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Conservación e importancia funcional del enlace carbono-oxígeno-hidrógeno en las metiltransferasas dependientes de
Scott Horowitz1, Lynnette M A Dirk, Joseph D Yesselman
1Howard Hughes Medical Institute , Ann Arbor, Michigan 48109, United States.
Journal of the American Chemical Society
|October 8, 2013
Resumen
Los enlaces hidrógenos CH··O no convencionales estabilizan la unión de S-adenosilmetionina (AdoMet) y la alineación del grupo metilo en las metiltransferasas. Este hallazgo revela un mecanismo evolutivo compartido para la metilación dependiente de AdoMet en diversas clases de enzimas.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- Biología evolutiva Biología evolutiva.
Sus antecedentes:
- La metilación dependiente de S-adenosilmetionina (AdoMet) es crucial para el metabolismo celular y la señalización.
- Las metiltransferasas dependientes de AdoMet, a pesar de las diversas clases, comparten un mecanismo catalítico conservado.
- Los determinantes fundamentales de este mecanismo compartido de transferencia de metilo siguen siendo en gran medida indefinidos.
Objetivo del estudio:
- Investigar las características estructurales y mecánicas subyacentes de las metiltransferasas dependientes de AdoMet.
- Identificar las interacciones conservadas que coordinan el grupo metilo AdoMet en diferentes clases de metiltransferasas.
- Aclarar el papel de estas interacciones en la unión de AdoMet, la estabilización del estado de transición y la catálisis.
Principales métodos:
- Análisis de la estructura cristalina de alta resolución de varias metiltransferasas.
- Cálculos de química cuántica para evaluar las fuerzas de interacción.
- Estudios bioquímicos y estructurales de un modelo de lisina metiltransferasa y su mutante en el sitio activo.
- Experimentos de dinámica cristalográfica y RMN.
Principales resultados:
- Los enlaces hidrógenos no convencionales carbono-oxígeno (CH···O) coordinan consistentemente el grupo metilo AdoMet en diferentes clases de metiltransferasas.
- Los cálculos de la química cuántica confirman que estas interacciones CH···O son inusualmente fuertes.
- El análisis mutacional demuestra que estas interacciones son vitales para la unión de AdoMet de alta afinidad y la estabilización del estado de transición.
- La dinámica de RMN revela que los enlaces CH···O restringen el movimiento del grupo metilo, ayudando a la alineación catalítica.
Conclusiones:
- El enlace hidrógeno metil CH··O es una característica evolutiva convergente en las metiltransferasas dependientes de AdoMet.
- Estas interacciones median un mecanismo universal para la transferencia de metilo, esencial para la función de la enzima.
- La comprensión de estas interacciones proporciona información fundamental sobre la estrategia catalítica conservada de las metiltransferasas.
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