Regiospecific hydroxylase and O-methyltransferase for the biosynthesis of anticancer alkaloids in Tabernaemontana elegans (toad tree)
Bibliographic record
Abstract
Monoterpenoid indole alkaloids (MIAs) are a structurally diverse class natural products with significant medicinal properties. Bis-MIAs, such as chemotherapeutic vinblastine and anti-autophagic conodurine, are synthesized through enzymatic coupling of monomeric MIAs, often requiring specific modifications to activate reactive centers. In this study, we report the identification and characterization of a regiospecific enzyme pair, coronaridine 11-hydroxylase (TeC11H) and 11-hydroxycoronaridine O-methyltransferase (TeHCOMT), from Tabernaemontana elegans (toad tree). The C11-methoxylation of coronaridine activates C10 and C12 on the indole for subsequent coupling with a vobasinyl monomer, representing a critical transformation in the biosynthesis of a series of 11-methoxycoronaridine derived bis-iboga-vobasinyl MIAs in T. elegans root with potent anticancer and anti-autophagy activities. Biochemical analysis and homology modeling of TeC11H and TeHCOMT, along with their Tabernanthe iboga (iboga) homologs for coronaridine C10-methoxylation, reveal key residues at their highly similar active sites responsible for distinct regioselectivity, demonstrating how coronaridine is oriented to favour C11 or C10 methoxylation. Our discovery sheds light on the coordinated specification of active sites in metabolically linked enzymes during evolutionary adaptation in different lineages. TeC11H and TeHCOMT represent a valuable tool for metabolic engineering, offering new opportunities to biosynthesize anticancer alkaloids and explore the therapeutic potential of novel bis-MIAs.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".