School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, Heilongjiang, China.
New Hope Dairy Co, Ltd, Chengdu 610063, Sichuan, China.
Bioorg Chem. 2022 Nov;128:106097. doi: 10.1016/j.bioorg.2022.106097. Epub 2022 Aug 13.
As the development of hyperuricemia (HUA) and gout continues to accelerate worldwide, there is increasing interest in the use of xanthine oxidase (XO) inhibitors as therapeutic agents for the management of HUA and gout. In the present study, XO inhibitory peptides were identified from whey protein isolate (WPI) hydrolysates, and the underlying inhibitory mechanism and in vivo activities was investigated. WPI hydrolysates were isolated and purified, and two peptides (ALPM and LWM) with lower binding energy were screened by molecular docking. The result showed that these two peptides interacted with residues around the active site of XO through hydrogen bond and hydrophobic interaction. The IC values of ALPM and LWM were 7.23 ± 0.22 and 5.01 ± 0.31 mM, respectively. According to the Lineweaver-Burk curve, the inhibition types of ALPM and LWM were non-competitive inhibition. Circular dichroism (CD) spectra indicated ALPM and LWM could change the secondary structure of XO. Molecular dynamics simulations revealed that XO-peptide complexes were more stable and compact than XO. Moreover, animal studies have shown that ALPM and LWM have anti-hyperuricemia effects in vivo. This study suggested that ALPM and LWM can be considered as natural XO inhibitors for the treatment of HUA.
随着高尿酸血症（HUA）和痛风在全球范围内的不断加速发展，人们对黄嘌呤氧化酶（XO）抑制剂作为 HUA 和痛风治疗药物的应用越来越感兴趣。本研究从乳清蛋白分离物（WPI）水解物中鉴定出 XO 抑制肽，并对其潜在的抑制机制和体内活性进行了研究。WPI 水解物被分离和纯化，通过分子对接筛选出两个结合能较低的肽（ALPM 和 LWM）。结果表明，这两个肽通过氢键和疏水相互作用与 XO 活性部位周围的残基相互作用。ALPM 和 LWM 的 IC 值分别为 7.23 ± 0.22 和 5.01 ± 0.31 mM。根据 Lineweaver-Burk 曲线，ALPM 和 LWM 的抑制类型为非竞争性抑制。圆二色性（CD）光谱表明，ALPM 和 LWM 可以改变 XO 的二级结构。分子动力学模拟表明，XO-肽复合物比 XO 更稳定和紧凑。此外，动物研究表明，ALPM 和 LWM 在体内具有抗高尿酸血症作用。本研究表明，ALPM 和 LWM 可以被认为是治疗 HUA 的天然 XO 抑制剂。
