Engineering microbial platforms for diversified biosynthesis of antidepressant tryptophan-derived neuroactive compounds.

Tryptophan-drived neuroactive compounds, including serotonin, melatonin, 5-hydroxytryptophan (5-HTP), psilocybin, and related indole derivatives, represent an important class of therapeutics for depression and other neuropsychiatric disorders. However, conventional production through chemical synthesis or natural extraction remains limited by low sustainability, poor selectivity, and high manufacturing costs. Advances in synthetic biology, metabolic engineering, and enzyme engineering have enabled the development of microbial cell factories for the efficient biosynthesis of these high-value compounds. This Review highlights recent progress in engineering microbial platforms for antidepressant tryptophan derivatives, focusing on tryptophan overproduction, hydroxylation biocatalysts, downstream biosynthetic pathways, and cofactor engineering. We further discuss the emerging roles of bacterial heme-dependent tryptophan hydroxylases and AI-assisted enzyme and pathway engineering in expanding the biosynthetic toolbox. Finally, we outline current challenges and future opportunities for integrating intelligent strain design with advanced bioprocess engineering to advance the biomanufacturing of tryptophan-derived neuroactives.