<br>硫酯酶作为化学酶法合成大环内酯的工具,Chemical Communications

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硫酯酶作为化学酶法合成大环内酯的工具
Chemical Communications ( IF 4.3 ) Pub Date : 2024-03-01 , DOI: 10.1039/d4cc00401a
André R Paquette ₁ , Jordan T Brazeau-Henrie ₁ , Christopher N Boddy ₁

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大环化合物是一种关键的官能团，可以赋予分子独特的性质。它们的合成导致了许多杰出化学方法的发展，但仍然具有挑战性。硫酯酶 (TE) 结构域经常负责天然产物生物合成中的大环化，并为大环化合物的酶促合成提供独特的优势。在这篇专题文章中，我们描述了我们的工作，以表征 TE 的底物选择性并使用这些酶作为生物催化剂。我们的努力表明，线性硫酯活化底物负载在底物选择性有限的TE上，生成酰基酶中间体。我们表明，酰基-酶中间体的环化可以具有高度选择性，并且酰基-酶中间体的竞争性水解。控制 TE 介导的大环化与水解的机制是 TE 生物化学中尚未解决的重大问题。通过将TE用于大环缩酚肽天然产物的化学酶全合成，证明了TE作为生物催化剂的潜力。本文重点介绍了 TE 作为生物催化剂的优势和潜力及其局限性，开辟了令人兴奋的研究机会，包括通过 TE 工程来优化这些强大的生物催化剂。

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Thioesterases as tools for chemoenzymatic synthesis of macrolactones

Macrocycles are a key functional group that can impart unique properties into molecules. Their synthesis has led to the development of many outstanding chemical methodologies and yet still remains challenging. Thioesterase (TE) domains are frequently responsible for macrocyclization in natural product biosynthesis and provide unique strengths for the enzymatic synthesis of macrocycles. In this feature article, we describe our work to characterize the substrate selectivity of TEs and to use these enzymes as biocatalysts. Our efforts have shown that the linear thioester activated substrates are loaded on TEs with limited substrate selectivity to generate acyl–enzyme intermediates. We show that cyclization of the acyl–enzyme intermediates can be highly selective, with competing hydrolysis of the acyl–enzyme intermediates. The mechanisms controlling TE-mediated macrocyclization versus hydrolysis are a significant unsolved problem in TE biochemistry. The potential of TEs as biocatalysts was demonstrated by using them in the chemoenzymatic total synthesis of macrocyclic depsipeptide natural products. This article highlights the strengths and potential of TEs as biocatalysts as well as their limitations, opening exciting research opportunities including TE engineering to optimize these powerful biocatalysts.

更新日期：2024-03-01

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