Structure and inhibition of diaminopimelic acid epimerase by slow‐binding <i>α</i>‐methyl amino acids
Bibliographic record
Abstract
Abstract Cofactor‐independent racemases and epimerases produce D‐amino acids from their L‐isomers for a variety of biological processes. These enzymes operate via an unusual mechanism that relies on an active site cysteine thiolate (p K a ~ 8.5) to deprotonate an amino acid α ‐carbon (p K a ~ 29) and are of interest not only because of their biocatalytic potential for D‐amino acid production, but also because many play key roles in biology and are antibiotic targets. However, obtaining crystal structures of these enzymes, especially in their closed, substrate‐ or inhibitor‐bound conformations, is difficult. In this work, we characterized diaminopimelic acid (DAP) epimerase from the cyanobacterium Anabaena . DAP epimerase has long been of interest as an antibiotic target as it converts L,L‐DAP to D,L‐DAP for lysine and peptidoglycan biosynthesis. We solved three crystal structures of this enzyme in its closed, inhibitor‐bound conformation, up to a resolution of 1.5 Å. Two structures show the enzyme covalently bound through its catalytic cysteine residues to previously reported aziridine‐based inhibitors. One structure unexpectedly shows the enzyme bound to a different compound, D,L‐ α ‐methylDAP, presumably produced as a synthetic byproduct. Stereoselective synthesis of L,L‐ and D,L‐ α ‐methylDAP followed by inhibition assays shows that these compounds are slow‐binding inhibitors of DAP epimerase. α ‐MethylDAP inhibitors provide a more accessible alternative to aziridine‐based inhibitors to obtain crystal structures of DAP epimerase in its closed conformation. Comparisons of bacterial, cyanobacterial, and plant DAP epimerases provided here offer new insights into functional and structural differences between these 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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| 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".