Towards the structure of an unusual nonribosomal peptide synthetase
Bibliographic record
Abstract
Cereulide synthetase (Ces) is a macromolecular machine that produces a toxin involved in severe and lethal food poisoning. Ces belongs to the nonribosomal peptide synthetase (NRPS) family protein, and as such, it employs an assembly line mechanism to generate its cereulide product. The assembly line for cereulide differs from the canonical NRPS pathway because it adds hydroxy acids instead of amino acids at half of the positions in the molecule. To achieve this, the megaenzyme selects alpha keto acids through specialized adenylation domains and then reduces them to hydroxy acids in embedded ketoreductase domains, before adding them to the growing depsipeptide. Several details on the structural features of this unusual NRPS remain unknown. Here we report a full biochemical characterization of this highly complex megaenzyme. We obtained the kinetic constants of each of its four adenylation domains and probed the side chain selectivity for its alpha keto acid – recognizing adenylation domains. Also, we report that the activating protein MbtH is not required for full activity of the assembly line. Finally, we show that each of the modules can be inhibited through mechanism-based inhibitors, which can restrain the conformational flexibility paving the way for structural studies by X-ray crystallography.
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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 | 0.000 |
| 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".