Ancient gene clusters govern the initiation of monoterpenoid indole alkaloid biosynthesis and C3 stereochemistry inversion
Bibliographic record
Abstract
The inversion of C3 stereochemistry in monoterpenoid indole alkaloids (MIAs), derived from the central precursor strictosidine (3S), is essential for producing pharmacologically important 3 R MIAs and spirooxindoles such as reserpine. While early MIA biosynthesis preserves the 3S configuration, the mechanism underlying C3 inversion has remained unresolved. Here, we identify and biochemically characterize a conserved oxidase-reductase pair in Gentianales: heteroyohimbine/yohimbine/corynanthe C3-oxidase (HYC3O) and C3-reductase (HYC3R), which together invert the 3S stereochemistry to 3 R across diverse substrates. HYC3O and HYC3R are encoded within biosynthetic gene clusters in Rauvolfia tetraphylla and Catharanthus roseus, homologous to a geissoschizine synthase (GS) cluster also uncovered. Comparative genomics indicate that the GS cluster originated at the base of Gentianales (~135 Mya), coinciding with the evolution of the strictosidine synthase cluster, whereas the reserpine cluster arose later. These findings uncover the genomic and biochemical basis of key events driving MIA diversification beyond canonical vinblastine and ajmaline pathways. Inversion of C3 stereochemistry of monoterpenoid indole alkaloids (MIAs) has to occur at some point during their biosynthesis; however, the mechanism has remained unresolved. Here, the authors report an oxidase–reductase enzyme pair encoded within a gene cluster and demonstrate their collaborative role in inverting MIA C3 stereochemistry.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".