Stuffed Epimerase Domains of Pyochelin Biosynthesis are Defunct Methyltransferases
Bibliographic record
Abstract
Bacteria and fungi use nonribosomal peptide synthetases (NRPSs) to generate secondary metabolites called nonribosomal peptides (NRPs). A common feature of NRPs is the incorporation of D -stereocenter amino acids, which enhance chemical functionality and confer resistance to proteolytic degradation. Typically, these stereochemical inversions arise from dedicated epimerase domains, which are well-characterized. However, 2-hydroxyphenylthiazoline-containing natural products lack these conventional tailoring domains and are instead proposed to utilize noncanonical epimerase domains embedded, or “stuffed”, within the mobile loop of NRPS adenylation domains. The stereochemistry of the final natural product does not align with the absence or presence of the stuffed epimerase domain, so we examined the adenylation-epimerase didomains of 2-hydroxyphenylthiazoline siderophores from Pseudomonas aeruginosa (pyochelin, R stereochemistry at 4’) and Streptomyces venezuelae (watasemycin, S at 4’). For comparison, we also examined the biosynthesis of enantiopyochelin ( S at 4’) by the homologous enzyme from Pseudomonas protegens, which lacks the stuffed epimerase domain. Substrate and product analogs were synthesized to probe the epimerase chemistry. While the variants performed adenylation chemistry, epimerase activity was not enzymatically catalyzed. Indeed, racemization was spontaneous for the 2-hydroxyphenylthiazoline ethyl ester analogues and for intermediates isolated from the enzymes. These data suggest that noncanonical stuffed epimerase domains of 2-hydroxyphenylthiazoline natural products are catalytically defunct methyltransferases and possibly an evolutionary remnant.
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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 | 0.000 |
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 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".