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Estabilidad inesperada de las beta-N-acetilneuraminidas de arilo en solución neutra: implicaciones biológicas para
Veedeeta Dookhun1, Andrew J Bennet
1Department of Chemistry, Simon Fraser University, Burnaby, B.C., Canada.
Journal of the American Chemical Society
|May 19, 2005
Resumen
La hidrólisis no enzimática de las aril beta-D-N-acetilneuraminidas se produce a través de cuatro vías. La mayor reactividad de un compuesto se atribuye a la tensión estérica, no a la asistencia anómica.
Área de la Ciencia:
- Química de los carbohidratos Química de los carbohidratos
- Mecanismos de reacción orgánica.
- Química biofísica y bioquímica.
Sus antecedentes:
- La hidrólisis no enzimática de los enlaces glucósidos es crucial en los sistemas biológicos.
- La comprensión de estos mecanismos informa el diseño de fármacos y la estabilidad del biomaterial.
- Los N-acetilneuraminuros de arilo sirven como sustratos modelo para el estudio de la actividad de la sialidasa.
Objetivo del estudio:
- Para dilucidar los mecanismos de la hidrólisis no enzimática para las aril beta-D-N-acetilneuraminidas.
- Investigar los factores que influyen en las velocidades y vías de hidrólisis.
- Determinar el papel de los efectos anoméricos y la tensión estérica en la reactividad.
Principales métodos:
- Síntesis de un panel de siete beta-D-N-acetilneuraminidas de arilo.
- Estudios cinéticos a través de un rango de pH y temperaturas.
- Análisis de los productos de reacción y las estructuras de estado de transición utilizando parámetros cinéticos (beta(lg), valores de m, parámetros de activación).
Principales resultados:
- La hidrólisis procede a través de cuatro vías distintas: catalizada por ácido, espontánea (formas neutrales y aniónicas) y promovida por bases.
- Se observó una mejora significativa de la velocidad (>100 veces) para la alfa-D-N-acetilneuraminida (5) en comparación con la beta-D-N-acetilneuraminida (4a).
- Los parámetros cinéticos (beta, lg, valores de m, parámetros de activación) son inconsistentes con la asistencia del carboxilato anómero.
Conclusiones:
- La cepa estérica del estado fundamental en las aril alfa-D-N-acetilneuraminidas es el principal impulsor de su mayor reactividad.
- Los mecanismos de hidrólisis no enzimáticos son complejos, ya que implican múltiples vías de competencia.
- Estos hallazgos proporcionan información sobre la estabilidad química y la reactividad de los derivados del ácido siálico.
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