Actin–Curcumin Interaction: Insights into the Mechanism of Actin Polymerization Inhibition

Abstract

Curcumin, derived from rhizomes of the Curcuma longa plant, is known to possess a wide range of medicinal properties. We have examined the interaction of curcumin with actin and determined their binding and thermodynamic parameters using isothermal titration calorimetry. Curcumin is weakly fluorescent in aqueous solution, and binding to actin enhances fluorescence several fold with a large blue shift in the emission maximum. Curcumin inhibits microfilament formation, which is similar to its role in inhibiting microtubule formation. We synthesized a series of stable curcumin analogues to examine their affinity for actin and their ability to inhibit actin self-assembly. Results show that curcumin is a ligand with two symmetrical halves, each of which possesses no activity individually. Oxazole, pyrazole, and acetyl derivatives are less effective than curcumin at inhibiting actin self-assembly, whereas a benzylidiene derivative is more effective. Cell biology studies suggest that disorganization of the actin network leads to destabilization of filaments in the presence of curcumin. Molecular docking reveals that curcumin binds close to the cytochalasin binding site of actin. Further molecular dynamics studies reveal a possible allosteric effect in which curcumin binding at the "barbed end" of actin is transmitted to the "pointed end", where conformational changes disrupt interactions with the adjacent actin monomer to interrupt filament formation. Finally, the recognition and binding of actin by curcumin is yet another example of its unique ability to target multiple receptors.

Recent Updates in Curcumin Pyrazole and Isoxazole Derivatives: Synthesis and Biological Application

“…Pyrazole derivatives of curcumin, extensively obscured IL-6, TNF-α and GM-CSF production by NHBE cells, down regulated the level of active serine peptidase inhibitor. [72] A comparative structure-activity study revealed three modifications, namely i) enolized dicarbonyl moiety and/or replacement by pyrazole, ii) hydrogenation of the interaryl linker, and iii) (dihydro) prenylation scrutinize mPGES-1/5-LO inhibition. [71] Curcumin inhibits microfilament formation, which is similar to its role in inhibiting microtubule formation.…”

“…Curcumin is softly fluorescent in aqueous solution which binds to actin and augments fluorescence several fold with a large blue shift in the emission maximum (Table 13). [72] A comparative structure-activity study revealed three modifications, namely i) enolized dicarbonyl moiety and/or replacement by pyrazole, ii) hydrogenation of the interaryl linker, and iii) (dihydro) prenylation scrutinize mPGES-1/5-LO inhibition.…”

Inhibition of dengue virus by curcuminoids

“…Our results indicate that the curcuminoids inhibit lipogenesis and thereby inhibiting DENV replication. The curcuminoids tested in this study also lead to actin depolymerization similar to curcumin (Dhar et al, 2015) in DENV2-infected cells. Actin plays important roles in entry, viral replication and assembly.…”

“…A reduction in viral replication of DENV and WNV was also observed by blocking the actin function (Ang et al, 2010;Colpitts et al, 2011). Native curcumin has been shown to inhibit actin polymerization with an IC50 of 16 μM (Dhar et al, 2015) in DENV2-infected cells. To test if the curcuminoids caused actin disorganization, phalloidin staining method was used to image F-actin ( Fig 5) and the results indicate that the curcuminoids caused actin disorganization similar to the parent curcumin in DENV2 infected cells.…”

Low Dosed Curcumin Combined with Visible Light Exposure Inhibits Renal Cell Carcinoma Metastatic Behavior in Vitros

“…Indeed, curcumin has been shown in tumor cell models to disorganize the architecture of actin microfilaments, leading to destabilization and a decrease in F-actin polymerization [41,42]. Dhar et al assumed an allosteric effect in which curcumin binding at the "barbed end" of actin is transmitted to the "pointed end," where conformational changes disrupt interactions with the adjacent actin monomer to interrupt filament formation [43]. There is also evidence that curcumin stops the physical interaction of cortactin with p120 catenin, which then may inhibit migration [44].…”