Orchestrating Physiological Homeostasis: The Spatial and Cellular Heterogeneity of Tryptophan Transport and Metabolism

In addition to being incorporated into proteins, tryptophan (Trp) is increasingly recognized as a critical metabolic hub orchestrating systemic physiological homeostasis through interactions among the digestive, nervous and immune systems. This review systematically delineates the latest advancements in the molecular mechanisms governing the spatial and cellular heterogeneity of Trp transport. We summarize the sophisticated transmembrane machinery of Trp transport in intestinal epithelial cells, including angiotensin-converting enzyme 2-dependent broad neutral amino acid transporter 1 complex in absorptive enterocytes and L-type amino acid transporter 1/alanine, serine, cysteine transporter 2-mediated uptake in secretory enterochromaffin cells. Additionally, the albumin-binding dynamics of Trp in tryptophan 2,3-dioxygenase-mediated hepatic first-pass gating and its metabolic shunting to peripheral tissues are also discussed in this review. By bridging micro-level transport mechanisms with macro-level physiological regulation, this review provides a comprehensive framework for understanding the pleiotropic functions of Trp and identifies transporter-enzyme coupling as a potential target for therapeutic intervention in metabolic disorders, neurodegenerative diseases, and immune dysfunction.