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Descubrimiento de nuevas enzimas y vías metabólicas mediante el uso de la estructura y el contexto del genoma
Suwen Zhao1, Ritesh Kumar, Ayano Sakai
11] Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA [2].
Nature
|September 24, 2013
Resumen
Este estudio utiliza el acoplamiento computacional de metabolitos y el contexto de la vía para predecir con precisión la función enzimática e identificar nuevas vías metabólicas en las bacterias. Este enfoque guiado por la estructura supera los desafíos en la asignación de la función de la proteína y ayuda en el descubrimiento de nuevos procesos biológicos.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Estructural Biología estructural.
- La genómica es la genómica.
Sus antecedentes:
- La asignación de funciones de proteínas a partir de proyectos de genoma es difícil debido a la sobrepredicción y los errores de anotación.
- Se están desarrollando estrategias computacionales, incluido el acoplamiento de metabolitos, para el descubrimiento funcional utilizando estructuras de proteínas.
- Las vías metabólicas bacterianas a menudo residen en grupos de genes, proporcionando el contexto para la asignación funcional.
Objetivo del estudio:
- Demostrar la utilidad de los enfoques guiados por la estructura para predecir las especificidades del sustrato de la enzima y las vías metabólicas.
- Identificar correctamente la función y la vía de un enzima no caracterizado previamente (PDB 2PMQ).
- Para confirmar el papel de osmólito de la betaína trans-4-hidroxi-L-prolina (tHyp-B).
Principales métodos:
- Acoplamiento de metabolitos a estructuras de proteínas (3D) para predecir las especificidades del sustrato.
- Analizando los grupos de genes bacterianos y el contexto de las vías.
- Ensayos enzimáticos in vitro, análisis genéticos, metabolómica y transcriptómica.
Principales resultados:
- Predijo con precisión la 2-epimerización de tHyp-B y cHyp-B por la enzima con PDB 2PMQ.
- Identificó correctamente la vía catabólica que involucra a la Hyp-B 2-epimerasa.
- Se confirmaron las actividades enzimáticas, se identificaron los intermediarios de la vía y se estableció el papel de osmolito de tHyp-B a través de múltiples métodos experimentales.
Conclusiones:
- Las predicciones funcionales guiadas por la estructura, combinadas con el contexto de la vía, son efectivas para descubrir nuevas vías metabólicas.
- El acoplamiento de metabolitos mejora la fiabilidad de la predicción de las especificidades del sustrato de la enzima.
- Este enfoque valida la función de proteínas no caracterizadas y aclara nuevas vías biológicas.
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