By the same authors

From the same journal

Phylogeny-Aware Chemoinformatic Analysis of Chemical Diversity in Lamiaceae Enables Iridoid Pathway Assembly and Discovery of Aucubin Synthase

Research output: Contribution to journalArticlepeer-review


  • Carlos E. Rodríguez-López
  • Yindi Jiang
  • Mohamed O. Kamileen
  • Benjamin R. Lichman
  • Benke Hong
  • Brieanne Vaillancourt
  • C. Robin Buell
  • Sarah E. O'Connor


Publication details

JournalMolecular Biology and Evolution
DateAccepted/In press - 2 Mar 2022
DateE-pub ahead of print - 17 Mar 2022
DatePublished (current) - 1 Apr 2022
Issue number4
Number of pages18
Early online date17/03/22
Original languageEnglish


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.

Bibliographical note

Publisher Copyright:
© 2022 The Author(s) 2022. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.

    Research areas

  • chemical diversity, cheminformatics, comparative biochemistry, cytochrome P450, iridoids, pathway reconstruction

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