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Diseño retrosintético de enzimas de cobre dinuclear para la cicloadición de azido-alquina a través de aminoácidos no

Yunjong Lee¹, Jaewon Moon¹, Kyu Jin Son¹

¹Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea.

Journal of the American Chemical Society

|October 21, 2025

Resumen

Los investigadores diseñaron una proteína para catalizar las reacciones de cicloadición azida-alquina catalizadas por cobre (CuAAC), logrando tasas superiores a las de los ligandos de referencia. Este avance utiliza precursores codificados genéticamente para los ligandos multidentados en la ingeniería de las metalloenzimas.

Área de la Ciencia:

La bioquímica
Química bioorgánica
Ingeniería de proteínas

Sus antecedentes:

La cicloadición azida-alquina catalizada por cobre (CuAAC) es vital para aplicaciones sintéticas y biológicas, confiando en ligandos de unión al cobre optimizados.
No existen ligandos basados en proteínas diseñados específicamente para catalizar la reacción CuAAC.

Objetivo del estudio:

Desarrollar un nuevo ligando basado en proteínas de abajo hacia arriba para la catálisis de CuAAC.
Diseñar un homodímero natural en una metalloenzima funcional que imite las estructuras conocidas del ligando CuAAC.

Principales métodos:

Diseño de proteínas retrosintéticas que incorporan aminoácidos quelantes de metales a través de aminoácidos no canónicos clicables.
Modificación post-traduccional mediada por CuAAC para el desarrollo de ligandos.
Ingeniería de la dTDP-4-ceto-6-deoxy-D-hexulosa 3,5-epimerasa para crear motivos multidentados que contienen triazol.

Principales resultados:

La proteína construida R79TP demostró una actividad significativa de CuAAC con sustratos exógenos.
Se obtuvieron velocidades catalíticas superiores a las de un ligando de referencia, lo que sugiere un mecanismo de cobre dinuclear.
Se creó con éxito un andamio de proteínas con cuatro átomos donantes de nitrógeno para dos sitios de unión de cobre.

Conclusiones:

Los precursores codificados genéticamente ofrecen una poderosa estrategia para crear ligandos multidentados dentro de las proteínas.
Este trabajo amplía el alcance de la ingeniería de las metalloenzimas y la catálisis bioortogonal.
La proteína diseñada proporciona información mecánica sobre las reacciones mediadas por cobre y el potencial para futuras aplicaciones.

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