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<p>The synthesis of non-canonical amino acids (ncAAs) has recently made tremendous progress in the field of biocatalysis, with enzymes such as transaminases, dehydrogenases, and ammonia lyases being used. Frameworks of β-branched aromatic D-amino acids are crucial for the efficacy of pharmaceuticals, influencing spatial conformation, binding modes with receptors and pharmacokinetic properties. However, there is a scarcity of studies on the efficient synthesis of β-branched D-amino acids, which has significantly hindered the advancement of structure-activity relationship (SAR) studies. Here, we present the asymmetric synthesis of β-branched aromatic D-amino acid analogues catalyzed by PLP-dependent transaminase <i>Bs</i>DAAT (from <i>Bacillus sp</i>. strain YM-1), an efficient transamination system that relies on the dynamic kinetic resolution (DKR) process. Through docking analysis and concise enzyme engineering, we successfully obtain various aromatic D-amino acids with β-substitution in high yields (up to 99%), <i>dr</i> ratios (&gt;20:1) and <i>ee</i> values (up to 99%). These β-branched aromatic D-amino acids are then successfully introduced into the modifications of the antineoplastic reagent Lanreotide.</p>

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Concise construction of β-branched aromatic D-amino acids via transaminase-catalyzed dynamic kinetic resolution

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Zhenling Liu,
  • Wei Zhai,
  • Zhihua Zeng,
  • Xinxin Meng,
  • Yilin Shi,
  • Jing Huang,
  • Ping Su,
  • Xiaohui Yan,
  • Li-Cheng Yang

摘要

The synthesis of non-canonical amino acids (ncAAs) has recently made tremendous progress in the field of biocatalysis, with enzymes such as transaminases, dehydrogenases, and ammonia lyases being used. Frameworks of β-branched aromatic D-amino acids are crucial for the efficacy of pharmaceuticals, influencing spatial conformation, binding modes with receptors and pharmacokinetic properties. However, there is a scarcity of studies on the efficient synthesis of β-branched D-amino acids, which has significantly hindered the advancement of structure-activity relationship (SAR) studies. Here, we present the asymmetric synthesis of β-branched aromatic D-amino acid analogues catalyzed by PLP-dependent transaminase BsDAAT (from Bacillus sp. strain YM-1), an efficient transamination system that relies on the dynamic kinetic resolution (DKR) process. Through docking analysis and concise enzyme engineering, we successfully obtain various aromatic D-amino acids with β-substitution in high yields (up to 99%), dr ratios (>20:1) and ee values (up to 99%). These β-branched aromatic D-amino acids are then successfully introduced into the modifications of the antineoplastic reagent Lanreotide.