The biosynthesis of N-acylated tryptazolone in Mycobacterium tuberculosis and related bacteria
Bibliographic record
Abstract
The ability of Mycobacterium tuberculosis (Mtb) to thrive within its host is due in part to its complex lipid metabolism, aspects of which remain poorly understood. We recently reported the production of N -acylated tyrazolones, a class of oxazolones, by the tyzACB gene cluster in Mtb. We now report that Mtb also produces N -acylated tryptazolones using a second biosynthetic cluster, trzAS . TrzA catalyzed the N -acylation of L-tryptophan with highest specificity for C 5:0 -CoA among acyl-CoAs ( k cat /K m 2.3 ± 0.3 × 10 3 M −1 s −1 ). Similarly, TrzS, comprising a ThiF-like cyclase fused to a flavin-dependent oxidase, catalyzed the ATP-dependent cyclization and O 2 -dependent desaturation of the acylated amino acid to yield an N -acylated tryptazolone. Consistent with AlphaFold structural predictions, the D217A and R540A variants of TrzS were deficient in cyclase and desaturase activities, respectively. These variants and substrate-limitation studies established that the order of cyclization and desaturation is obligate, in contrast to the corresponding reactions in tyrazolone biosynthesis. Strains of Rhodococcus jostii RHA1 expressing trzAS from Mtb, Mycobacterium smegmatis , and RHA1, respectively, produced acyl-tryptophan and tryptazolones with different acyl chain lengths, indicating that the homologs have distinct substrate preferences. Using an optimized extraction method, tryptazolones were detected in M. smegmatis and RHA1. Finally, the acyl-tryptophan intermediates mainly accumulated in the culture supernatant, while tryptazolones were more abundant inside the cells. Elucidating the tryptazolone biosynthesis pathway in Mtb highlights the diversity of oxazolones in mycolic acid-producing bacteria, broadens our understanding of mycobacterial lipid metabolism, and opens exciting avenues for exploring the physiological roles of these small molecules.
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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) | 0.000 | 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 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".