Model of Tryptophan Metabolism, Readily Scalable Using Tissue-specific Gene Expression Data

Background: Changes in tryptophan metabolism are associated with various diseases. Results: A comprehensive model of human tryptophan metabolism was constructed and verified with existing experimental data. Conclusion: The subtle balance of tryptophan derivatives required for proper brain function is sensitive to alterations in peripheral tissues. Significance: The model is applicable as a diagnostic tool to study disease related changes in tryptophan metabolism. Tryptophan is utilized in various metabolic routes including protein synthesis, serotonin, and melatonin synthesis and the kynurenine pathway. Perturbations in these pathways have been associated with neurodegenerative diseases and cancer. Here we present a comprehensive kinetic model of the complex network of human tryptophan metabolism based upon existing kinetic data for all enzymatic conversions and transporters. By integrating tissue-specific expression data, modeling tryptophan metabolism in liver and brain returned intermediate metabolite concentrations in the physiological range. Sensitivity and metabolic control analyses identified expected key enzymes to govern fluxes in the branches of the network. Combining tissue-specific models revealed a considerable impact of the kynurenine pathway in liver on the concentrations of neuroactive derivatives in the brain. Moreover, using expression data from a cancer study predicted metabolite changes that resembled the experimental observations. We conclude that the combination of the kinetic model with expression data represents a powerful diagnostic tool to predict alterations in tryptophan metabolism. The model is readily scalable to include more tissues, thereby enabling assessment of organismal tryptophan metabolism in health and disease.