Mechanism of action of pyridazine analogues on protein tyrosine phosphatase 1B (PTP1B).
The inhibitory effect on PTP1B caused by the addition of pyridazine analogues has been investigated. Biophysical techniques, that is, mass spectrometry (MS), nuclear magnetic resonance (NMR), and isothermal titration calorimetry (ITC) were used for the characterization. Pyridazine analogues cause catalytic oxidation of the reducing agent, generating hydrogen peroxide that oxidizes the active site cysteine on the enzyme, leading to enzyme inactivation. Two additional compound classes show the same effect. We found one common structural feature in these molecules that allows the reaction with triplet molecular oxygen to be less endothermic. A proposed mechanism for the catalytic redox cycle is described.
Tjernberg
Agneta
A
Department of Structural Chemistry, Biovitrum AB, SE-112 76 Stockholm, Sweden. agneta.tjernberg@biovitrum.com
Hallén
Dan
D
Schultz
Johan
J
James
Stephen
S
Benkestock
Kurt
K
Byström
Styrbjörn
S
Weigelt
Johan
J
D002384:Catalysis; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011724:Pyridazines / Q000145:classification / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D011724:Pyridazines; D006861:Hydrogen Peroxide; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases