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Síntesis de ADP-ribosa dimérica y su estructura con poli (ADP-ribosa) glicohidrolase humana

Michael J Lambrecht¹, Matthew Brichacek¹, Eva Barkauskaite²

¹†Department of Chemistry, Roger Adams Laboratory, University of Illinois, 600 South Mathews, Urbana, Illinois 61801, United States.

Journal of the American Chemical Society

|February 24, 2015

Resumen

Los dímeros de ADP-ribosa sintetizados químicamente proporcionan poli (ADP-ribosa) homogéneo (PAR) para los estudios estructurales. Este avance permite la primera estructura cocristalina de PARG humano, avanzando nuestra comprensión de las interacciones PAR-proteína en los procesos celulares.

Área de la Ciencia:

La bioquímica es la bioquímica.
Biología Molecular Biología Molecular
Síntesis Química La síntesis química es el proceso de síntesis química.

Sus antecedentes:

La poli-ADP-ribosilización (PAR) es una modificación crucial después de la traducción involucrada en la reparación del ADN, la regulación de la cromatina, la transcripción y la apoptosis.
La obtención de poli (ADP-ribosa) homogénea (PAR) ha sido un reto, lo que dificulta los estudios sobre sus interacciones con proteínas como la poli (ADP-ribosa) glucohidrolasa (PARG).

Objetivo del estudio:

Para sintetizar químicamente dímeros homogéneos de ADP-ribosa y fragmentos PAR relacionados.
Determinar la primera estructura cocristalina del sustrato PARG humano y la enzima.
Desarrollar nuevas sondas PAR para ensayos bioquímicos.

Principales métodos:

Síntesis química del dimero de ADP-ribosa y el dimero alquinilado.
Cocristalización del PARG humano con el dimer ADP-ribosa.
Síntesis de biotina y sondas PAR etiquetadas con fluoróforo.
Ensayos de unión basados en la polarización por fluorescencia.
Evaluación de los fragmentos de PAR sintetizados como sustratos PARG.

Principales resultados:

Síntesis química exitosa del dímero de ADP-ribosa, permitiendo el aislamiento de un sustrato homogéneo.
Determinación de la primera estructura cocristalina del sustrato de la enzima PARG en humanos.
Desarrollo de sondas PAR etiquetadas para ensayos de unión.
Identificación de las características mínimas para el reconocimiento y la escisión del sustrato PARG.

Conclusiones:

La síntesis química ofrece una ruta alternativa al PAR homogéneo y sus análogos.
La estructura cocristalina proporciona información sobre las interacciones PARG con el sustrato.
Las nuevas sondas PAR facilitan los estudios bioquímicos de las interacciones PAR-proteína.
Comprender el metabolismo de PAR es crucial para varios procesos celulares.

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