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La catálisis de la crotonasa permite la producción flexible de prolinas y carbapenams funcionalizados
Refaat B Hamed1, Luc Henry, J Ruben Gomez-Castellanos
1Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.
Journal of the American Chemical Society
|November 19, 2011
Resumen
Las enzimas diseñadas crean derivados de prolina funcionalizados y beta-lactamas bicíclicos. Este biocatálisis avanza en la síntesis estereoselectiva y produce moléculas complejas con centros cuaternarios.
Área de la Ciencia:
- Biocatálisis y ingeniería de enzimas.
- La síntesis orgánica es la síntesis orgánica.
- Química medicinal es la química de los medicamentos.
Sus antecedentes:
- Las sintasas de carboximetilprolina (CMPS) son enzimas que participan en la biosíntesis de productos naturales.
- Los CMPS de ingeniería pueden expandir su alcance de sustrato y sus capacidades catalíticas.
- Los beta-lactamas bicíclicos son importantes motivos estructurales en los productos farmacéuticos.
Objetivo del estudio:
- Demostrar la versatilidad biocatalítica de los CMPSs de tipo silvestre y de ingeniería.
- Para preparar derivados funcionalizados de la 5-carboximetilprolina.
- Para convertir estos derivados en nuevos beta-lactamas bicíclicos.
Principales métodos:
- Utilizó sintasas de carboximetilprolina (CMPS) de tipo silvestre y de ingeniería.
- Utilizó aldehídos de aminoácidos y la malonil-coenzima A como sustratos.
- Convirtió los derivados de prolina resultantes en beta-lactamas bicíclicos utilizando la carbapenam sintetasa.
Principales resultados:
- Preparados derivados funcionalizados de 5-carboximetilprolina metilados en varias posiciones de anillo.
- Logró la síntesis estereoselectiva de compuestos con centros cuaternarios en C-2 o C-5 utilizando CMPSs de ingeniería.
- Con éxito sintetizó nuevos beta-lactamas bicíclicos a partir de los derivados de la prolina.
Conclusiones:
- Las enzimas de la superfamilia de las crotonasas son valiosas para el biocatálisis estereoselectivo.
- Las vías de biosíntesis de carbapenem pueden ser diseñadas para la nueva producción de beta-lactam bicíclico.
- Los biocatalizadores diseñados muestran potencial para crear moléculas complejas con centros cuaternarios.
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