Antagonistic Polyphenol Interactions Underlie the α-Glucosidase Inhibitory Activity of Keemun Black Tea.

The α-glucosidase inhibitory activity of Keemun black tea arises from complex interactions among its major polyphenols, which cannot be reliably predicted from the activities of isolated compounds. In this study, eight dominant polyphenols were investigated using a quantitative reconstruction-omission framework designed to reflect typical household tea brewing. The fully reconstructed system recovered approximately 72% of the inhibitory activity of the diluted native infusion, supporting the functional representativeness of the selected compounds. Systematic omission experiments revealed that antagonistic interactions, particularly among theaflavins, dominated the net inhibitory outcome, with removal of the most potent inhibitor, theaflavin-3,3'-digallate (TFDG), paradoxically increasing overall activity. Pairwise Combination Index analysis further demonstrated concentration-dependent biphasic interactions, exemplified by the epigallocatechin-3-gallate (EGCG)-TFDG pair, while molecular docking suggested overlapping binding sites as a potential structural basis for competitive inhibition. Collectively, this work provides a system-level dissection of α-glucosidase inhibition in black tea. Although the reconstructed system does not fully capture all contributions, the proposed framework offers a generalizable strategy for investigating interaction-driven bioactivity in complex dietary matrices and for further mechanistic studies.