Abstract
AbstractThe kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was developed to investigate its complex network kinetics and non-steroidal anti-inflammatory drugs (NSAIDs) efficacy in differentin vitroandin vivoconditions. To correctly describe the complex mechanism of PGHS-1 catalysis, we developed a microscopic approach to modelling of intricate network dynamics of 35 intraenzyme reactions among 24 intermediate states of the enzyme. The developed model quantitatively describes interconnection between cyclooxygenase and peroxidase enzyme activities; substrate (arachidonic acid, AA) and reducing cosubstrate competitive consumption; enzyme self-inactivation; autocatalytic role of AA; enzyme activation threshold, and synthesis of intermediate PGG2and final PGH2products under wide experimental conditions. In the paper we provided the detailed description of the enzyme catalytic cycle, model calibration based on a series ofin vitrokinetic data and model validation using experimental data on the regulatory properties of PGHS-1.The validated model of PGHS-1 with a unified set of kinetic parameters is applicable forin silicoscreening and prediction of the inhibition effects of NSAIDs and their combination on the balance of pro-thrombotic (thromboxane) and anti-thrombotic (prostacyclin) prostaglandin biosynthesis in platelets and endothelial cells expressing PGHS-1.
Publisher
Cold Spring Harbor Laboratory
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