Urate-lowering effect of delphinidin-3-glucoside in red kidney beans via binding to the FAD site of the XO enzyme.

BACKGROUND

The incidence of hyperuricemia (HUA) is increasing globally, posing serious health risks. The discovery of natural urate-lowering agents is urgently needed.

OBJECTIVE

To discover natural urate-lowering agents and investigate their effect and action mechanisms for ameliorating HUA.

METHODS

Our study comprehensively explored the association between the intake of 13 specific legume varieties in the US population. A composition-target-metabolic (C-T-M) pathway network was constructed to identify key agents and their interactions with key proteins, which were verified by molecular dynamics simulations (MD) and surface plasmon resonance (SPR). Biochemical, in vitro, and in vivo metabolomic studies in male ICR mice were conducted to examine the effects of the key agent in red kidney beans on uric acid production and other metabolisms.

RESULTS

We found that consuming red kidney beans was robustly negatively associated with the risk of HUA. Based on the C-T-M network, delphinidin-3-glucoside (Dp-3G) was identified as the key agent in red kidney beans, focusing on its binding to xanthine oxidase (XO) enzyme. This interaction was subsequently verified by MD and SPR, revealing that Dp-3G binds to the FAD site of the XO enzyme, thereby blocking electron transfer during enzyme catalysis involving Moco, [2Fe-2S], and FAD. Dp-3G consistently reduces uric acid production under biochemical, in vitro, and in vivo conditions and reverses metabolic abnormalities related to HUA in mice, including methionine, proline, and folate.

CONCLUSIONS

This study identifies Dp-3G, a novel natural agent enriched in red kidney beans, as capable of occupying the FAD site of the XO enzyme, thereby interfering with uric acid synthesis, and suggesting its potential for preventing and treating HUA.