Melatonin inhibits matrix metalloproteinase‐9 activity by binding to its active site

Abstract

The zinc-dependent matrix metalloproteinases (MMPs) are key enzymes associated with extracellular matrix (ECM) remodeling; they play critical roles under both physiological and pathological conditions. MMP-9 activity is linked to many pathological processes, including rheumatoid arthritis, atherosclerosis, gastric ulcer, tumor growth, and cancer metastasis. Specific inhibition of MMP-9 activity may be a promising target for therapy for diseases characterized by dysregulated ECM turnover. Potent MMP-9 inhibitors including an indole scaffold were recently reported in an X-ray crystallographic study. Herein, we addressed whether melatonin, a secretory product of pineal gland, has an inhibitory effect on MMP-9 function. Gelatin zymographic analysis showed a significant reduction in pro- and active MMP-9 activity in vitro in a dose- and time-dependent manner. In addition, a human gastric adenocarcinoma cell line (AGS) exhibited a reduced (~50%) MMP-9 expression when incubated with melatonin, supporting an inhibitory effect of melatonin on MMP-9. Atomic-level interaction between melatonin and MMP-9 was probed with computational chemistry tools. Melatonin docked into the active site cleft of MMP-9 and interacted with key catalytic site residues including the three histidines that form the coordination complex with the catalytic zinc as well as proline 421 and alanine 191. We hypothesize that under physiological conditions, tight binding of melatonin in the active site might be involved in reducing the catalytic activity of MMP-9. This finding could provide a novel approach to physical docking of biomolecules to the catalytic site of MMPs, which inhibits this protease, to arrest MMP-9-mediated inflammatory signals.

Melatonin limits the expression of profibrogenic genes and ameliorates the progression of hepatic fibrosis in mice

“…28 Previous studies have shown that melatonin inhibits MMP-9 activity via binding to its active site and via MT1 receptor signaling pathway. 41,42 Consequently, data obtained indicate that reduction in ECM deposition by melatonin could contribute to the alleviation of liver fibrosis, confirming results from rats treated with CCl 4 that were given gallic acid 43 or extracts from Acanthopanax koreanum. 44 Oxidative stress is one the most important stimuli to activate HSCs and plays a key role in the development of fibrosis.…”

Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis

“…For example, melatonin has been shown to inhibit the expression and activity of MMP-2 and MMP-9 in both in vitro and in vivo models (32,39,41). A recent study has shown that melatonin inhibits MMP-9 by binding to its active site, which represents another possible mechanisms for the alteration in fibrosis during constant darkness (48). Melatonin has been show to diminish the secretion of TGF-␤ from hepatic stellate cells (25).…”

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

“…Melatonin induces apoptosis and reduces invasiveness of HepG2 cells in vitro through TIMP-1 upregulation and attenuation of MMP-9 activity via NFκB signal pathway [196] . Rudra et al [192] reported that melatonin reduces MMP-9 activity in AGS cell line and binds directly to its active site.…”

“…Melatonin is a naturally occurring antioxidant synthesized mainly by the pineal gland of vertebrates and also found in many edible plant products [191] . Recent research documents that consumption of tropical fruit enhances the serum melatonin level as well as raises the antioxidant capacity of blood serum [191,192] . Melatonin retards the development of cancer in different animal models and possesses strong anti-proliferative and proapoptotic effects in various cancer cells.…”