The inhibitory kinetics and mechanism of dietary vitamins D₃and B₂on xanthine oxidase

Abstract

Dietary guidelines to promote health are usually based on the patterns' prediction on disease risk of foods and nutrients. Overactivity of xanthine oxidase (XO) is the underlying cause of gout. Herein, the inhibitory kinetics and mechanism of dietary vitamins D3 and B2 on XO were investigated by multispectroscopic methods and a molecular modeling technique. The results showed that vitamin D3 competitively inhibited XO with an inhibition constant of 26.93 ± 0.42 μM by inserting into the active cavity of XO interacting with the surrounding amino acid residues through hydrogen bond and van der Waals forces. Vitamin D3 bound to XO thereby induced the structural compactness of XO which in turn hindered the binding of substrate xanthine to cause the inhibition on XO. Vitamin B2 exhibited a mixed-type inhibition by binding to the vicinity of the active cavity with an inhibition constant of 37.76 ± 0.87 μM through hydrophobic interactions and a feeble hydrogen bond, and it induced the unfolding of the XO structure and an increase of the flexible loops (β-turns and random coils) which might move to cover the active pocket and reduce the binding of the substrate xanthine, and then lead to a lower catalytic activity of the enzyme. In addition, vitamins D3 and B2 showed a synergistic effect on inhibiting the activity of XO in a certain range of concentration. These findings may provide new insights into the inhibitory mechanism of vitamins D3 and B2 on XO and functional research of the vitamins in the supplementary treatment of gout.

Vitamin D Effects on Lipid Profile and Uric Acid Levels in the Experimental Model of Metabolic Disorders in Fructose Fed Wistar Rats

“…This in turn hindered the binding of substrate xanthine and caused the inhibition of xanthine oxidase. Vitamin D competitively inhibits xanthine oxidase by inserting into the active cavity of the enzyme interacting with surrounding amino acids residues through hydrogen bond and van der Waals forces [16]. Based on these findings, we could assume that the lower uric acid levels in vitamin D treated animals are due to the interaction of this vitamin with the enzyme xanthine oxidase.…”

“…There is growing evidence that vitamin D and uric acid metabolism pathways are related and there is a connection between hyperuricemia and low vitamin D levels [2,6,11,16,19]. Metabolic disorders such as fatty liver may be strongly affected and even caused by an excessive fructose intake [4].…”

Identification of pyrazolotriazinones as potential agents for hyperuricemia treatment by using in vitro and in silico studies

“…Figure 4 shows a 2D graphic description of the ligand interactions for the most active of each series. For 2e, it was observed a hydrogen binding with Glu802 residue, which was reported as essential for enzymatic catalysis, playing a key role in the hydroxylation of the substrate [15]. For its part, 3c presented a π-cation interaction with Tyr1140 residue that contributed to an important binding affinity for this compound [15].…”

Screening and Inhibition Mechanism of Xanthine Oxidase Inhibitors in Ethanolic Extracts of Chimonanthus salicifolius Hu Leaves

“…Inhibitor types were analyzed by the Lineweaver-Burk plots. [39] The following equations can be used to describe competitive inhibition:…”