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Emergencia de la función en las proteínas P450: un estudio combinado de mecánica cuántica/mecánica molecular y

Rajeev Ramanan¹, Kshatresh Dutta Dubey¹, Binju Wang¹

¹Institute 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

|April 10, 2016

Resumen

Este estudio revela cómo las enzimas P450SPα hidroxilan los ácidos grasos utilizando peróxido de hidrógeno (H2O2). La unión al sustrato estabiliza un intermediario clave, permitiendo la α-hidroxilación selectiva a través de un mecanismo radical.

Área de la Ciencia:

La bioquímica
Enzimología
Química computacional

Sus antecedentes:

Las enzimas del citocromo P450 son cruciales para el metabolismo de varios compuestos.
Comprender el mecanismo de P450SPα en la hidroxilación de ácidos grasos es importante para el desarrollo de fármacos y estudios metabólicos.
El peróxido de hidrógeno (H2O2) es un oxidante clave en algunas reacciones catalizadas por P450.

Objetivo del estudio:

Para aclarar el mecanismo detallado de la hidroxilación de ácidos grasos dependientes de H2O2 por P450SPα.
Investigar los factores que controlan la regioselectividad y la enantioselectividad de esta reacción.
Explorar el papel de los residuos del sitio activo en la función y evolución de las enzimas.

Principales métodos:

Simulaciones combinadas de mecánica cuántica y mecánica molecular (QM/MM).
Simulaciones de dinámica molecular.
Análisis de la estructura del sitio activo de la enzima y las interacciones con el sustrato.

Principales resultados:

El H2O2 sirve como un oxidante sustituto, formando el Compuesto I (Cpd I) a través de la escisión del enlace homolítico O-O.
La unión al sustrato estabiliza el complejo Fe-H2O2, facilitando la formación de Cpd I y previniendo reacciones secundarias.
Los residuos del sitio activo Arg241 y Pro242 dictan la α-regioselectividad y la S-enantioselectividad mediante el control de la unión al sustrato y la activación del enlace C-H.

Conclusiones:

El estudio aclara el mecanismo de activación de H2O2 y el origen de la selectividad en la hidroxilación de ácidos grasos mediada por P450SPα.
Los residuos del sitio activo desempeñan un papel fundamental en la dirección de la vía de reacción y en garantizar una alta selectividad.
Las comparaciones con enzimas P450 relacionadas destacan las estrategias evolutivas para la diversificación funcional.

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