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Conocimiento de la formación del andamio de esteroides a partir de la estructura de la cicloasa oxidosqualeno humana
Ralf Thoma1, Tanja Schulz-Gasch, Brigitte D'Arcy
1F. Hoffmann-La Roche AG, Pharma Research Discovery Chemistry, 4070 Basel, Switzerland.
Nature
|November 5, 2004
Resumen
La oxidosqualeno ciclasa (OSC) es clave para la biosíntesis del colesterol. Nuevas estructuras cristalinas revelan cómo el OSC forma lanosterol, ayudando al diseño de nuevos medicamentos para reducir el colesterol.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Descubrimiento de Drogas Descubrimiento de Drogas
Sus antecedentes:
- La oxidosqualeno ciclasa (OSC), también conocida como lanosterol sintasa, es crucial para sintetizar el andamio de esteroides en organismos superiores.
- OSC cataliza la ciclización selectiva del 2,3-oxidosqualeno en lanosterol, un precursor en la biosíntesis del colesterol.
- A pesar de décadas de investigación, el mecanismo preciso de la compleja cascada de ciclización de OSC sigue siendo incompletamente entendido.
Objetivo del estudio:
- Para aclarar el mecanismo de la oxidosqualeno ciclasa (OSC) en la catalización de la formación de lanosterol.
- Proporcionar información estructural sobre el papel de la OSC en la biosíntesis del colesterol para el desarrollo potencial de fármacos.
- Facilitar el diseño basado en la estructura de nuevos fármacos anticolesterolemicos dirigidos a la OSC.
Principales métodos:
- Se empleó cristalografía de rayos X para determinar las estructuras de la OSC. ligada a la membrana humana.
- Cristalización de la OSC en complejo con un inhibidor para bajar el colesterol.
- Cristalización de la OSC en complejo con su producto de reacción, el lanosterol.
Principales resultados:
- Se obtuvieron dos estructuras cristalinas de OSC humano: una compleja con un inhibidor y otra con lanosterol.
- La estructura con el inhibidor proporciona una base para el diseño basado en la estructura de nuevos inhibidores de la OSC con potencial para reducir el colesterol.
- La estructura con lanosterol aclara cómo OSC logra la especificidad del producto en su reacción de ciclización altamente exotérmica.
Conclusiones:
- Las estructuras cristalinas presentadas ofrecen información crítica sobre el mecanismo y la especificidad de la oxidosqualeno ciclasa.
- Estos hallazgos allanan el camino para el diseño racional de nuevos agentes anticolesterolemicos dirigidos a OSC.
- OSC sigue siendo un objetivo prometedor para el desarrollo de nuevas estrategias terapéuticas para controlar los niveles de colesterol.
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