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La química de coordinación de cobalto y azufre impulsa la carga en la metionina sintasa
Romila Mascarenhas1, Arkajit Guha1, Zhu Li1
1Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
Journal of the American Chemical Society
|November 2, 2023
Resumen
La proteína de tráfico de cobalamina humana MMADHC utiliza enlaces lábiles de cobalto y azufre para transferir la vitamina B12 a la metionina sintasa. Este mecanismo explica la homocistinuria en pacientes con variantes de MMADHC.
Área de la Ciencia:
- La bioquímica
- Biología molecular
- La biofísica
Sus antecedentes:
- La cobalamina (vitamina B12) es un cofactor organometálico esencial en los mamíferos.
- La cobalamina es transportada por las chaperonas a su enzima diana, la metionina sintasa.
- La química de coordinación cobalto-azufre (Co-S) es típicamente labile y rara en los sistemas biológicos.
Objetivo del estudio:
- Investigar el mecanismo por el cual la proteína de tráfico de cobalamina humana MMADHC descarga la cobalamina en la metionina sintasa.
- Esclarecer el papel de la labilidad de coordinación Co-S en la transferencia de cobalamina.
Principales métodos:
- Ensayos bioquímicos para estudiar las interacciones proteína-proteína y la transferencia de cofactores.
- Análisis estructural de los complejos de la MMADHC-cobalamina y la MMADHC-metionina sintasa (implicado).
- Análisis de las variantes clínicas de MMADHC para evaluar la relevancia fisiológica.
Principales resultados:
- MMADHC utiliza Cys-261 como el ligando axial inferior de la cobalamina.
- La formación compleja con metionina sintasa desencadena la pérdida del ligando de nitrógeno, formando tiolato-cobalamina de cinco coordenadas.
- Cys-262 facilita el desplazamiento nucleófilo, completando la transferencia del cofactor y liberando el MMADHC oxidado.
Conclusiones:
- MMADHC explota la labilidad química de los enlaces Co-S para una transferencia eficiente de cobalamina.
- El mecanismo identificado proporciona una explicación molecular para la homocistinuria asociada con las variantes de MMADHC.
- Este estudio revela un papel biológico novedoso para la coordinación labil de Co-S en el tráfico de cofactores.
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