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Characterization of Protein Tyrosine Phosphatase 1B Inhibition by Chlorogenic Acid and Cichoric Acid
James M Lipchock1, Heidi P Hendrickson2, Bonnie B Douglas1,2
1Department of Chemistry, Washington College , Chestertown, Maryland 21620, United States.
Abstract:
Protein tyrosine phosphatase 1B (PTP1B) is a known regulator of the insulin and leptin signaling pathways and is an active target for the design of inhibitors for the treatment of type II diabetes and obesity. Recently, cichoric acid (CHA) and chlorogenic acid (CGA) were predicted by docking methods to be allosteric inhibitors that bind distal to the active site. However, using a combination of steady-state inhibition kinetics, solution nuclear magnetic resonance experiments, and molecular dynamics simulations, we show that CHA is a competitive inhibitor that binds in the active site of PTP1B. CGA, while a noncompetitive inhibitor, binds in the second aryl phosphate binding site, rather than the predicted benzfuran binding pocket. The molecular dynamics simulations of the apo enzyme and cysteine-phosphoryl intermediate states with and without bound CGA suggest CGA binding inhibits PTP1B by altering hydrogen bonding patterns at the active site. This study provides a mechanistic understanding of the allosteric inhibition of PTP1B.
Insights
Cichoric acid (CHA) competitively inhibits Protein Tyrosine Phosphatase 1B (PTP1B) at the active site. Chlorogenic acid (CGA) noncompetitively inhibits PTP1B by altering active site hydrogen bonding.
Area of Science:
- Biochemistry
- Pharmacology
- Molecular Biology
Background:
- Protein tyrosine phosphatase 1B (PTP1B) is a key regulator of insulin and leptin signaling.
- PTP1B is a therapeutic target for type II diabetes and obesity.
- Cichoric acid (CHA) and chlorogenic acid (CGA) were previously predicted as allosteric PTP1B inhibitors.
Purpose of the Study:
- To investigate the inhibitory mechanisms of CHA and CGA on PTP1B.
- To elucidate the binding sites and modes of CHA and CGA on PTP1B.
- To provide a mechanistic understanding of PTP1B inhibition by these compounds.
Main Methods:
- Steady-state enzyme inhibition kinetics.
- Solution Nuclear Magnetic Resonance (NMR) spectroscopy.
- Molecular Dynamics (MD) simulations.
Main Results:
- CHA acts as a competitive inhibitor, binding directly to the PTP1B active site.
- CGA functions as a noncompetitive inhibitor, binding to the second aryl phosphate site.
- MD simulations revealed CGA binding alters active site hydrogen bonding, inhibiting PTP1B function.
- The study identified discrepancies between predicted and actual binding sites for CHA and CGA.
Conclusions:
- CHA and CGA exhibit distinct inhibitory mechanisms against PTP1B, differing from initial predictions.
- This research clarifies the molecular basis of PTP1B inhibition by CHA and CGA.
- The findings offer insights for the rational design of PTP1B inhibitors for metabolic diseases.
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