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Las enzimas bacterianas similares al cGAS sintetizan diversas señales de nucleótidos
Aaron T Whiteley1,2, James B Eaglesham1,2, Carina C de Oliveira Mann1,2
1Department of Microbiology, Harvard Medical School, Boston, MA, USA.
Nature
|February 22, 2019
Resumen
Los investigadores descubrieron una nueva familia de enzimas bacterianas, las nucleotidiltransferasas similares a los nucleótidos cíclicos (CD-NTasas), que producen diversos di- y trinucleótidos cíclicos. Estas moléculas impactan las interacciones huésped-patógeno y la dinámica de la comunidad microbiana.
Área de la Ciencia:
- Microbiología
- La bioquímica
- Biología estructural
Sus antecedentes:
- Los dinucleótidos cíclicos (CDN) son mensajeros secundarios bacterianos cruciales involucrados en la homeostasis y la virulencia.
- Las CDN bacterianas pueden desencadenar respuestas inmunes del huésped a través de receptores de reconocimiento de patrones durante la infección.
Objetivo del estudio:
- Para examinar sistemáticamente los nucleótidos de señalización bacteriana.
- Identificar nuevas enzimas involucradas en la síntesis de CDN.
- Caracterizar la estructura y la función de las nucleotidiltransferasas recién descubiertas.
Principales métodos:
- Evaluación bioquímica sistemática de los nucleótidos de señalización bacteriana.
- Expresión y purificación de las proteínas.
- Cristalografía de rayos X para determinar las estructuras de las enzimas.
- Ensayos bioquímicos para analizar la actividad enzimática y la formación de productos.
- Ensayos celulares para evaluar la activación del receptor del huésped.
Principales resultados:
- Descubrimiento de una gran familia de nucleotidiltransferasas similares al cGAS/DncV (CD-NTasas).
- Las CD-NTasas sintetizan una amplia gama de dinucleótidos cíclicos (CDN) utilizando tanto nucleótidos de purina como pirimidina.
- El análisis estructural reveló sitios activos conservados de la enzima responsables de la selección de nucleótidos.
- Identificación de los productos de trinucleótidos cíclicos además de las CDN.
- Demostración de que estas moléculas cíclicas activan receptores huéspedes distintos.
Conclusiones:
- Las CD-NTasas representan una familia conservada de enzimas con una amplia especificidad de sustrato.
- Los diversos productos de nucleótidos cíclicos sintetizados por las CD-NTasas pueden modular las interacciones huésped-patógeno y huésped-microbiota.
- Estos hallazgos amplían nuestra comprensión de las moléculas de señalización bacteriana y su impacto en la inmunidad y la ecología del huésped.
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