Effect of proximal ligand substitutions on the carbene and nitrene transferase activity of myoglobin
Effect of proximal ligand substitutions on the carbene and nitrene transferase activity of myoglobin
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DOI：
10.1016/j.tet.2019.03.009
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发表时间：
2019-04-19
期刊：
影响因子：
2.1
通讯作者：
Fasan, Rudi
中科院分区：
文献类型：
--
作者：
Moore, Eric J.;Fasan, Rudi
工程肌红蛋白最近被证明是非生物碳和亚硝基转移反应的有效催化剂。在这里，我们研究了用蛋白原性（Cys、Ser、Tyr、Asp）和非蛋白原性Lewis碱性氨基酸（3-（3′-吡啶基）-丙氨酸、对氨基苯丙氨酸和β -（3-噻吩基）-丙氨酸）取代保守的血红素配位组氨酸残基对金属蛋白在这些非生物转化中的反应性的影响。这些研究表明，近端组氨酸残基与天然和非天然氨基酸的突变导致稳定的肌红蛋白变体，可以作为碳烯和亚硝基转移酶。此外，用天冬氨酸残基取代近端组氨酸得到基于肌红蛋白的催化剂，能够在非还原条件下促进立体选择性烯烃环丙烷化。总的来说，这些研究表明，近端配体取代为调整基于肌红蛋白的碳和亚硝基转移催化剂的反应性提供了一种有前途的策略，并首次提供了基于吡啶、噻吩和苯胺的非天然氨基酸用于金属蛋白工程的可行性的原理证明。(C) 2019 Elsevier Ltd.版权所有。
Engineered myoglobins were recently shown to be effective catalysts for abiological carbene and nitrene transfer reactions. Here, we investigated the impact of substituting the conserved heme-coordinating histidine residue with both proteinogenic (Cys, Ser, Tyr, Asp) and non-proteinogenic Lewis basic amino acids (3-(3'-pyridyl)-alanine, p-aminophenylalanine, and beta-(3-thienyl)-alanine), on the reactivity of this metalloprotein toward these abiotic transformations. These studies showed that mutation of the proximal histidine residue with both natural and non-natural amino acids result in stable myoglobin variants that can function as both carbene and nitrene transferases. In addition, substitution of the proximal histidine with an aspartate residue led to a myoglobin-based catalyst capable of promoting stereoselective olefin cyclopropanation under nonreducing conditions. Overall, these studies demonstrate that proximal ligand substitution provides a promising strategy to tune the reactivity of myoglobin-based carbene and nitrene transfer catalysts and provide a first, proof-of-principle demonstration of the viability of pyridine-, thiophene-, and aniline-based unnatural amino acids for metalloprotein engineering. (C) 2019 Elsevier Ltd. All rights reserved.