Competitive protein tyrosine phosphatase 1B (PTP1B) inhibitors, prenylated caged xanthones from Garcinia hanburyi and their inhibitory mechanism.
Protein tyrosine phosphatase 1B (PTP1B) plays important role in diabetes, obesity and cancer. The methanol extract of the gum resin of Garcinia hanburyi (G. hanburyi) showed potent PTP1B inhibition at 10µg/ml. The active compounds were identified as prenylated caged xanthones (1-9) which inhibited PTP1B in dose-dependent manner. Carboxybutenyl group within caged motif (A ring) was found to play a critical role in enzyme inhibition such as 1-6 (IC50s=0.47-4.69µM), whereas compounds having hydroxymethylbutenyl 7 (IC50=70.25µM) and methylbutenyl 8 (IC50>200µM) showed less activity. The most potent inhibitor, gambogic acid 1 (IC50=0.47µM) showed 30-fold more potency than ursolic acid (IC50=15.5µM), a positive control. In kinetic study, all isolated xanthones behaved as competitive inhibitors which were fully demonstrated with Km, Vmaxand Kik/Kivratio. It was also proved that inhibitor 1 operated under the enzyme isomerization model having k5=0.0751µM-1S-1, k6=0.0249µM-1S-1and Kiapp=0.499µM. To develop a pharmacophore model, we explored the binding sites of compound 1 and 7 in PTP1B. These modeling results were in agreement with our findings, which revealed that the inhibitory activities are tightly related to caged motif and prenyl group in A ring.
Division of Applied Life Science (BK21 Plus), IALS, Gyeongsang National University, Jinju 52828, Republic of Korea.
Xue Fei
XF
Tan
Division of Applied Life Science (BK21 Plus), IALS, Gyeongsang National University, Jinju 52828, Republic of Korea.
Zia
Z
Uddin
Division of Applied Life Science (BK21 Plus), PMBBRC, RINS, Gyeongsang National University, Jinju 52828, Republic of Korea.
Chanin
C
Park
Division of Applied Life Science (BK21 Plus), IALS, Gyeongsang National University, Jinju 52828, Republic of Korea.
Yeong Hun
YH
Song
Division of Applied Life Science (BK21 Plus), PMBBRC, RINS, Gyeongsang National University, Jinju 52828, Republic of Korea.
Minky
M
Son
Division of Applied Life Science (BK21 Plus), PMBBRC, RINS, Gyeongsang National University, Jinju 52828, Republic of Korea. Electronic address: kwlee@gnu.ac.kr.
Keun Woo
KW
Lee
Division of Applied Life Science (BK21 Plus), IALS, Gyeongsang National University, Jinju 52828, Republic of Korea. Electronic address: khpark@gnu.ac.kr.
Ki Hun
KH
Park
D066241:Carbon-13 Magnetic Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D029760:Garcinia / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors*; D066244:Proton Magnetic Resonance Spectroscopy; D055672:Static Electricity; D044004:Xanthones / Q000302:isolation & purification / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D044004:Xanthones; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
Competitive inhibitor; G. hanburyi; Molecular modeling; PTP1B; Prenylated caged xanthones