Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake.
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 alpha and epsilon, 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.
Zhang
Wei
W
National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, PR China.
Hong
Di
D
Zhou
Yueyang
Y
Zhang
Yinan
Y
Shen
Qiang
Q
Li
Jing-Ya
JY
Hu
Li-Hong
LH
Li
Jia
J
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors*; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism*; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
D004365:Drugs, Chinese Herbal; D005947:Glucose; D010649:Phenylalanine; D054648:Protein Phosphatase 2; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D011972:Receptor, Insulin; D014315:Triterpenes; D000097245:Ursolic Acid; C514931:UA 0713; C516607:PTPN1 protein, human; C516610:Ptpn1 protein, rat