Enzymatic epimerization of monoterpene indole alkaloids in Kratom.

Allwin McDonald, Yoko Nakamura, Carsten Schotte, Kin Lau, Ryan Alam, Adriana A Lopes, C Robin Buell, Sarah O'Connor
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Abstract

Monoterpene indole alkaloids (MIAs) are a large, structurally diverse class of bioactive natural products. These compounds are biosynthetically derived from a stereoselective Pictet-Spengler condensation that generates a tetrahydro-β-carboline scaffold characterized by a 3 S stereocenter. However, a subset of MIAs contain a non-canonical 3 R stereocenter. Herein, we report the basis for 3 R -MIA biosynthesis in Mitragyna speciosa (Kratom). We discover the presence of the iminium species, 20 S -3-dehydrocorynantheidine, which led us to hypothesize that isomerization of 3 S to 3 R occurs by oxidation and stereoselective reduction downstream of the initial Pictet-Spengler condensation. Isotopologue feeding experiments implicated young leaves and stems as the sites for pathway biosynthesis, facilitating the identification of an oxidase/reductase pair that catalyzes this epimerization. This enzyme pair has broad substrate specificity, suggesting that the oxidase and reductase may be responsible for the formation of many 3 R -MIAs and downstream spirooxindole alkaloids in Kratom. These enzymes allow biocatalytic access to a range of previously inaccessible pharmacologically active compounds.

单萜吲哚类生物碱的酶外聚体化。
单萜吲哚生物碱(MIAs)是一类结构多样的大型生物活性天然产物。这些化合物是由立体选择性Pictet-Spengler缩合反应生物合成的,该缩合反应生成以3s立体中心为特征的四氢β-碳碱支架。然而,mia的一个子集包含一个非规范的3r立体中心。本文报道了Mitragyna speciosa (Kratom)中3r -MIA生物合成的基础。我们发现了20 S -3-脱氢corynantheidine的存在,这使我们假设3s到3r的异构化是通过氧化和初始picet - spengler缩合下游的立体选择还原发生的。同位素摄食实验表明,幼嫩的叶片和茎是途径生物合成的位点,促进了催化这种外映体化的氧化酶/还原酶对的鉴定。该酶对具有广泛的底物特异性,这表明氧化酶和还原酶可能是Kratom中许多3r - mia和下游螺烷吲哚生物碱形成的原因。这些酶允许生物催化获得一系列以前无法获得的药理学活性化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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