The Leptospermum scoparium (Mānuka)-Specific Nectar and Honey Compound 3,6,7-Trimethyllumazine (LepteridineTM) That Inhibits Matrix Metalloproteinase 9 (MMP-9) Activity
Abstract
:1. Introduction
2. Materials and Methods
2.1. Physicochemical Properties
2.2. Molecular Docking
2.3. MMP-9 Fluorescent and Colorimetric Activity Assays
2.4. Mass Spectrometry Activity Analyses
2.5. Expression in E. coli, Denaturing Purification, and On-Column Refolding of Recombinant Human Matrix Metalloproteinase 9 (MMP-9) in Its Latent Form (His-Tagged proMMP-9cat)
2.6. Protein Quantitation
2.7. SDS/PAGE Electrophoresis and Western Blotting
2.8. Generation of Activated Human MMP-9cat from His-Tagged proMMP-9cat
2.9. His-Tagged proMMP-9cat and MMP-9cat Gelatinase Activity Assay
2.10. LepteridineTM-Simulated Digestion
2.11. Statistical Analysis
3. Results
3.1. Modelling of LepteridineTM as a Putative Ligand for MMP-9 and Other Inflammatory Mediators
3.2. Fluorescence and Colorimetric Spectrometry Assessment of LepteridineTM’s Ability to Inhibit MMP-9 Activity
3.3. Purification and Characterisation of Recombinant proMMP-9cat
3.4. Gelatin Zymography Assessment of LepteridineTM and Its Ability to Inhibit His-Tagged proMMP-9cat and MMP-9cat Activity
3.5. Gastric Stability of LepteridineTM
4. Discussion
5. Conclusions
6. Intellectual Property
- WO/2017/099612—Marker Compounds of Leptospermum Honeys and Methods of Isolation and Assaying Thereof.
- WO/2021/002763—Use of a Composition Comprising 3,6,7-Trimethyllumazine for Preventing, Ameliorating, or Treating MMP-9-Associated Conditions and Inflammation.
- LepteridineTM is a trademark of Comvita Limited for 3,6,7-trimethyllumazine. All references to the Lepteridine trademark in this article are with the authorisation of Comvita Limited.
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Candidate | Rationale | Citation |
---|---|---|
MMP-9 | Key role in extracellular matrix remodelling, cell proliferation, and inflammatory pathways including cytokine and chemokine processing. Associated with gastric mucosal damage and ulcer formation. | [31,58,65] |
EDNRB | Receptor for ET-1 produced by gastrointestinal tract. Evokes dysregulation of cytokine production and a feature of inflammatory bowel disease. | [66] |
PTGS2 | Intestinal immune response regulation. | [67] |
JAK1 | Receptor for several inflammatory cytokines. Target of some ulcerative colitis medications. | [68] |
HSP90 | Upregulated in inflammation and coordinates transcriptional response. Potential inflammatory bowel disease treatment target. | [69] |
PC | Potential mediator of metabolic stress-driven inflammation and oxidative stress. | [70] |
TGM2 | Can regulate cytokine-induced gene transcription via nuclear factor-κB. Upregulated in an inflammatory state and wounds. | [71,72] |
ANPEP | Removes amino acids from peptide substrates. Plays key roles in hormone regulation, maturation, and degradation of bioactive peptides including inflammatory cytokines. | [73] |
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Candidate | Docking Structure | GoldScore | ChemScore | Compound Similarity | Likely Binding, or Interacting with Inhibitor Residues/Domains |
---|---|---|---|---|---|
MMP9 | 6ESM | 53.47 | 16.81 | Active/Inactive | No |
EDNRB | 6K1Q | 48.35 | 17.63 | NA | Unclear |
PTGS2 | 5IKR | 44.33 | 11.77 | Inactive | No |
JAK1 | 6N7A | 43.32 | 19.33 | Active/Inactive | Weak |
HSP90 | 5XRD | 40.27 | 13.63 | Inactive | Weak |
PC | 3BG3 | 37.94 | 11.39 | Inactive | No |
TGM2 | 1KV3 | 37.52 | 20.38 | Active/Inactive | Weak |
ANPEP | 4FYT | 36.05 | 15.03 | Inactive | Weak |
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Lin, B.; Nair, S.; Fellner, D.M.J.; Nasef, N.A.; Singh, H.; Negron, L.; Goldstone, D.C.; Brimble, M.A.; Gerrard, J.A.; Domigan, L.; et al. The Leptospermum scoparium (Mānuka)-Specific Nectar and Honey Compound 3,6,7-Trimethyllumazine (LepteridineTM) That Inhibits Matrix Metalloproteinase 9 (MMP-9) Activity. Foods 2023, 12, 4072. https://doi.org/10.3390/foods12224072
Lin B, Nair S, Fellner DMJ, Nasef NA, Singh H, Negron L, Goldstone DC, Brimble MA, Gerrard JA, Domigan L, et al. The Leptospermum scoparium (Mānuka)-Specific Nectar and Honey Compound 3,6,7-Trimethyllumazine (LepteridineTM) That Inhibits Matrix Metalloproteinase 9 (MMP-9) Activity. Foods. 2023; 12(22):4072. https://doi.org/10.3390/foods12224072
Chicago/Turabian StyleLin, Bin, Smitha Nair, Daniel M. J. Fellner, Noha Ahmed Nasef, Harjinder Singh, Leonardo Negron, David C. Goldstone, Margaret A. Brimble, Juliet A. Gerrard, Laura Domigan, and et al. 2023. "The Leptospermum scoparium (Mānuka)-Specific Nectar and Honey Compound 3,6,7-Trimethyllumazine (LepteridineTM) That Inhibits Matrix Metalloproteinase 9 (MMP-9) Activity" Foods 12, no. 22: 4072. https://doi.org/10.3390/foods12224072