Multienzyme One-Pot Cascades Incorporating Methyltransferases for the Strategic Diversification of Tetrahydroisoquinoline Alkaloids.
Multienzyme One-Pot Cascades Incorporating Methyltransferases for the Strategic Diversification of Tetrahydroisoquinoline Alkaloids.
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DOI：
10.1002/anie.202104476
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发表时间：
2021-08-16
期刊：
影响因子：
--
通讯作者：
Hailes HC
中科院分区：
文献类型：
--
作者：
Subrizi F;Wang Y;Thair B;Méndez-Sánchez D;Roddan R;Cárdenas-Fernández M;Siegrist J;Richter M;Andexer JN;Ward JM;Hailes HC
四氢异喹啉（THIQ）环系统存在于多种结构多样的天然产物中，表现出广泛的生物活性。通过在体外建立级联反应来模拟这些生物碱的生物合成途径的路线代表了一种成功的策略，并且可以提供比传统合成方法更好的立体选择性。S-腺苷甲硫氨酸（SAM）依赖性甲基转移酶在THIQs的生物合成和多样化中至关重要;然而，它们的应用往往受到SAM成本高和底物范围低的体外限制。在这项研究中，我们描述了甲基转移酶在体外多酶级联反应中的应用，包括原位生成SAM。多达七种酶用于在酶制备规模上天然和非天然THIQ的区域选择性多样化。甲基转移酶的区域选择性取决于C-1处的基团和THIQs中氟的存在。一个有趣的双重活动也被发现的儿茶酚甲基转移酶，发现能够区域选择性甲基化两种不同的儿茶酚在一个单一的分子。开发了体外多酶级联反应，从而可规模化合成甲基化四氢异喹啉生物碱。反应从简单的结构单元如多巴胺或l-酪氨酸开始一锅法发生。选择的甲基转移酶的使用使区域选择性甲基化。当存在多于一个儿茶酚部分时，甲基化可针对一个或多个羟基。
The tetrahydroisoquinoline (THIQ) ring system is present in a large variety of structurally diverse natural products exhibiting a wide range of biological activities. Routes to mimic the biosynthetic pathways to such alkaloids, by building cascade reactions in vitro, represents a successful strategy and can offer better stereoselectivities than traditional synthetic methods. S‐Adenosylmethionine (SAM)‐dependent methyltransferases are crucial in the biosynthesis and diversification of THIQs; however, their application is often limited in vitro by the high cost of SAM and low substrate scope. In this study, we describe the use of methyltransferases in vitro in multi‐enzyme cascades, including for the generation of SAM in situ. Up to seven enzymes were used for the regioselective diversification of natural and non‐natural THIQs on an enzymatic preparative scale. Regioselectivites of the methyltransferases were dependent on the group at C‐1 and presence of fluorine in the THIQs. An interesting dual activity was also discovered for the catechol methyltransferases used, which were found to be able to regioselectively methylate two different catechols in a single molecule. In vitro multi‐enzyme cascade reactions were developed leading to the scalable synthesis of methylated tetra‐hydroisoquinoline alkaloids. The reactions occurred in one‐pot starting from simple building blocks such as dopamine or l‐tyrosine. The use of selected methyltransferases enabled regioselective methylations. When more than one catechol moiety was present, methylations could be directed towards one or more hydroxyl group.
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DOI：
10.1002/anie.201508287
发表时间：
2016-02-18
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Law BJ;Bennett MR;Thompson ML;Levy C;Shepherd SA;Leys D;Micklefield J
通讯作者：
Micklefield J
影响因子：
3.8
作者：
FRENZEL, T;ZENK, MH
通讯作者：
ZENK, MH
影响因子：
5.6
作者：
Gurkok, Tugba;Ozhuner, Esma;Unver, Turgay
通讯作者：
Unver, Turgay
DOI：
10.1073/pnas.1306101110
发表时间：
2013-08-06
影响因子：
11.1
作者：
Lee, Jaeheon;Hao, Yue;Mitchell, Douglas A.
通讯作者：
Mitchell, Douglas A.
影响因子：
16.6
作者：
Mordhorst, Silja;Siegrist, Jutta;Andexer, Jennifer N.
通讯作者：
Andexer, Jennifer N.