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Direct asymmetric synthesis of β-branched aromatic α-amino acids using engineered phenylalanine ammonia lyases
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Direct asymmetric synthesis of β-branched aromatic α-amino acids using engineered phenylalanine ammonia lyases
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Journal Article
Direct asymmetric synthesis of β-branched aromatic α-amino acids using engineered phenylalanine ammonia lyases
2024
Overview
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.
β-Branched aromatic α-amino acids are valuable building blocks in natural products and pharmaceutically active compounds, but their synthesis is challenging due to the presence of two stereocenters. Here, the authors design phenylalanine ammonia lyases variants for the direct asymmetric synthesis of β-branched aromatic α-amino acids and reveal the reasons for enzyme’s inability to accept β-methyl cinnamic acid.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 82/80
/ 82/83
/ Amino Acids, Aromatic - biosynthesis
/ Amino Acids, Aromatic - metabolism
/ Ammonia
/ Analogs
/ E coli
/ Escherichia coli - metabolism
/ Humanities and Social Sciences
/ Phenylalanine Ammonia-Lyase - chemistry
/ Phenylalanine Ammonia-Lyase - genetics
/ Phenylalanine Ammonia-Lyase - metabolism
/ Science
