Modeling Enzyme Competition in Eicosanoid Metabolism in Macrophage Cells Using a Cybernetic Framework

Cellular metabolism is a complex process involving the consumption and production of metabolites, as well as the regulation of enzyme synthesis and activity. Modeling of metabolic processes is important to understand the underlying mechanisms, with a wide range of applications in metabolic engineering and health sciences. Cybernetic modeling is a powerful technique that accounts for unknown intricate regulatory mechanisms in complex cellular processes. It models regulation as goal-oriented, where the levels and activities of enzymes are modulated by the cybernetic control variables to achieve the cybernetic objective. This study used cybernetic model to study the enzyme competition between arachidonic acid (AA) and eicosapentaenoic acid (EPA) metabolism in murine macrophages. AA and EPA compete for the shared enzyme cyclooxygenase. Upon external stimuli, AA produces proinflammatory 2-series prostaglandins and EPA metabolizes to antiinflammatory 3-series prostaglandins, where proinflammatory and antiinflammatory responses are necessary for homeostasis. The cybernetic model adequately captured the experimental data for control and EPA-supplemented conditions. The model is validated by performing an F-test, conducting leave-one-out-metabolite cross-validation, and predicting an unseen experimental condition. The cybernetic variables provide insights into the competition between AA and EPA for the cyclooxygenase enzyme. Predictions from our model suggest that the system undergoes a switch from a predominantly proinflammatory state in the control to an antiinflammatory state with EPA-supplementation. The model can also be used to analytically determine the AA and EPA concentrations required for the switch to occur. The quantitative outcomes enhance understanding of proinflammatory and antiinflammatory metabolism in RAW 264.7 macrophages.