英国曼彻斯特大学Turner, Nicholas J.团队开发了用于共轭还原和还原胺化的多功能生物催化剂。相关研究成果发表在2022年4月6日出版的《自然》。
手性胺非对映体广泛存在于医药和农药中，但它们的制备往往依赖于低效的多步合成。这些有价值的化合物必须不对称制造，因为它们的生化特性可能因分子手性的不同而不同。
该文中，研究人员报道了一种用于胺合成的多功能生物催化剂，其使用的机理是以前未报道的。这种酶（EneIRED）在宏基因组亚胺还原酶（IRED）集合中鉴定，起源于未分类的假单胞菌物种，具有一种不同寻常的活性位点结构，促进胺激活的共轭烯烃还原，然后还原胺化。该酶可将多种α，β-不饱和羰基与胺偶联，以有效制备含有多达三个立体中心的手性胺非对映体。研究人员进行了机制和结构研究，以描述EneIRED催化的各个步骤的顺序，从而提出了整体催化循环的建议。
研究工作表明，IRED家族可以作为一个平台，促进进一步发现酶活性，并应用于合成生物学和有机合成。
附：英文原文
Title: Multifunctional biocatalyst for conjugate reduction and reductive amination
Author: Thorpe, Thomas W., Marshall, James R., Harawa, Vanessa, Ruscoe, Rebecca E., Cuetos, Anibal, Finnigan, James D., Angelastro, Antonio, Heath, Rachel S., Parmeggiani, Fabio, Charnock, Simon J., Howard, Roger M., Kumar, Rajesh, Daniels, David S. B., Grogan, Gideon, Turner, Nicholas J.
Issue&Volume: 2022-04-06
Abstract: Chiral amine diastereomers are ubiquitous in pharmaceuticals and agrochemicals1, yet their preparation often relies on low-efficiency multi-step synthesis2. These valuable compounds must be manufactured asymmetrically, as their biochemical properties can differ based on the chirality of the molecule. Herein we characterize a multifunctional biocatalyst for amine synthesis, which operates using a mechanism that is, to our knowledge, previously unreported. This enzyme (EneIRED), identified within a metagenomic imine reductase (IRED) collection3 and originating from an unclassified Pseudomonas species, possesses an unusual active site architecture that facilitates amine-activated conjugate alkene reduction followed by reductive amination. This enzyme can couple a broad selection of α,β-unsaturated carbonyls with amines for the efficient preparation of chiral amine diastereomers bearing up to three stereocentres. Mechanistic and structural studies have been carried out to delineate the order of individual steps catalysed by EneIRED, which have led to a proposal for the overall catalytic cycle. This work shows that the IRED family can serve as a platform for facilitating the discovery of further enzymatic activities for application in synthetic biology and organic synthesis.
DOI: 10.1038/s41586-022-04458-x
Source: https://www.nature.com/articles/s41586-022-04458-x