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Bases estructurales de la especificidad de los donantes de acilo terminados en carboxilo en una aciltransferasa

Fei Xiao¹, Sheng Dong, Yang Liu¹

¹Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003 Qingdao, China.

Journal of the American Chemical Society

|August 18, 2020

Resumen

Los investigadores identificaron la enzima BmmI, un homólogo de la beta-lactamasa, responsable de la malonilación y sucinilación de las macrolactinas (MLN). Este descubrimiento avanza en la comprensión de los mecanismos de resistencia a los medicamentos y ayuda en el desarrollo de nuevos agentes antimicrobianos.

Área de la Ciencia:

La bioquímica
Enzimología
Descubrimiento de drogas

Sus antecedentes:

Las macrolactinas (MLN) son agentes vitales contra la degeneración macular y los tumores.
Los MLN malonilados/succinilados muestran eficacia contra las bacterias multirresistentes.
La enzima que cataliza la modificación de MLN no fue identificada.

Objetivo del estudio:

Identificar la enzima responsable de la malonilación y sucinilación de las macrolactinas.
Para aclarar el mecanismo y la especificidad del sustrato de esta enzima.
Para guiar la ingeniería racional de enzimas para el desarrollo de fármacos.

Principales métodos:

Identificación y caracterización de las enzimas.
Determinación de la estructura cristalina del BmmI.
Mutagénesis dirigida al sitio y ingeniería enzimática.

Principales resultados:

Se identificó un homólogo de la beta-lactamasa, BmmI, como la aciltransferasa.
BmmI une tioesters de ácido alquilo C3-C5 a MLN A, con variantes diseñadas que aceptan cadenas más largas.
Los datos estructurales y de mutagénesis revelaron residuos clave (Arg292, Lys76) y una geometría en forma de agujero de oxyanión para el reconocimiento y la catálisis del sustrato.

Conclusiones:

BmmI es la enzima clave para modificar las macrolactinas, mejorando sus propiedades antimicrobianas.
La comprensión del mecanismo de BmmI proporciona información sobre la selectividad de la aciltransferasa.
Este trabajo facilita la ingeniería enzimática para el desarrollo de nuevos agentes terapéuticos.

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