.
Conclusiones:
- Los ácidos amidometilborónicos inhiben la DD-peptidasa R39 a través de una inesperada formación de adducto tricovalente, expandiendo los modos conocidos de inhibición de la serina amidohidrolasa.
- Los hallazgos proporcionan una comprensión estructural y mecanicista detallada de esta nueva vía de inhibición, que podría guiar el diseño de nuevos agentes terapéuticos.
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