天然胺脱氢酶生物催化还原胺化制备手性短烷基胺和氨基醇

Laurine Ducrot, M. Bennett, Adam A Caparco, J. Champion, A. Bommarius, A. Zaparucha, G. Grogan, C. Vergne‐Vaxelaire
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引用次数: 1

摘要

光学活性小分子,尤其是短链手性胺,是化学工业中的关键化合物和各种药物的前体。他们的化学-生物催化生产已经在商业规模上建立起来,主要是通过脂肪酶催化的分解,导致ChiPros™ 产品等。然而,由于低对映体过量,它们的生物催化合成对于非常短链的C4至C5胺仍然具有挑战性。为了补充转氨酶最近提供的可能性,本工作描述了使用胺脱氢酶(AmDHs)的替代生物催化途径。在没有任何蛋白质工程的情况下,一些已经描述的野生型AmDH(CfusAmDH、MsmeAmDH、MicroAmDH和MATOUAmDH2)被证明对羟基化或未官能化的小2-氨基烷烃的合成是有效的。在50mM下转化率高达97.1%,并且获得了中等至高的对映选择性,特别是对于(S)-1-甲氧基丙-2-胺(98.1%)、(S)-3-氨基丁-1-醇(99.5%)、(3S)-3-氨基丁-2-醇(99.4%)和具有MsmeAmDH的小(S)-丁-2-胺(93.6%)。在150 mM底物浓度下成功地进行了半制备放大实验,用于合成(S)-丁-2-胺和(S)-1-甲氧基丙-2-胺,后者被称为“(S)-MOIPA”。建模研究提供了一些初步结果,解释了在这些酶的活性位点中具有挑战性的大小相似的取代基之间进行区分的基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Biocatalytic Reductive Amination by Native Amine Dehydrogenases to Access Short Chiral Alkyl Amines and Amino Alcohols
Small optically active molecules, and more particularly short-chain chiral amines, are key compounds in the chemical industry and precursors of various pharmaceuticals. Their chemo-biocatalytic production on a commercial scale is already established, mainly through lipase-catalyzed resolutions leading to ChiPros™ products among others. Nevertheless, their biocatalytic synthesis remains challenging for very short-chain C4 to C5 amines due to low enantiomeric excess. To complement the possibilities recently offered by transaminases, this work describes alternative biocatalytic access using amine dehydrogenases (AmDHs). Without any protein engineering, some of the already described wild-type AmDHs (CfusAmDH, MsmeAmDH, MicroAmDH, and MATOUAmDH2) were shown to be efficient for the synthesis of hydroxylated or unfunctionalized small 2-aminoalkanes. Conversions up to 97.1% were reached at 50 mM, and moderate to high enantioselectivities were obtained, especially for (S)-1-methoxypropan-2-amine (98.1%), (S)-3-aminobutan-1-ol (99.5%), (3S)-3-aminobutan-2-ol (99.4%), and the small (S)-butan-2-amine (93.6%) with MsmeAmDH. Semi-preparative scale-up experiments were successfully performed at 150 mM substrate concentrations for the synthesis of (S)-butan-2-amine and (S)-1-methoxypropan-2-amine, the latter known as “(S)-MOIPA”. Modeling studies provided some preliminary results explaining the basis for the challenging discrimination between similarly sized substituents in the active sites of these enzymes.
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