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Intermedio no covalente de la timidilato sintasa: ¿verdad o ficción?

Svetlana A Kholodar¹, Amnon Kohen¹

¹Department of Chemistry, The University of Iowa , Iowa City, Iowa 52242-1727, United States.

Journal of the American Chemical Society

|June 22, 2016

Resumen

Los investigadores sintetizaron un nuevo intermediario en la actividad de la timidilato sintasa, revelando un nuevo objetivo farmacológico para las terapias anticancerígenas y antibióticas. Este descubrimiento desafía el mecanismo tradicional y abre caminos para inhibidores innovadores de la biosíntesis del ADN.

Área de la Ciencia:

La bioquímica
Enzimología
Descubrimiento de drogas

Sus antecedentes:

La timidilata sintasa es crucial para la síntesis de ADN y un objetivo clave para los medicamentos antimicrobianos y anticancerígenos.
El mecanismo de la enzima implica un enlace covalente con una cisteína del sitio activo, con productos intermedios típicamente escindidos en la liberación del producto.

Objetivo del estudio:

Investigar un bisubstrato intermedio propuesto no unido covalentemente de la timidilato sintasa.
Explorar un nuevo y no tradicional mecanismo de actividad de la timidilato sintasa.
Para identificar nuevos fármacos dirigidos a la biosíntesis del ADN.

Principales métodos:

Síntesis del bisubstrato intermedio no unido covalentemente propuesto.
Caracterización química y cinética del intermediario sintetizado.
Estudios computacionales y experimentales para apoyar el mecanismo propuesto.

Principales resultados:

Síntesis exitosa del intermediario bisubstrato no covalentemente unido previsto.
Demostración de la capacidad química y cinética del intermediario.
Pruebas que apoyan un enlace covalente lábil y un mecanismo enzimático no tradicional.

Conclusiones:

Los hallazgos validan un mecanismo no tradicional previsto para la timidilato sintasa.
El intermediario sintetizado representa un nuevo fármaco prometedor para inhibir la biosíntesis del ADN.
Esta investigación abre nuevas posibilidades para desarrollar nuevos agentes anticancerígenos y antibióticos.

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