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Engineered Biosynthesis of β‐Alkyl Tryptophan Analogues
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2018-10-12 , DOI: 10.1002/anie.201807998
Christina E. Boville 1 , Remkes A. Scheele 1 , Philipp Koch 1 , Sabine Brinkmann-Chen 1 , Andrew R. Buller 2 , Frances H. Arnold 1
Affiliation  

Noncanonical amino acids (ncAAs) with dual stereocenters at the α and β positions are valuable precursors to natural products and therapeutics. Despite the potential applications of such bioactive β‐branched ncAAs, their availability is limited due to the inefficiency of the multistep methods used to prepare them. Herein we report a stereoselective biocatalytic synthesis of β‐branched tryptophan analogues using an engineered variant of Pyrococcus furiosus tryptophan synthase (PfTrpB), PfTrpB7E6. PfTrpB7E6 is the first biocatalyst to synthesize bulky β‐branched tryptophan analogues in a single step, with demonstrated access to 27 ncAAs. The molecular basis for the efficient catalysis and broad substrate tolerance of PfTrpB7E6 was explored through X‐ray crystallography and UV/Vis spectroscopy, which revealed that a combination of active‐site and remote mutations increase the abundance and persistence of a key reactive intermediate. PfTrpB7E6 provides an operationally simple and environmentally benign platform for the preparation of β‐branched tryptophan building blocks.

中文翻译:

β-烷基色氨酸类似物的工程生物合成

在α和β位置具有双立体中心的非规范氨基酸(ncAAs)是天然产物和治疗剂的宝贵前体。尽管此类具有生物活性的β分支ncAA具有潜在的应用前景,但由于用于制备它们的多步方法效率低下,因此其可用性受到限制。在本文中,我们报告了使用激烈热球菌色氨酸合酶(Pf TrpB),Pf TrpB 7E6的工程变体对β支链色氨酸类似物进行立体选择性生物催化合成。Pf TrpB 7E6是第一个通过一步即可合成庞大的β支化色氨酸类似物的生物催化剂,已证明可使用27种ncAA。通过X射线晶体学和UV / Vis光谱学探索了Pf TrpB 7E6有效催化和广泛的底物耐受性的分子基础,这表明活性位点和远程突变的组合增加了关键反应中间体的丰度和持久性。Pf TrpB 7E6为制备β支链色氨酸构建基块提供了一个操作简单且对环境无害的平台。
更新日期:2018-10-12
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