Stereochemical insights into sarpagan and akuammiline alkaloid biosynthesis
Bibliographic record
Abstract
Sarpagan and akuammiline monoterpenoid indole alkaloids (MIAs) are a class of bioactive plant-derived compounds with significant pharmaceutical potential. These alkaloids are formed through oxidative cyclization of geissoschizine, catalyzed by homologous cytochrome P450 monooxygenases (CYP) known as sarpagan bridge enzymes (SBEs) and rhazimal synthases (RHSs). However, a long-standing discrepancy exists between the expected C16 stereochemistry of enzymatic products and the stereochemistry of naturally occurring derivatives. This study investigates C16 stereochemistry outcomes after geissoschizine cyclization and subsequent enzymatic transformations in six MIA-producing species. We combine comparative gene discovery, in planta gene silencing of Catharanthus roseus SBE, in vitro enzyme characterization, and intermediate nuclear magnetic resonance analysis. We identify and characterize five new CYPs and a new akuammidine aldehyde reductase alongside two known enzymes from Alstonia scholaris, Amsonia tabernaemontana, Catharanthus roseus, Rauvolfia serpentina, Tabernaemontana elegans, and Vinca minor. RHS enzymes consistently produce the 16R rhazimal stereoisomer. SBEs likely yield 16R polyneuridine aldehyde and, to a lesser extent, its 16S epimer akuammidine aldehyde. Downstream aldehyde reductases, deformylases, and decarbomethoxylases further epimerize C16, generating species-specific stereochemical diversity. This work demonstrates the enzymatic tailoring steps that govern C16 stereochemistry in sarpagan MIA biosynthesis, offering new insight into stereochemical diversification and pathway evolution in plant specialized metabolism.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".