Intramolecular Cyclization and a Retro-Ene Reaction Enable the Rapid Fragmentation of a Vitamin B1-derived Breslow Intermediate
Bibliographic record
Abstract
In solution, analogues of the Breslow intermediate formed during catalysis by benzoylformate decarboxylase (BFDC) undergo rapid, irreversible fragmentation. The ability of BFDC to prevent this reaction and preserve its’ cofactor is a striking example of an enzyme ‘steering’ a reactive intermediate towards a productive pathway. To understand how BFDC suppresses the off-pathway reactivity of this Breslow intermediate, a clear mechanistic understanding of the fragmentation reaction is required. Here, DFT calculations reveal an unexpected mechanism for the solution-phase fragmentation that involves an intramolecular cyclization and a subsequent retro-ene reaction to release the final products. Free energy profiles demonstrate that this pathway is significantly more facile than the previously proposed mechanism that invoked Breslow intermediate enolates as intermediates. Additional computations have been performed to understand why related Breslow intermediates do not undergo analogous fragmentation reactions. Calculations performed with two closely related Breslow intermediates suggest that subtle differences in the relative values of ∆G‡ for protonation and fragmentation dictate whether a given intermediate will fragment or not. These differences and the fragmentation mechanism unveiled in this work have ramifications for the catalytic mechanism of BFDC and other thiamin-dependent enzymes and will provide general lessons related to the control of reactive intermediates by enzymes.
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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) | 0.000 | 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 | 0.001 |
| 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".