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Mecanismo catalítico y especificidad del producto de la histona lisina metiltransferasa SET7/9: un estudio QM/MM-FE
1Department of Chemistry, New York University, New York 10003, USA.
Journal of the American Chemical Society
|January 26, 2006
Resumen
La metilación de la histona lisina regula la actividad génica. La enzima SET7/9 cataliza esto a través de una reacción S(N) 2, con especificidad lograda al prevenir las conformaciones cercanas al ataque de la dimetilación.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Química computacional es la química computacional.
Sus antecedentes:
- La metilación de la histona lisina es un mecanismo epigenético clave que regula la estructura de la cromatina y la expresión génica.
- Comprender el mecanismo de reacción y la especificidad de las histonas metiltransferasas es crucial para descifrar la regulación génica.
Objetivo del estudio:
- Para investigar el mecanismo de reacción y la especificidad del producto de la histona lisina metiltransferasa SET7/9.9.
- Proporcionar una comprensión teórica del proceso catalítico utilizando métodos computacionales.
Principales métodos:
- Cálculos de energía libre mecánica cuántica/mecánica molecular (QM/MM-FE) desde el principio.
- Se emplearon simulaciones de dinámica molecular para estudiar la enzima SET7/9.
- Las barreras de la energía libre se calcularon a nivel de MP2 ((6-31+G) QM / MM.
Principales resultados:
- La reacción de transferencia de metilo catalizada por SET7/9 sigue un mecanismo de sustitución nucleófila en línea S(N) 2.
- Se identificó un estado de transición con un 70% de carácter disociativo.
- La barrera de energía libre calculada (20,4 +/- 1,1 kcal/mol) coincide estrechamente con las estimaciones experimentales (20,9 kcal/mol).
- Las fluctuaciones de la barrera se correlacionan con la distancia y el ángulo de ataque nucleófilo.
- La especificidad de la monometiltransferasa de SET7/9 surge de las conformaciones de ataque cercano interrumpidas para la dimetilación.
Conclusiones:
- El estudio aclara el mecanismo de reacción detallado de SET7/9, confirmando su naturaleza S(N) 2.
- Los hallazgos computacionales apoyan las observaciones experimentales sobre la barrera catalítica de la enzima.
- El mecanismo de la especificidad del producto de SET7/9 como monometiltransferasa se explica a través del control conformacional.
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