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Efectos evolutivos en el sustrato ligado pKa en la dihidrofolato reductasa
Anil R Mhashal1, Yaron Pshetitsky1, Christopher M Cheatum2
1Department of Chemistry , Bar-Ilan University , Ramat-Gan 5290002 , Israel.
Journal of the American Chemical Society
|November 7, 2018
Resumen
Las enzimas llamadas dihidrofolato reductasa (DHFR) evolucionaron para unirse a los sustratos de manera más efectiva. Este estudio muestra que el aumento de la basicidad enzimática se correlaciona con la reducción del agua en el sitio activo, lo que sugiere una adaptación evolutiva.
Área de la Ciencia:
- La bioquímica
- Enzimología
- Evolución molecular
Sus antecedentes:
- La dihidrofolato reductasa (DHFR) es crucial en el metabolismo del folato.
- Comprender la evolución de la isoforma DHFR proporciona información sobre la adaptación de las enzimas.
- La modulación del substrato pKa es clave para la eficiencia catalítica de la enzima.
Objetivo del estudio:
- Investigar el impacto de la estructura del sitio activo de DHFR en la pKa del sustrato.
- Para explorar las tendencias evolutivas en las isoformas de DHFR.
- Para correlacionar la hidratación del sitio activo con la basicidad del sustrato.
Principales métodos:
- Utilizó un método de perturbación de energía libre híbrido de Mecánica Cuántica / Mecánica Molecular (QM / MM).
- Se ha calculado el pKa de la posición N5 del 7,8-dihidrofolato.
- Se analizaron las diferencias estructurales y la dinámica de las moléculas de agua en varias isoformas de DHFR.
Principales resultados:
- Se observó un aumento progresivo de la basicidad N5 de las isoformas de DHFR primitivas a las evolucionadas.
- Se encontró una correlación entre la disminución de la hidratación del sitio activo y el aumento de la N5 pKa.
- Identificó el papel del bucle M20 en la modulación de la hidrofobia y la flexibilidad del sitio activo.
Conclusiones:
- El nivel de hidratación del sitio activo influye directamente en el pKa del 7,8-dihidrofolato unido.
- La progresión evolutiva en DHFR implica la exclusión de agua del sitio activo, mejorando la unión al sustrato.
- El bucle M20 es un elemento estructural clave en la regulación de la hidratación del sitio activo y la evolución de las enzimas.
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