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Zheng, Wenlong; Yu, Haoran; Fang, Sai; Chen, Kaitong; Wang, Zhe; Cheng, Xiuli; Xu, Gang; Yang, Lirong; Wu, Jianping
ACS catalysis, 03/2021, Letnik: 11, Številka: 6Journal Article
l-Threonine aldolase (LTA) is an attractive tool in organic chemistry for catalyzing the formation of β-hydroxy-α-amino acids with two chiral centers. The enzyme has a strict selectivity for Cα of β-hydroxy-α-amino acids but a moderate selectivity for Cβ , limiting its wide applications in stereospecific carbon–carbon bond synthesis. Here, a combinatorial active-site saturation test/iterative saturation mutagenesis (CAST/ISM) strategy was applied to accelerate directed evolution of LTA in diastereoselectivity. A total of 27 amino acid residues lining the substrate pocket were selected and divided into two groups based on their functional region. In silico screening and site-directed saturation mutagenesis identified six (3 + 3) amino acid residues of them with a significant effect on diastereoselectivity. The ISM strategy was then performed in and between each group to obtain the best combinatorial mutation. As a result, a variant RS1 (Y8H/Y31H/I143R/N305R) was obtained with a dramatically improved preference for the synthesis of l-syn-3-4-(methylsulfonyl)phenylserine. The product with a de value of 99.5% (73.2% conv) was produced in a 20 L reactor, which is promising in the industrial synthesis of aromatic l-syn-β-hydroxy-α-amino acids with LTA. The variant also represented a significant selective improvement to other l-phenylserine derivatives. The de values of 2-NO2-, 4-NO2-, H-, and 4-CH4-substituted l-phenylserine derivatives were more than 99% syn by dynamic control. The insight of the mutant model suggests that the binding pocket of the active center was reshaped.
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