Direct asymmetric synthesis of β-branched aromatic α-amino acids using engineered phenylalanine ammonia lyases

Chenghai Sun (), Gen Lu, Baoming Chen, Guangjun Li, Ya Wu, Yannik Brack, Dong Yi, Yu-Fei Ao, Shuke Wu, Ren Wei, Yuhui Sun, Guifa Zhai () and Uwe T. Bornscheuer ()
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Chenghai Sun: University of Greifswald
Gen Lu: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation
Baoming Chen: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation
Guangjun Li: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation
Ya Wu: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation
Yannik Brack: University of Greifswald
Dong Yi: National Key Laboratory of Lead Druggability Research
Yu-Fei Ao: University of Greifswald
Shuke Wu: Huazhong Agriculture University
Ren Wei: University of Greifswald
Yuhui Sun: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation
Guifa Zhai: Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation
Uwe T. Bornscheuer: University of Greifswald

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract β-Branched aromatic α-amino acids are valuable building blocks in natural products and pharmaceutically active compounds. However, their chemical or enzymatic synthesis is challenging due to the presence of two stereocenters. We design phenylalanine ammonia lyases (PAL) variants for the direct asymmetric synthesis of β-branched aromatic α-amino acids. Based on extensive computational analyses, we unravel the enigma behind PAL’s inability to accept β-methyl cinnamic acid (β-MeCA) as substrate and achieve the synthesis of the corresponding amino acids of β-MeCA and analogs using a double (PcPAL-L256V-I460V) and a triple mutant (PcPAL-F137V-L256V-I460V). The reactions are scaled-up using an optimized E. coli based whole-cell biotransformation system to produce ten β-branched phenylalanine analogs with high diastereoselectivity (dr > 20:1) and enantioselectivity (ee > 99.5%) in yields ranging from 41-71%. Moreover, we decipher the mechanism of PcPAL-L256V-I460V for the acceptance of β-MeCA and converting it with excellent stereoselectivity by computational simulations. Thus, this study offers an efficient method for synthesizing β-branched aromatic α-amino acids.

Date: 2024
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DOI: 10.1038/s41467-024-52613-x

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