The Leptospermum scoparium (Mānuka)-Specific Nectar and Honey Compound 3,6,7-Trimethyllumazine (LepteridineTM) That Inhibits Matrix Metalloproteinase 9 (MMP-9) Activity
Author:
Lin Bin1, Nair Smitha1, Fellner Daniel M. J.2, Nasef Noha Ahmed3ORCID, Singh Harjinder3, Negron Leonardo4, Goldstone David C.15ORCID, Brimble Margaret A.125ORCID, Gerrard Juliet A.12, Domigan Laura6, Evans Jackie C.7, Stephens Jonathan M.7, Merry Troy L.578, Loomes Kerry M.15ORCID
Affiliation:
1. School of Biological Sciences and Institute for Innovation in Biotechnology, The University of Auckland, Auckland 1142, New Zealand 2. School of Chemical Sciences, The University of Auckland, Auckland 1142, New Zealand 3. Riddet Institute, Massey University, Palmerston North 4410, New Zealand 4. Callaghan Innovation, Gracefield Innovation Quarter, 69 Gracefield Road, Lower Hutt 5010, New Zealand 5. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1142, New Zealand 6. Department of Chemical and Materials Engineering, The University of Auckland, Auckland 1142, New Zealand 7. Comvita NZ Limited, 23 Wilson Road South, Bay of Plenty, Paengaroa 3189, New Zealand 8. Discipline of Nutrition, School of Medical Sciences, The University of Auckland, Auckland 1142, New Zealand
Abstract
3,6,7-trimethyllumazine (Lepteridine™) is a newly discovered natural pteridine derivative unique to Mānuka (Leptospermum scoparium) nectar and honey, with no previously reported biological activity. Pteridine derivative-based medicines, such as methotrexate, are used to treat auto-immune and inflammatory diseases, and Mānuka honey reportedly possesses anti-inflammatory properties and is used topically as a wound dressing. MMP-9 is a potential candidate protein target as it is upregulated in recalcitrant wounds and intestinal inflammation. Using gelatin zymography, 40 μg/mL LepteridineTM inhibited the gelatinase activities of both pro- (22%, p < 0.0001) and activated (59%, p < 0.01) MMP-9 forms. By comparison, LepteridineTM exerted modest (~10%) inhibition against a chromogenic peptide substrate and no effect against a fluorogenic peptide substrate. These findings suggest that LepteridineTM may not interact within the catalytic domain of MMP-9 and exerts a negligible effect on the active site hydrolysis of small soluble peptide substrates. Instead, the findings implicate fibronectin II domain interactions by LepteridineTM which impair gelatinase activity, possibly through perturbed tethering of MMP-9 to the gelatin matrix. Molecular modelling analyses were equivocal over interactions at the S1′ pocket versus the fibronectin II domain, while molecular dynamic calculations indicated rapid exchange kinetics. No significant degradation of synthetic or natural LepteridineTM in Mānuka honey occurred during simulated gastrointestinal digestion. MMP-9 regulates skin and gastrointestinal inflammatory responses and extracellular matrix remodelling. These results potentially implicate LepteridineTM bioactivity in Mānuka honey’s reported beneficial effects on wound healing via topical application and anti-inflammatory actions in gastrointestinal disorder models via oral consumption.
Funder
Callaghan Innovation PhD scholarships (B.L., S.N.) and Comvita NZ Ltd.
Subject
Plant Science,Health Professions (miscellaneous),Health (social science),Microbiology,Food Science
Reference73 articles.
1. Honey and Health: A Review of Recent Clinical Research;Samarghandian;Pharmacogn. Res.,2017 2. Ranneh, Y., Akim, A.M., Hamid, H.A., Khazaai, H., Fadel, A., Zakaria, Z.A., Albujja, M., and Bakar, M.F.A. (2021). Honey and its nutritional and anti-inflammatory value. BMC Complement. Med. Ther., 21. 3. Scepankova, H., Combarros-Fuertes, P., Fresno, J.M., Tornadijo, M.E., Dias, M.S., Pinto, C.A., Saraiva, J.A., and Estevinho, L.M. (2021). Role of Honey in Advanced Wound Care. Molecules, 26. 4. Carter, D.A., Blair, S.E., Cokcetin, N.N., Bouzo, D., Brooks, P., Schothauer, R., and Harry, E.J. (2016). Therapeutic Manuka Honey: No Longer So Alternative. Front. Microbiol., 7. 5. The evidence supporting the use of honey as a wound dressing;Molan;Int. J. Low. Extrem. Wounds,2006
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