Role of curcumin's phenolic –OH group in the inhibition of Helicobacter pylori CagA phosphorylation

Abstract

Helicobacter pylori is a pathogenic bacterium that causes various gastric diseases in humans. It secretes virulence factors such as the CagA protein, which plays a crucial role in its pathogenesis. The C-terminal domain (CTD) of the CagA protein plays a crucial role in facilitating its attachment to host cell membranes and interacting with various intracellular proteins. These interactions are essential for the growth and infection of H. pylori. Strain-specific sequence polymorphism of H. pylori, specifically at the C-terminal of the CagA protein, is responsible for its differential oncogenic potential.Curcumin is a natural compound with pharmacological properties like anti-oxidant, anti-bacterial, anti-inflammatory, and anti-cancer effects. Additionally, several studies have reported the anti-H. pylori effects of curcumin. In this study, we investigated mechanisms of binding of curcumin and its non-oxidizable derivatives (acetalcurcumin and diacetalcurcumin) with CTD of CagA protein. We used computational strategies such as docking and molecular dynamics simulation for the analysis. Curcumin was found to have more binding affinity with the CagA protein than its acetal and diacetal analogs. This suggests that the OH-group present in the structure of curcumin, which gets modified in its acetal and diacetal analogs, may have an essential role in the interaction with the CagA protein.Results showed that curcumin binds to the residues within the active pocket formed by the EPIYA-C motif and CM motif located in the C-terminal domain (CTD) of the CagA protein. Additionally, curcumin was observed to interact with the TYR970 residue within the EPIYA-C motif of the CTD of the CagA protein. Notably, TYR970 phosphorylation is a known event during H. pylori-mediated pathogenesis. Therefore, this study suggests that curcumin's anti-H. pylori activity may be triggered by inhibiting the phosphorylation of the CagA protein.