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Rational redesign of the loop dynamics of carbonyl reductase LfSDR1 to improve the stereoselectivity for asymmetric synthesis of bulky chiral alcohols.
Yue, Xiaoping; Li, Yitong; Wei, Mankun; Duan, Yu; Yang, Lin; Chen, Fen-Er.
Afiliación
  • Yue X; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs, Fudan University, Shanghai 200433, China; School of Chemical Engineering, Jiangxi Normal University, Nanchang 330022, Ch
  • Li Y; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs, Fudan University, Shanghai 200433, China.
  • Wei M; School of life science, Jiangxi Normal University, Nanchang 330022, China.
  • Duan Y; School of life science, Jiangxi Normal University, Nanchang 330022, China.
  • Yang L; School of Chemical Engineering, Jiangxi Normal University, Nanchang 330022, China. Electronic address: linyang2023@jxnu.edu.cn.
  • Chen FE; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan University, Shanghai 200433, China; Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs, Fudan University, Shanghai 200433, China; School of Chemical Engineering, Jiangxi Normal University, Nanchang 330022, Ch
Int J Biol Macromol ; 274(Pt 2): 133345, 2024 Aug.
Article en En | MEDLINE | ID: mdl-38944066
ABSTRACT
Engineering biocatalysts with enhanced stereoselectivity is highly desirable, and active-site loop dynamics play an important role in its regulation. However, knowledge of their precise roles in catalysis and evolution is limited. Here, we used the strategy of Rosetta enzyme design combined molecular dynamic simulations (MDs) to reprogram the landscapes of the key active-site loop dynamics of the carbonyl reductase LfSDR1 to improve stereoselectivity. The key flexible loop in the active site showed the potential to regulate the catalytic properties. A library of virtual variants was produced using the Rosetta design and assessed dynamic effect of the loop with the aid of MDs. A potential candidate was obtained with significant stereoselectivity (ee > 99 %) compared to the wild-type (ee = 42 %) without loss of catalytic activity or thermostability. The molecular basis of the catalytic property enhancement was flanked by MDs, which revealed the role of the G92L mutation in regulating loop dynamics to stabilize the environment of the active site. Finally, a series of the challenge bulky substrate derivatives were assessed using the G92L variant, and all showed improved stereoselectivity ee > 99 %. This study provides novel insights for improving stereoselectivity through rational engineering of the loop dynamics of biocatalysts.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Dominio Catalítico / Oxidorreductasas de Alcohol / Alcoholes / Simulación de Dinámica Molecular Idioma: En Revista: Int J Biol Macromol Año: 2024 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Dominio Catalítico / Oxidorreductasas de Alcohol / Alcoholes / Simulación de Dinámica Molecular Idioma: En Revista: Int J Biol Macromol Año: 2024 Tipo del documento: Article