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Un citocromo P450 sirve como una inesperada terpena ciclasa durante la biosíntesis de los meroterpenoides fúngicos

Yit-Heng Chooi¹, Young J Hong, Ralph A Cacho

¹Department of Chemical and Biomolecular Engineering and ‡Department of Chemistry and Biochemistry, University of California , Los Angeles, California 90095, United States.

Journal of the American Chemical Society

|October 29, 2013

Resumen

La viridicatumtoxina, un meroterpenoide fúngico, se sintetiza sin una típica ciclasa de terpenos. Una enzima del citocromo P450, VrtK, cataliza de manera única su compleja formación de anillos espirobicíclicos.

Área de la Ciencia:

La bioquímica es la bioquímica.
Química de Productos Naturales Química de Productos Naturales
Enzimología Enzimología.

Sus antecedentes:

Viridicatumtoxin (1) es un meroterpenoide fúngico caracterizado por un sistema de anillos espirobicíclicos únicos.
La biosíntesis de tales estructuras complejas a menudo implica ciclases de terpenos dedicados, que estaban notablemente ausentes en el clúster de genes identificados de Penicillium aethiopicum.

Objetivo del estudio:

Para aclarar el mecanismo de la biosíntesis de la viridicatumtoxina, en particular la formación de su núcleo espirobicíclico único.
Identificar y caracterizar la enzima responsable de la etapa de ciclización en ausencia de una terpena ciclasa canónica.

Principales métodos:

Investigó las funciones de las enzimas del citocromo P450 VrtE y VrtK del grupo de genes vrt.
Realizó experimentos de alimentación utilizando toxina previridicatum acíclica en Saccharomyces cerevisiae diseñada para expresar VrtK.
Utilizó el modelado químico cuántico para explorar intermediarios y vías de reacción.

Principales resultados:

El citocromo P450 VrtE cataliza la C5-hidroxilación, mientras que VrtK es responsable de la formación del anillo espirobíclico.
Se confirmó que VrtK es la única enzima requerida para ciclizar la fracción geranilo de la toxina previridicatum.
El modelado químico cuántico propuso un nuevo intermedio carbocativo terciario (E) y un mecanismo de reacción que involucra desplazamientos de alquilo y alquilación de Friedel-Crafts.

Conclusiones:

VrtK representa la primera enzima del citocromo P450 identificada capaz de catalizar la ciclización de terpenos.
El mecanismo propuesto implica una oxidación mediada por P450 que inicia la formación de carbocationes, seguida de reordenamientos y ciclización.
Los estudios computacionales proporcionaron información sobre el curso estereocímico de esta reacción de ciclización de terpenos sin precedentes.

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