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Estados de transición diferenciados por sustrato de la metilación de lisina catalizada SET7/9
Shi Chen, Kanishk Kapilashrami, Chamara Senevirathne
1Department of Biochemistry , Albert Einstein College of Medicine , Bronx , New York 10461 , United States.
Journal of the American Chemical Society
|April 30, 2019
Resumen
Las enzimas pueden estabilizar múltiples estados de transición (TS) para una catálisis eficiente. La enzima SET7/9 utiliza dos TS distintos para metilizar diferentes sustratos, un hallazgo crucial para comprender la versatilidad de la enzima.
Área de la Ciencia:
- La bioquímica
- Enzimología
- Biología estructural
Sus antecedentes:
- Las reacciones enzimáticas dependen de la estabilización del estado de transición (TS) para la aceleración de la velocidad.
- Comprender si las enzimas pueden estabilizar múltiples TS para una sola reacción sigue siendo un desafío significativo.
- Las proteína lisina metiltransferasas (PKMTs) son enzimas cruciales involucradas en la regulación epigenética.
Objetivo del estudio:
- Investigar si el PKMT SET7/9 puede acomodar y utilizar múltiples estados de transición distintos.
- Aclarar las bases estructurales y mecánicas de la estabilización TS dependiente del sustrato de SET7/9.
- Explorar las implicaciones de múltiples TS para la eficiencia de las enzimas y la promiscuidad del sustrato.
Principales métodos:
- Utilizó efectos de isótopos cinéticos experimentales para sondear los mecanismos de reacción.
- Métodos computacionales empleados para determinar y restringir las estructuras de estado de transición.
- Centrado en la enzima SET7/9 en complejo con sus sustratos fisiológicos H3 y p53.
Principales resultados:
- Se ha demostrado que SET7/9 adopta dos estados de transición estructuralmente distintos para la metilación de H3K4 y p53K372.
- Caracterizó estos TS como un SN casi simétrico y un SN extremadamente temprano, respectivamente.
- Se observó que estos TS de SET7/9 difieren de los reportados para otros PKMTs.
Conclusiones:
- SET7/9 exhibe una notable flexibilidad al utilizar múltiples estados de transición para catalizar la metilación.
- Esta estrategia multi-TS es probablemente esencial para la amplia especificidad de sustrato de SET7/9 y su alta eficiencia catalítica.
- Los hallazgos sugieren que la estabilización de TS múltiple puede ser un mecanismo común en otros PKMT y enzimas.
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