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Las redes de reactividad calculada mecánica cuántica/mecánica molecular revelan cómo el citocromo P450cam y su
Binju Wang1, Chunsen Li2,3, Kshatresh Dutta Dubey1
1†Institute of Chemistry and The Lise Meitner-Minerva Center for Computational Quantum Chemistry, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Journal of the American Chemical Society
|May 27, 2015
Resumen
Los cálculos mecánicos cuánticos / mecánicos moleculares revelan una nueva vía catalítica en las enzimas P450, descartando un "segundo oxidante" y explicando la epoxidación específica del sustrato por el mutante T252A.
Área de la Ciencia:
- Bioquímica y Enzimología.
- Química computacional es la química computacional.
- Biología Estructural Biología estructural.
Sus antecedentes:
- Las enzimas del citocromo P450 catalizan reacciones oxidativas cruciales.
- El mecanismo de la catálisis de P450, en particular el papel del Compuesto I (Cpd I), ha sido ampliamente estudiado.
- Se investigó una mutación (treonina-252-a-alanina, T252A) en P450cam para comprender el papel del transbordador de protones.
Objetivo del estudio:
- Para investigar la larga cuestión de un "segundo oxidante" en las enzimas P450.
- Para dilucidar el mecanismo catalítico del mutante P450cam T252A.
- Para identificar la vía responsable de la epoxidación del 5-metilenilcámforo por el mutante T252A.
Principales métodos:
- Se emplearon cálculos mecánicos cuánticos / mecánicos moleculares (QM / MM).
- Las redes de reactividad se generaron mediante la investigación de los candidatos oxidantes: Cpd I, hidroperoxido férrico y peróxido de hidrógeno férrico (Fe (III) (O2H2)).
- Se analizó el papel de las interacciones de sustrato y proteína en los intermediarios estabilizadores.
Principales resultados:
- Se identificó una "segunda vía de acoplamiento", iniciada por el intermedio Fe (III) (O2H2) intermedio.
- Esta vía implica la homólisis O-O y la abstracción H, lo que lleva a la formación de Cpd I.
- Las interacciones entre el sustrato (5-metilenilcámforo) y las proteínas dictan la persistencia y la reactividad del Fe (III) (O2H2), influyendo en la epoxidación y previniendo la oxidación del alcanfor.
Conclusiones:
- El estudio descarta un "segundo oxidante" e identifica una vía de acoplamiento adicional en P450cam.
- La mutación T252A permite una nueva vía que involucra Fe (III) (O2H2) para la epoxidación del sustrato.
- Los resultados conducen a un ciclo catalítico revisado para el citocromo P450cam, destacando la interacción del sustrato con la proteína.
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