Structural Investigation of Melatonin Metabolites as Calmodulin Antagonists and potential Nitric Oxide Synthase Inhibitors
Bibliographic record
Abstract
Nitric oxide synthase (NOS) is a flavo‐hemoprotein that catalyzes the conversion of L‐arginine to L‐citrulline in the production nitric oxide (NO). Mammalian NOS exists in three isoforms: endothelial NOS (eNOS), inducible NOS (iNOS) and neuronal NOS (nNOS). Each isoform requires calmodulin (CaM) for activation as CaM binding induces a conformational change, which facilitates electron transfer within the NOS peptide via a highly dynamic process. NO overproduction is implicated in several neurodegenerative and inflammatory conditions including septic shock, epilepsy, myocarditis and Alzheimer's, thus the development of a NOS isoform‐specific inhibitor is of clinical significance. Previous research has shown that N1‐acetyl‐5‐methoxykynuramine (AMK), a metabolite of melatonin (aMT), is a CaM‐dependant inhibitor of nNOS in rat striatum1,2. Despite attenuation of nNOS activity demonstrated both in vitro and in vivo, there has yet to be a comprehensive structural analysis of AMK‐CaM‐NOS complexes. To further validate possible therapeutic applications, we conducted an investigation of AMK interactions with CaM and the CaM‐NOS binding domain for all three NOS isoforms. Our results showed CaM‐AMK binding using gel shift assays, while circular dichroism (CD) results displayed the greatest spectral differences when AMK was added to the CaM‐nNOS complex. This indicates potential isoform‐dependent variation in NOS inhibition due to differences in the CaM‐NOS binding domain. These results were substantiated by subsequent multidimensional NMR experiments, in which the largest differences in chemical shifts occurred when inhibitors were added to the CaM‐nNOS sample, primarily amongst residues found in the N‐lobe of CaM. Our investigation provides significant insight into the potential of AMK as an isoform‐specific NOS inhibitor. Support or Funding Information This work was funded by the NSERC of Canada. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0.000 |
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".