Formation of a Stable Iminol Intermediate in the Redox Regulation Mechanism of Protein Tyrosine Phosphatase 1B (PTP1B)
Bibliographic record
Abstract
Abstract Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme in a variety of physiological processes including insulin and leptin signaling. Experimentally it has been previously suggested to form an enzyme-derived sulfenyl-amide intermediate as a means of protecting an active site cysteinyl against overoxidation. In this study, key aspects of the mechanism by which PTP1B mediates against overoxidation of its active site cysteinyl has been examined via multiscale computational enzymology (e.g., molecular dynamics simulations and high-level hybrid quantum mechanics/molecular mechanics). Several possible initial reactive complexes containing an active site sulfenic acid (oxidized cysteinyl) were considered, as well as possible reaction pathways and intermediates. Importantly, the only enzymatically feasible mechanism for formation of a putative sulfenyl-amide intermediate occurs via a stepwise pathway. The only feasible mechanism was found to occur in a stepwise fashion, in which a stable iminol intermediate is formed. This step has an activation energy of 48.6 kJ mol–1. Later, a much more stable iminol intermediate is formed in which a noncovalent electrostatic interaction of the sulfenic acid sulfur antibonding orbital with the iminol nitrogen lone pair was found to occur. Subsequently, a cyclic sulfenyl-amide is formed with a concomitant proton transfer from Glu115 to the sulfenic acid oxygen. Our results suggest that Glu115 and His214 play a crucial role in the mechanism. These results could contribute to the discovery of PTP1B inhibitors and the stabilization of the enzyme oxidized form.
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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 | 0.001 |
| 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".