Dual Anti-/Prooxidant Behaviors of Flavonoids Pertaining to Cu(II)-Catalyzed Tyrosine Nitration of the Insulin Receptor Kinase Domain in an Antidiabetic Study

• Published in: Journal of agricultural and food chemistry Vol. 68; no. 22; pp. 6202 - 6211
• Main Authors: Fang, Xu, Gao, Wanxia, Yang, Zhen, Gao, Zhonghong, Li, Hailing
• Format: Journal Article
• Language: English
• Published: United States 03.06.2020
• Subjects: Antioxidants - chemistry; Antioxidants - metabolism; Catalysis; Copper - chemistry; Humans; Hydrogen Peroxide - chemistry; Hydrogen Peroxide - metabolism; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - metabolism; Kinetics; Nitrates - chemistry; Nitrates - metabolism; Protein Domains; Reactive Oxygen Species - chemistry; Receptor, Insulin - chemistry; Receptor, Insulin - metabolism; Tyrosine - chemistry; copper; flavonoid; tyrosine phosphorylation; insulin receptor kinase domain; tyrosine nitration
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.0c01676

Flavonoid, as a potent antioxidant, exerts many beneficial effects in type 2 diabetes, whereas the prooxidative property may be also important in vivo if copper is involved. Here, we chose an insulin receptor kinase domain fragment (KK-1, residues 1126-1165), containing the A-loop of the receptor as well as three key autophosphorylation sites (Tyr , Tyr , and Tyr ) associated with receptor signal transduction to investigate the roles and the structure-activity relationship of three antidiabetic flavonoids (kaempferol, luteolin, and apigenin) and two others with a similar structure (diosmetin and genistein), on modulation of Cu(II)-mediated tyrosine nitration and the corresponding effect on its functional phosphorylation in the Cu /H O /NO system. We found that both properties of flavonoid played roles on inhibition of Cu(II)-mediated protein nitration in the H O /NO system: (1) on the one hand, flavonoid scavenged free radicals as antioxidants, inhibited tyrosine nitration, and thus inhibited the reduction of tyrosine phosphorylation caused by tyrosine nitration; and (2) on the other hand, flavonoid promoted OH production as a prooxidant, which increased 3,3'-dityrosine formation. The formation of 3,3'-dityrosine decreased Cu -induced tyrosine nitration and thus interfered with its phosphorylation. This study confirms that the weight relationship between antioxidation and prooxidation of a flavonoid needs to be studied clearly before nutritional and medical applications.