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Measuring In Vitro ATPase Activity for Enzymatic Characterization
Published on: August 23, 2016
Estado de oxidación de la cisteína del sitio activo en la proteína tirosina fosfatasa 1B
Rob L M van Montfort1, Miles Congreve, Dominic Tisi
1Astex Technology Ltd, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK.
Nature
|June 13, 2003
Resumen
El estrés oxidativo puede dañar irreversiblemente la proteína tirosina fosfatasa 1B (PTP1B). Los investigadores descubrieron un intermediario protector de sulfenil-amida que previene el daño de PTP1B y puede ayudar a su reactivación.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Biología Estructural Biología estructural.
Sus antecedentes:
- Las fosfatasas de proteína tirosina (PTP) regulan las vías críticas de señalización celular.
- La desregulación de las PTP está relacionada con enfermedades como el cáncer, la diabetes y la hipertensión.
- El estado redox celular influye en la actividad de PTP a través de la oxidación de la cisteína, pero se desconocen los mecanismos de protección contra el daño irreversible.
Objetivo del estudio:
- Para dilucidar los mecanismos estructurales que impiden la oxidación irreversible de la cisteína catalítica de PTP1B.
- Para identificar los intermediarios protectores en la inhibición oxidativa de PTP1B.
- Comprender el papel de estos intermediarios en la regulación y reactivación de PTP1B.
Principales métodos:
- Se utilizó cristalografía de rayos X para determinar las estructuras de PTP1B. oxidado.
- Identificación y caracterización de nuevas especies de cisteína oxidada en PTP1B.
- Pruebas bioquímicas para evaluar la reversibilidad de la oxidación por glutatión.
Principales resultados:
- Las estructuras cristalinas revelaron formas de ácido sulfénico, sulfínico y sulfónico de PTP1B.
- Se identificó una nueva especie de sulfenil-amida, formada por la oxidación catalítica de la cisteína.
- La formación de la sulfenil-amida induce cambios significativos en el sitio activo de PTP1B.
- Este intermediario de sulfeno-amida es reversible por el agente reductor celular glutatión.
Conclusiones:
- La sulfenil-amida es un intermediario protector contra el daño oxidativo irreversible en el PTP1B.
- Este intermediario puede desempeñar un papel en la reactivación de PTP1B por los tiolos biológicos.
- La sulfenil-amida representa un estado regulador único de PTP1B bajo condiciones oxidativas.
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