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Diseño y evolución de una enzima con un mecanismo organocatalítico no canónico
Ashleigh J Burke1, Sarah L Lovelock1, Amina Frese1
1Manchester Institute of Biotechnology, School of Chemistry, University of Manchester, Manchester, UK.
Nature
|May 28, 2019
Resumen
Los investigadores diseñaron una enzima novedosa utilizando diseño computacional y evolución de laboratorio. Esta enzima utiliza Nδ-metilhistidina, un aminoácido modificado, para catalizar eficientemente la hidrólisis de ésteres, superando las limitaciones del código genético estándar.
Área de la Ciencia:
- Biocatálisis y ingeniería enzimática
- Biología sintética
- Química computacional
Sus antecedentes:
- Las limitaciones del código genético restringen el diseño de enzimas para nuevas funciones catalíticas.
- Los nucleófilos canónicos en los sitios activos de la enzima pueden formar intermedios no reactivos, lo que dificulta la eficiencia catalítica.
- La organocatálisis de moléculas pequeñas ofrece estrategias mecanicistas para el diseño de enzimas.
Objetivo del estudio:
- Desarrollar una enzima hidrolítica utilizando un aminoácido no canónico como un nucleófilo catalítico.
- Superar las limitaciones de los nucleófilos canónicos en el diseño de enzimas empleando Nδ-metilhistidina.
- Para expandir el repertorio de reacciones catalizadas por enzimas a través de la expansión del código genético.
Principales métodos:
- Diseño computacional de enzimas combinado con evolución en el laboratorio.
- Incorporación de Nδ-metilhistidina como nucleófilo catalítico.
- Protocolos de evolución dirigida adaptados para un código genético expandido.
- Análisis cristalográfico para elucidar los mecanismos catalíticos.
Principales resultados:
- Generación de una enzima hidrolítica utilizando Nδ-metilhistidina.
- Se ha logrado un aumento de la eficiencia catalítica de la hidrólisis de ésteres de más de 9.000 veces en comparación con la Nδ-metilhistidina libre.
- Se identificaron las principales adaptaciones catalíticas a través de estudios cristalográficos durante la evolución dirigida.
- Se ha demostrado que la Nδ-metilhistidina es un sustituto genéticamente codificable de la dimetilaminopiridina.
Conclusiones:
- La Nδ-metilhistidina permite una catálisis eficiente mediante la prevención de la formación de un intermediario acil-enzimático.
- Este enfoque amplía el alcance del diseño de enzimas para transformaciones químicas valiosas.
- La Nδ-metilhistidina codificada genéticamente ofrece una plataforma versátil para la ingeniería de nuevos biocatalizadores.
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