Recycling Upstream Redox Enzymes Expands the Regioselectivity of Cycloaddition in Pseudo-Aspidosperma Alkaloid Biosynthesis.
Recycling Upstream Redox Enzymes Expands the Regioselectivity of Cycloaddition in Pseudo-Aspidosperma Alkaloid Biosynthesis.
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DOI：
10.1021/jacs.2c08107
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发表时间：
2022-11-02
影响因子：
15
通讯作者：
O'Connor, Sarah E.
中科院分区：
文献类型：
--
作者：
Kamileen, Mohamed O.;DeMars II, Matthew D.;Hong, Benke;Nakamura, Yoko;Paetz, Christian;Lichman, Benjamin R.;Sonawane, Prashant D.;Caputi, Lorenzo;O'Connor, Sarah E.
自然界利用环加成反应生成复杂的天然产物支架。脱氢赛可定是一种高活性的生物合成中间体，它通过环加成反应生成几种生物碱支架，这些支架是长春花碱和伊博金等重要药理化合物的前体。在这里，我们报告了脱氢塞卡定如何经历氧化还原化学，这反过来又允许环加成反应具有替代的区域选择性。通过将脱氢Secodine与作用于该途径上游的还原酶和氧化酶生物合成酶孵育，我们可以在体外和通过从上游中间体在植物中重组的方式获得稀有的假顶壳生物碱伪-tabersonine和伪-vincadifformine。我们提出了一种逐步的机制，通过对酶中间体的结构表征和对氚标记的掺入进行监测，来解释假的tabersonine支架的形成。这一发现突显了植物如何利用氧化还原酶从普通前体中对映体选择性地生成新的支架。
Nature uses cycloaddition reactions to generate complex natural product scaffolds. Dehydrosecodine is a highly reactive biosynthetic intermediate that undergoes cycloaddition to generate several alkaloid scaffolds that are the precursors to pharmacologically important compounds such as vinblastine and ibogaine. Here we report how dehydrosecodine can be subjected to redox chemistry, which in turn allows cycloaddition reactions with alternative regioselectivity. By incubating dehydrosecodine with reductase and oxidase biosynthetic enzymes that act upstream in the pathway, we can access the rare pseudoaspidosperma alkaloids pseudo-tabersonine and pseudo-vincadifformine, both in vitro and by reconstitution in the plant Nicotiana benthamiana from an upstream intermediate. We propose a stepwise mechanism to explain the formation of the pseudo-tabersonine scaffold by structurally characterizing enzyme intermediates and by monitoring the incorporation of deuterium labels. This discovery highlights how plants use redox enzymes to enantioselectively generate new scaffolds from common precursors.
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影响因子：
56.9
作者：
Caputi, Lorenzo;Franke, Jakob;O'Connor, Sarah E.
通讯作者：
O'Connor, Sarah E.
影响因子：
1.8
作者：
Cocquet, G;Rool, P;Ferroud, C
通讯作者：
Ferroud, C
DOI：
10.1074/jbc.ra118.004060
发表时间：
2018-09-07
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Farrow SC;Kamileen MO;Meades J;Ameyaw B;Xiao Y;O'Connor SE
通讯作者：
O'Connor SE
影响因子：
15
作者：
Farrow, Scott C.;Kamileen, Mohamed O.;O'Connor, Sarah E.
通讯作者：
O'Connor, Sarah E.
影响因子：
18
作者：
Pluskal, Tomas;Torrens-Spence, Michael P.;Weng, Jing-Ke
通讯作者：
Weng, Jing-Ke