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Inhibidores coordinadores del hemo de la neuronal de óxido nítrico sintasa. La coordinación hierro-tioéter se
Jeffrey D Martell1, Huiying Li, Tzanko Doukov
1Department of Chemistry, Center for Molecular Innovation and Drug Discovery, and Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208-3113, USA.
Journal of the American Chemical Society
|December 18, 2009
Resumen
Este estudio presenta la primera estructura cristalina de un inhibidor de tioéter unido al hemo, revelando conocimientos sobre la inhibición neuronal de la óxido nítrico sintasa (nNOS). Las interacciones tioéter-hemo son más débiles de lo esperado, con la unión influenciada por el hierro hemo.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Química Medicinal La Química Medicinal es un campo de estudio de la química medicinal.
- Biología Estructural Biología estructural.
Sus antecedentes:
- Las interacciones hemo-tioéter son comunes con los ligandos de la metionina.
- Los inhibidores de la coordinación del hemo (tipo II) basados en tioéter son raros debido a la inestabilidad del enlace Fe-S.
Objetivo del estudio:
- Diseñar y caracterizar un nuevo inhibidor basado en tioéter de la neuronal óxido nítrico sintasa (nNOS).
- Para aclarar las bases estructurales de la coordinación tioéter-hemo en nNOS.
Principales métodos:
- Se utilizaron espectrofotometría y cristalografía de rayos X para caracterizar la unión al inhibidor.
- Se sintetizó y evaluó una serie de compuestos de tioéter (3-8).
Principales resultados:
- Se obtuvo la primera estructura cristalina de un inhibidor del tioéter complejado con hierro hemo (nNOS).
- Los compuestos 4-8 exhibieron una inhibición de tipo I para los nNOS férricos, cambiando al tipo II al reducirse a los nNOS ferrosos.
- La ligadura de tioéter-hemo no aumentó la potencia inhibidora, contrariamente a las expectativas.
Conclusiones:
- El estudio proporciona la primera evidencia estructural de la coordinación tioéter-hemo en cualquier enzima hemo.
- La fuerza de enlace tioéter-hemo es más débil de lo que se suponía anteriormente, particularmente con el hemo férrico.
- Las interacciones hidrofóbicas son críticas para estabilizar la coordinación tioéter-hemo, con cambios estructurales sutiles que impactan significativamente en la conformación de la unión.
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