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Deconstrucción del sustrato y la no aditividad del reconocimiento enzimático

Sarah Barelier¹, Jennifer A Cummings, Alissa M Rauwerdink

¹Department of Pharmaceutical Chemistry, University of California - San Francisco , 1700 Fourth Street, Byers Hall, San Francisco, California 94158, United States.

Journal of the American Chemical Society

|May 6, 2014

Resumen

El descubrimiento de sustratos enzimáticos es un desafío. Se exploró el sondeo de enzimas con fragmentos moleculares más pequeños, en lugar de sustratos completos, pero se encontró ineficaz para identificar la función enzimática. Se recomiendan bibliotecas de metabolitos completos para la investigación de enzimas.

Área de la Ciencia:

La bioquímica es la bioquímica.
Enzimología Enzimología.
Biología Estructural Biología estructural.

Sus antecedentes:

La identificación de sustratos enzimáticos es crucial para comprender las vías y funciones biológicas.
Los métodos actuales para el descubrimiento de sustratos están limitados por la complejidad de las estructuras químicas que se pueden probar.
Se planteó la hipótesis de que los enfoques basados en fragmentos, exitosos en el descubrimiento de inhibidores, acelerarían la identificación del sustrato.

Objetivo del estudio:

Investigar la viabilidad de utilizar pequeños fragmentos moleculares para descubrir sustratos de enzimas.
Determinar si la exploración basada en fragmentos puede ayudar a asignar funciones a enzimas con funciones desconocidas.
Comprender las bases estructurales del reconocimiento enzima-sustrato a nivel granular.

Principales métodos:

Deconstrucción de sustratos conocidos de enzimas en 41 fragmentos superpuestos.
Prueba de la actividad del fragmento y la afinidad de unión en seis enzimas de tres superfamilias.
Cristalografía de rayos X para determinar la estructura de complejos de fragmentos de enzimas para un sustrato de β-lactamasa.

Principales resultados:

Los fragmentos, incluso los que contienen grupos reactivos, mostraron una actividad o unión mínima.
Las enzimas requieren la mayoría de las características del sustrato para el reconocimiento; la eliminación de un solo átomo reduce drásticamente la unión (hasta 6 órdenes de registro).
El análisis estructural reveló interacciones complejas necesarias para el reconocimiento del sustrato.

Conclusiones:

El descubrimiento de sustratos enzimáticos no es fácilmente susceptible a un enfoque basado en fragmentos.
Se necesitan porciones significativas de sustratos para el reconocimiento enzimático, lo que limita la utilidad de los pequeños fragmentos.
El desarrollo de bibliotecas de metabolitos completos es una estrategia más pragmática para el descubrimiento de la función enzimática.

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