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<p>Although artificial enzymes have significantly expanded the scope of enzyme-catalysed transformations, their construction typically relies on the irreversible incorporation of non-natural active sites. Inspired by natural cofactors, here we show a reversible binding strategy for artificial enzyme design using benzophenone adenine dinucleotide (BpAD), a photoactive NAD⁺ analogue that can integrate seamlessly into a broad range of NAD⁺-dependent protein scaffolds. The resulting artificial photoenzymes catalyse both inter- and intramolecular [2 + 2] cycloaddition reactions with excellent enantioselectivity, broad substrate compatibility and notable enantiodivergence. Computational studies confirm the precise binding mode of BpAD and reveal a key <i>exo</i>-attack pathway in the stepwise C–C bond formation mechanism. Notably, BpAD-catalysed reactions are highly orthogonal to those mediated by NAD⁺, allowing simultaneous use without interference. This work introduces a versatile and generalizable approach to artificial enzyme development, leveraging the inherent diversity of NAD⁺-dependent proteins for tailored catalytic applications.</p><p></p>

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An NAD⁺ analogue enables assembly of structurally diverse artificial photoenzymes for enantiodivergent [2 + 2] cycloadditions

  • 期刊论文

  • 发表日期：

    2025年8月12日

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  • Ping Du,
  • Jinsi Li,
  • Tai-Ping Zhou,
  • Jun Wang,
  • Wenhao Hu,
  • Haoyu Li,
  • Binju Wang,
  • Hui-Jie Pan

摘要

Although artificial enzymes have significantly expanded the scope of enzyme-catalysed transformations, their construction typically relies on the irreversible incorporation of non-natural active sites. Inspired by natural cofactors, here we show a reversible binding strategy for artificial enzyme design using benzophenone adenine dinucleotide (BpAD), a photoactive NAD⁺ analogue that can integrate seamlessly into a broad range of NAD⁺-dependent protein scaffolds. The resulting artificial photoenzymes catalyse both inter- and intramolecular [2 + 2] cycloaddition reactions with excellent enantioselectivity, broad substrate compatibility and notable enantiodivergence. Computational studies confirm the precise binding mode of BpAD and reveal a key exo-attack pathway in the stepwise C–C bond formation mechanism. Notably, BpAD-catalysed reactions are highly orthogonal to those mediated by NAD⁺, allowing simultaneous use without interference. This work introduces a versatile and generalizable approach to artificial enzyme development, leveraging the inherent diversity of NAD⁺-dependent proteins for tailored catalytic applications.