Bulky substrates of isoleucine 2-epimerase: α-Neopentylglycine and NV-5138
Bibliographic record
Abstract
Isoleucine 2-epimerase from Lactobacillus buchneri ( Lb IleE) catalyzes the pyridoxal 5′-phosphate-dependent, reversible, racemization or epimerization of nonpolar amino acids at the C-2 position. The integral role of the enzyme in the biosynthesis of branched-chain d -amino acids makes it a potential target for the development of antimicrobial agents. Probing the hydrophobic active-site pocket with a series of alkyl boronic acids, we show that the hydrophobic pocket accommodates the neopentyl group with enhanced binding affinity relative to the sec-butyl group. Subsequently, we show that Lb IleE catalyzes the racemization of l - and d -α-neopentylglycine, exhibiting binding affinities for these substrates 6- and 24-fold greater than those for l -Ile and d - allo -Ile, but with catalytic efficiencies ( k cat / K m ) reduced 46- and 27-fold, respectively. NV-5138 is a ligand of the leucine-binding site of Sestrin2, which activates the mechanistic target of rapamycin complex1 (mTORC1) and is structurally similar to α-neopentylglycine. Our demonstration that Lb IleE catalyzes the racemization of l -NV-5138 ( k cat / K m = 2.2 ± 0.2 s −1 M −1 ), along with the fact that L. buchneri can be present in the human gut microbiome, suggests that formation of d -NV-5138 could occur in humans when l -NV-5138 is used as a pharmacological intervention for depression. • Alkyl boronic acids are weak inhibitors of isoleucine 2-epimerase (IleE). • IleE's active-site hydrophobic pocket accommodates the neopentyl group. • IleE catalyzes the racemization of l - and d -α-neopenylglycine. • NV-5138, an mTORC1 activator, is a substrate for IleE.
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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 | 0.001 |
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".