Modeling enzyme competition in Eicosanoid metabolism in macrophage cells using a cybernetic framework.

Abstract

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 employed 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 (COX). Upon external stimuli, AA produces pro-inflammatory 2-series prostaglandins (PGs) and EPA metabolizes to anti-inflammatory 3-series PGs, where pro- and anti- inflammatory 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 COX enzyme. Predictions from our model suggest that the system undergoes a switch from a predominantly pro-inflammatory state in the control to an anti-inflammatory 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 pro- and anti-inflammatory metabolism in RAW 264.7 macrophages.