Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake

• Published in: Biochimica et biophysica acta Vol. 1760; no. 10; pp. 1505 - 1512
• Main Authors: Zhang, Wei, Hong, Di, Zhou, Yueyang, Zhang, Yinan, Shen, Qiang, Li, Jing-ya, Hu, Li-hong, Li, Jia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2006
• Subjects: Animals; Cell Line; CHO Cells; Competitive; Cricetinae; Derivative; Drugs, Chinese Herbal - pharmacology; Glucose - metabolism; Glucose uptake; Humans; Inhibitor; Insulin receptor; Phenylalanine - analogs & derivatives; Phenylalanine - pharmacology; Phosphorylation; Protein Phosphatase 2; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases - antagonists & inhibitors; PTP1B; Rats; Receptor, Insulin - metabolism; Traditional Chinese medicinal herb; Triterpenes - pharmacology; Ursolic Acid; Competitive; Glucose uptake; PTP1B; Derivative; Inhibitor; Ursolic acid; Traditional Chinese medicinal herb; Insulin receptor
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2006.05.009

Protein tyrosine phosphatase 1B (PTP1B) is a key element in the negative regulation of the insulin signaling pathway and may play an important role in diabetes and obesity. We identified ursolic acid, a natural pentacyclic triterpenoid that occurs widely in traditional Chinese medicinal herbs, as an inhibitor of PTP1B by screening an extract library of the traditional Chinese medicinal herbs used a diabetes clinic. By modifying urosolic acid, we designed and synthesized a derivative with a K i of 283 nM. As competitive inhibitors of PTP1B, ursolic acid and its derivative also inhibit T-cell protein tyrosine phosphatase and src homology phosphatase-2 but not leucocyte antigen-related phosphatase or protein tyrosine phosphatase α and ε, which are all possibly involved in the insulin pathway. The ursolic acid derivative enhanced insulin receptor phosphorylation in CHO/ hIR cells and stimulate glucose uptake in L6 myotubes.