Thimet Oligopeptidase (EP24.15), a Neuropeptide Processing Enzyme Regulating Xenin Signaling
Bibliographic record
Abstract
Xenin is a 25 amino acid neuropeptide with sequence homology and actions similar to hypothalamic and ileal neurotensin (a satiety factor) as well as binding to the neurotensin receptor. Xenin is produced by a subgroup of chromogranin A+ cells in the duodenum and this neurohormone is involved in glucose homeostasis and increases the response to glucose‐dependent insulinotropic peptide (GIP). Upon its release after ingestion Xenin inhibits secretion of pancreatic exocrine peptides in the gastrointestinal tract. The mode of regulating the peptide hormone Xenin remains elusive. The metalloendopeptidase EC 3.4.24.15 (thimet oligopeptidase, EP24.15) has been demonstrated to play a key role in the cleavage and subsequent regulation of several neuropeptides that also exist in the gut such as neurotensin and somatostatin. A systems biology approach to regulating signaling beginning from high throughput structural analyses, in silico molecular modeling and potential substrate screening implicated Xenin as a substrate of EP24.15 and thus, this enzyme as a possible regulator of Xenin signaling. To substantiate a potential regulatory mechanism for the functioning of Xenin, we first identified potential active site binding and cleavage sites, measured enzymatic parameters, performed structural studies, and determined if EP24.15 and Xenin are co‐expressed in gut regions relevant to glucose homeostasis. After proprietary in silico modeling paradigms identifying a potential favorable interaction, EP24.15 and Xenin were co‐incubated and subjected to matrix‐assisted laser desorption ionization time‐of‐flight (MADLI‐TOF) mass spectrometry to confirm that EP24.15 can cleave Xenin in vitro. Enzyme kinetics were performed with standards via high performance liquid chromatography yielding results consistent with known substrates. Notably, Xenin is cleaved in a homologous manner as neurotensin. Double‐label immunohistochemistry demonstrated Xenin and EP24.15 immunoreactivity within the mouse small intestine and specifically co‐expression within the intestinal mucosa and submucosa. Furthermore, there is co‐expression of EP24.15 and Xenin in cells of both human and mouse stomach in the gastric mucosa. Taken together this data suggests that EP24.15 may act to cleave Xenin in vivo and represents an additional facet of the control mechanism of glucose homeostasis. As a potential pharmacological therapeutic target, understanding regulation of Xenin by the neuropeptide processing enzyme, EP24.15, may provide insight into an alternative strategy for glucose regulation and diseases such as diabetes and obesity. Support or Funding Information Supported by NIH OD010662 (MJG) and CIHR MOP123208 (TMM)
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| 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".