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Eficiencia sintética en los mecanismos enzimáticos que involucran carbocationes: aristoloqueno sintasa
Rudolf K Allemann1, Neil J Young, Shuhua Ma
1School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, U.K. allemannrk@cf.ac.uk
Journal of the American Chemical Society
|October 9, 2007
Resumen
Un nuevo mecanismo para la ciclización del pirofosfato de farnesilo (FPP) al (+) -aristoloqueno por aristoloqueno sintasa implica la transferencia intramolecular directa de protones, que difiere de los modelos anteriores. Esta transferencia de protones es facilitada por la enzima, reduciendo la energía de activación y explicando la especificidad del sustrato.
Área de la Ciencia:
- La bioquímica y la química orgánica.
- Estudios de Enzimología y Mecanismo.
- Química computacional es la química computacional.
Sus antecedentes:
- La sintetasa de aristoloqueno cataliza la ciclización del pirofosfato de farnesilo (FPP) al (+) -aristoloqueno, un sesquiterpenoide clave.
- Mecanismos propuestos anteriores involucraron germacreno A como un intermediario, pero la evidencia experimental contradice esto.
- Comprender el mecanismo catalítico preciso es crucial para elucidar las vías de biosíntesis de terpenos.
Objetivo del estudio:
- Para dilucidar el mecanismo detallado de la ciclización carbocationic de FPP a (+) -aristolochene catalizado por aristolochene synthase.
- Investigar una nueva vía intramolecular de transferencia de protones propuesta para esta reacción enzimática.
- Para modelar computacionalmente las interacciones sustrato-enzima e identificar los residuos clave involucrados en la catálisis.
Principales métodos:
- Cálculos de orbitales moleculares (MO) ab initio de alto nivel.
- Computaciones de la teoría funcional de densidad (DFT) para determinar vías de reacción y barreras energéticas.
- Modelado del complejo sustrato-enzima para analizar las interacciones entre el FPP y la aristoloquina sintasa.
Principales resultados:
- Se propuso un nuevo mecanismo intramolecular de transferencia de protones, que difiere de los modelos anteriores de propagación de la carbocación.
- La barrera calculada para la transferencia directa intramolecular de protones es de aproximadamente 22 kcal/mol, reducida a 16-20 kcal/mol por la enzima.
- Se identificó una vía alternativa a través de una lanzadera de protones que involucra una molécula de agua unida al pirofosfato.
- El mecanismo propuesto se alinea con las observaciones experimentales de que el germacreno A no es un sustrato.
- El modelado computacional identificó a Trp 334 y Phe 178 como críticos para el posicionamiento del sustrato, consistente con los datos de mutagénesis que muestran perfiles de producto alterados tras la mutación.
Conclusiones:
- El estudio propone un nuevo mecanismo intramolecular de transferencia de protones para la biosíntesis de aristoloqueno, respaldado por evidencia computacional.
- La aristoloquina sintasa reduce significativamente la barrera de activación para esta transferencia de protones, mejorando la eficiencia catalítica.
- Los residuos específicos de aminoácidos (Trp 334, Phe 178) juegan un papel crucial en la unión y orientación del sustrato, guiando la vía de reacción y evitando ciclizaciones aberrantes.
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