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Mecanismo de la descarboxilación de la OMP en la orotidina 5'-monofosfato descarboxilasa

Hao Hu¹, Amy Boone, Weitao Yang

¹Department of Chemistry, Duke University, Durham, North Carolina 27708, USA. hao.hu@duke.edu

Journal of the American Chemical Society

|October 9, 2008

Resumen

La orotidina 5'-monofosfato descarboxilasa (ODCasa) probablemente utiliza un mecanismo de descarboxilación directa sin una molécula de agua. Esta molécula de agua estabiliza significativamente el inhibidor BMP, no el complejo enzima-sustrato.

Área de la Ciencia:

La bioquímica es la bioquímica.
Química computacional es la química computacional.
Catalización de enzimas por catalización de enzimas

Sus antecedentes:

El mecanismo catalítico de la orotidina 5 ext27 ext-monofosfato descarboxilasa (ODCasa) es objeto de debate, ya que las simulaciones anteriores no coincidían con las energías de activación experimentales.
Las simulaciones anteriores a menudo incluían una molécula de agua cerca del grupo de CO2 saliente, observada solo en estados unidos al inhibidor.

Objetivo del estudio:

Para investigar el papel de una molécula de agua específica en la catálisis de la ODCasa y la unión al inhibidor.
Para determinar el mecanismo catalítico preciso de ODCase utilizando métodos computacionales avanzados.

Principales métodos:

Simulaciones de Mecánica Cuántica/Mecánica Molecular (QM/MM) con teoría funcional de la densidad.
Simulaciones de la trayectoria de la energía libre para aclarar el mecanismo catalítico.
Cálculos vinculantes de energía libre para el complejo ODCase/BMP.

Principales resultados:

En ausencia de la molécula de agua, la ODCasa funciona a través de un mecanismo de descarboxilación directa.
El sitio activo de la enzima presenta un entorno electrostático sintonizado y enlaces de hidrógeno que contribuyen a la catálisis.
La molécula de agua contribuye significativamente a la energía libre de unión del complejo inhibidor de la ODCasa/BMP (-3 kcal/mol).

Conclusiones:

El complejo activo ODCasa/OMP probablemente carece de la molécula de agua, apoyando un mecanismo de descarboxilación directa.
El complejo ODCase/BMP con la molécula de agua representa mejor el análogo del estado de transición.
La consideración precisa de las moléculas de agua unidas a las proteínas es crucial para comprender la catálisis enzimática y la unión de ligandos.

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