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Engineering a C–N Lyase for Selective Hydroaminations With Sterically Demanding Amines
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DOI：10.1002/cctc.70891.png)
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Abstract
En 中文
The significance of L-aspartic acid derivatives lies in their multifaceted functionalities and their extensive utility as ‘green’ surfactants, tools for neurobiological research, and synthons for pharmaceuticals and food additives. This makes these noncanonical amino acids important molecules in scientific research and industrial applications. C─N lyases are attractive biocatalysts for the production of L-aspartic acid derivatives via asymmetric hydroamination of α,β-unsaturated carboxylic acids. However, the substrate scope of these enzymes is largely limited to small amines, as bulky aliphatic amines are generally poorly accepted. Here, we report the structure-based engineering of ethylenediamine-N,N’-disuccinic acid (EDDS) lyase enabling efficient and selective hydroaminations with large aliphatic amines as non-native substrates. This engineered C─N lyase shows up to a 600-fold increase in activity toward sterically demanding amines and even efficiently converts large non-native amines that are entirely unreactive with the wild-type enzyme. Molecular docking revealed that the mutations widened and enhanced the hydrophobicity of the amine-binding pocket, strengthening interactions with bulky aliphatic amines. The results underscore that structure-inspired protein engineering can be an efficient approach to enlarge the substrate scope of a C─N lyase, enabling the efficient enzymatic synthesis of various enantiopure L-aspartic acid derivatives (>99% ee), including compounds with potential applications as biodegradable surfactants.
Keywords:
biocatalysis
bulky amine
C-N lyases
directed evolution
protein engineering
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