Génomique Métabolique, Genoscope, Institut François Jacob, CEA, CNRS, Univ Evry, Université Paris-Saclay, 91057, Evry, France.
School of Pharmacy, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, 2006, Australia.
Nat Commun. 2024 Jun 10;15(1):4933. doi: 10.1038/s41467-024-49009-2.
Native amine dehydrogenases offer sustainable access to chiral amines, so the search for scaffolds capable of converting more diverse carbonyl compounds is required to reach the full potential of this alternative to conventional synthetic reductive aminations. Here we report a multidisciplinary strategy combining bioinformatics, chemoinformatics and biocatalysis to extensively screen billions of sequences in silico and to efficiently find native amine dehydrogenases features using computational approaches. In this way, we achieve a comprehensive overview of the initial native amine dehydrogenase family, extending it from 2,011 to 17,959 sequences, and identify native amine dehydrogenases with non-reported substrate spectra, including hindered carbonyls and ethyl ketones, and accepting methylamine and cyclopropylamine as amine donor. We also present preliminary model-based structural information to inform the design of potential (R)-selective amine dehydrogenases, as native amine dehydrogenases are mostly (S)-selective. This integrated strategy paves the way for expanding the resource of other enzyme families and in highlighting enzymes with original features.
天然胺脱氢酶为手性胺提供了可持续的获取途径，因此需要寻找能够转化更多种类羰基化合物的支架，以充分发挥这种替代传统还原胺化反应的潜力。在这里，我们报告了一种结合生物信息学、化学信息学和生物催化的多学科策略，在计算机上广泛筛选数十亿个序列，并使用计算方法有效地找到天然胺脱氢酶的特征。通过这种方式，我们全面概述了最初的天然胺脱氢酶家族，将其从 2011 个序列扩展到 17959 个序列，并确定了具有非报告底物谱的天然胺脱氢酶，包括受阻羰基和乙基酮，并且可以接受甲胺和环丙胺作为胺供体。我们还提供了初步的基于模型的结构信息，为潜在（R）选择性胺脱氢酶的设计提供信息，因为天然胺脱氢酶大多是（S）选择性的。这种综合策略为扩展其他酶家族的资源和突出具有原始特征的酶铺平了道路。
