Unlocking the function promiscuity of old yellow enzyme to catalyze asymmetric Morita-Baylis-Hillman reaction

Lei Wang, Yaoyun Wu, Jun Hu, Dejing Yin, Wanqing Wei, Jian Wen, Xiulai Chen, Cong Gao, Yiwen Zhou, Jia Liu, Guipeng Hu, Xiaomin Li, Jing Wu, Zhi Zhou, Liming Liu and Wei Song ()
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Lei Wang: Jiangnan University
Yaoyun Wu: Jiangnan University
Jun Hu: Jiangnan University
Dejing Yin: Jiangnan University
Wanqing Wei: Jiangnan University
Jian Wen: Jiangnan University
Xiulai Chen: Jiangnan University
Cong Gao: Jiangnan University
Yiwen Zhou: Jiangnan University
Jia Liu: Jiangnan University
Guipeng Hu: Jiangnan University
Xiaomin Li: Jiangnan University
Jing Wu: Jiangnan University
Zhi Zhou: Jiangnan University
Liming Liu: Jiangnan University
Wei Song: Jiangnan University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Exploring the promiscuity of native enzymes presents a promising strategy for expanding their synthetic applications, particularly for catalyzing challenging reactions in non-native contexts. In this study, we explore the promiscuous potential of old yellow enzymes (OYEs) to facilitate the Morita-Baylis-Hillman reaction (MBH reaction), leveraging substrate similarities between MBH reaction and reduction reaction. Using mass spectrometry and spectroscopic techniques, we confirm promiscuity of GkOYE in both MBH and reduction reactions. By blocking H- and H+ transfer pathways, we engineer GkOYE.8, which loses its reduction ability but enhances its MBH activity. The structural basis of MBH reaction catalyzed by GkOYE.8 is obtained through mutation studies and kinetic simulations. Furthermore, enantiocomplementary mutants GkOYE.11 and GkOYE.13 are obtained by directed evolution, exhibiting the ability to accept various aromatic aldehydes and alkenes as substrates. This study demonstrates the potential of leveraging substrate similarities to unlock enzyme functionalities, enabling the catalysis of new-to-nature reactions.

Date: 2024
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DOI: 10.1038/s41467-024-50141-2

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