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Mecanismo estructural de la regioselectividad en una deshidrogenasa acil-CoA bacteriana inusual
Jacquelyn M Blake-Hedges1,2,3, Jose Henrique Pereira2,4, Pablo Cruz-Morales2,3
1Department of Chemistry , University of California , Berkeley , California 94720 , United States.
Journal of the American Chemical Society
|December 4, 2019
Resumen
Este estudio revela cómo una enzima única, TcsD (gamma, delta-acil-CoA deshidrogenasa), forma alquenos terminales en la biosíntesis de productos naturales. Comprender su mecanismo regioselectivo ayuda a la ingeniería y el descubrimiento de enzimas.
Área de la Ciencia:
- La bioquímica
- Enzimología
- Biosíntesis de productos naturales
Sus antecedentes:
- Los alquenos terminales son valiosos para la ingeniería de la poliquetida sintasa (PKS), pero son poco comunes en los sistemas PKS naturales.
- Las deshidrogenasas de acil-CoA (ACAD) pueden formar alquenos terminales, pero su aparición natural y sus mecanismos no se comprenden completamente.
Objetivo del estudio:
- Para dilucidar el mecanismo de formación de alqueno terminal catalizado por el gamma, delta-ACAD, TcsD, involucrado en la biosíntesis de FK506.
- Comprender la base estructural de la regioselectividad y la especificidad de sustrato únicas de TcsD.
Principales métodos:
- Análisis bioquímico
- Análisis estructural
- Modelado de sustratos
- Identificación del homólogo de la enzima
Principales resultados:
- TcsD exhibe actividad regioselectiva en la posición gamma, delta en sustratos alfa y beta insaturados, a diferencia de los alfa y beta ACAD canónicos.
- Los residuos del sitio activo de la enzima y el posicionamiento del cofactor FAD dictan la regioselectividad única de TcsD.
- Se identificaron nuevos mecanismos de activación y posicionamiento del sustrato que involucran donantes de enlaces de hidrógeno.
- Se identificaron residuos clave, lo que permitió el descubrimiento de otros presuntos gamma, delta-ACAD en diversos grupos de genes.
Conclusiones:
- El estudio proporciona una comprensión mecanicista y estructural detallada de la actividad gamma delta-ACAD única de TcsD.
- Este trabajo facilita el descubrimiento de enzimas, la ingeniería y la caracterización de productos naturales mediante la identificación de determinantes clave de la función enzimática.
- Los hallazgos apoyan un enfoque poderoso para investigar reacciones enzimáticas únicas y predecir la función de la enzima.
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