Comparative analysis of the interaction between different flavonoids and PDIA3

Flavonoids, plant secondary metabolites present in fruits, vegetables, and products such as tea and red wine, show antioxidant, anti-inflammatory, antithrombotic, antiviral, and antitumor activity. PDIA3 is a member of the protein disulfide isomerase family mainly involved in the correct folding of newly synthetized glycoproteins. PDIA3 is associated with different human pathologies such as cancer, prion disorders, Alzheimer's disease, and Parkinson's diseases and it has the potential to be a pharmacological target. The interaction of different flavonoids with PDIA3 was investigated by quenching fluorescence analysis and the effects on protein activity were evaluated. A higher affinity was observed for eupatorin-5-methyl ether and eupatorin which also inhibit reductase activity of PDIA3 but do not significantly affect its DNA binding activity. The use of several flavonoids differing in chemical structure and functional groups allows us to make some consideration about the relationship between ligand structure and the affinity for PDIA3. The specific flavone backbone conformation and the degree of polarity seem to play an important role for the interaction with PDIA3. The binding site is probably similar but not equivalent to that of green tea catechins, which, as previously demonstrated, can bind to PDIA3 and prevent its interaction with DNA.