Phylogeny-Aware Chemoinformatic Analysis of Chemical Diversity in Lamiaceae Enables Iridoid Pathway Assembly and Discovery of Aucubin Synthase.
Phylogeny-Aware Chemoinformatic Analysis of Chemical Diversity in Lamiaceae Enables Iridoid Pathway Assembly and Discovery of Aucubin Synthase.
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DOI：
10.1093/molbev/msac057
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发表时间：
2022-04-10
影响因子：
10.7
通讯作者：
O'Connor, Sarah E.
中科院分区：
文献类型：
--
作者：
Rodriguez-Lopez, Carlos E.;Jiang, Yindi;Kamileen, Mohamed O.;Lichman, Benjamin R.;Hong, Benke;Vaillancourt, Brieanne;Buell, C. Robin;O'Connor, Sarah E.
关键词：
无数的报告描述了天然产品的分离和结构特征，但这些信息仍然脱节和利用不足。使用化学信息学的方法，我们利用报道的观察环烯醚萜葡萄糖苷与已知的一个大的环烯醚萜生产植物家族（唇形科），以产生一组生物合成途径，最好地解释现存的环烯醚萜化学多样性。我们开发了一种途径重建算法，通过反应连接环烯醚萜报告，并通过考虑属间的系统发育关系修剪此解决方案空间。我们制定了一个模型，模拟环烯醚萜苷的演变，以创建一个合成的数据集，用于选择的参数，将最好的重建途径，并将它们应用到环烯醚萜数据集，以生成途径假设。这些计算生成的途径，然后被用作选择和筛选生物合成酶候选人的基础。我们的模型被成功地应用于发现细胞色素P450酶从美洲Calligonpa，催化氧化的bartsioside桃叶珊瑚苷，预测我们的模型，尽管没有分子已观察到的属。我们还证明桃叶珊瑚苷合酶的活性在直系同源的荆条agnus，castus，和外群毛泡桐，进一步加强假设，使我们的模型，该反应是存在于祖先的生物合成途径。这是25年来关于表环烯醚萜苷生物合成的第一个系统性假设，并为环烯醚萜途径的简化工作奠定了基础。这项工作突出了如何策展和计算分析广泛可用的结构数据可以促进基于假设的基因发现。
Countless reports describe the isolation and structural characterization of natural products, yet this information remains disconnected and underutilized. Using a cheminformatics approach, we leverage the reported observations of iridoid glucosides with the known phylogeny of a large iridoid producing plant family (Lamiaceae) to generate a set of biosynthetic pathways that best explain the extant iridoid chemical diversity. We developed a pathway reconstruction algorithm that connects iridoid reports via reactions and prunes this solution space by considering phylogenetic relationships between genera. We formulate a model that emulates the evolution of iridoid glucosides to create a synthetic data set, used to select the parameters that would best reconstruct the pathways, and apply them to the iridoid data set to generate pathway hypotheses. These computationally generated pathways were then used as the basis by which to select and screen biosynthetic enzyme candidates. Our model was successfully applied to discover a cytochrome P450 enzyme from Callicarpa americana that catalyzes the oxidation of bartsioside to aucubin, predicted by our model despite neither molecule having been observed in the genus. We also demonstrate aucubin synthase activity in orthologues of Vitex agnus-castus, and the outgroup Paulownia tomentosa, further strengthening the hypothesis, enabled by our model, that the reaction was present in the ancestral biosynthetic pathway. This is the first systematic hypothesis on the epi-iridoid glucosides biosynthesis in 25 years and sets the stage for streamlined work on the iridoid pathway. This work highlights how curation and computational analysis of widely available structural data can facilitate hypothesis-based gene discovery.
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DOI：
10.1002/anie.201705010
发表时间：
2017-08-01
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Dang TT;Franke J;Tatsis E;O'Connor SE
通讯作者：
O'Connor SE
影响因子：
3.8
作者：
DAMTOFT, S;JENSEN, SR;KNUDSEN, TB
通讯作者：
KNUDSEN, TB
影响因子：
14.9
作者：
Apweiler, R;Bairoch, A;Yeh, LSL
通讯作者：
Yeh, LSL
影响因子：
3.8
作者：
DAMTOFT, S
通讯作者：
DAMTOFT, S
影响因子：
14.9
作者：
Finn RD;Coggill P;Eberhardt RY;Eddy SR;Mistry J;Mitchell AL;Potter SC;Punta M;Qureshi M;Sangrador-Vegas A;Salazar GA;Tate J;Bateman A
通讯作者：
Bateman A