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Tryptophan Metabolism in Health and Disease: Insights from Metabolomics

Tryptophan metabolism is a fundamental pathway in plants and animals. Tryptophan is an essential amino acid that is an important precursor for a variety of biomolecules, including neurotransmitters, hormones and proteins. Its metabolism leads to the production of a variety of metabolites, including kynurenine, 5-hydroxytryptamine and melatonin, which play key roles in a variety of physiological and pathophysiological processes, including neuronal function, immunity, aging and disease. Metabolomics is an analytical method that allows comprehensive analysis of small molecules in biological samples (e.g. blood or urine) to provide a snapshot of the metabolic state of an organism. It is a powerful tool for identifying metabolic pathways that are disturbed in disease, as well as for discovering potential biomarkers and therapeutic targets. It has been widely used to study changes in the levels of tryptophan and its metabolites in various diseases.

Case 1. Tryptophan metabolism changes in patients with Major Depressive Disorder (MDD) ⁽¹⁾

Tryptophan metabolism is a common metabolic pathway studied in the field of basic metabolism, but tryptophan and its metabolites play key roles in neuronal function, immunity, aging and other physiological processes, and are versatile therapeutic targets for cancer, neurodegeneration and a variety of other diseases.

Researchers first screened study cohorts that met the inclusion requirements. Forty-six eligible published data were screened from PubMed, Cochrane Library, Embase, Web of Science and MENDA databases for Meta-analysis.

Subsequently, peripheral blood differential metabolites were analyzed in depressed patients and controls. 23 were significantly different between the MDD and control groups, such as high expression of metabolites such as phosphatidylcholine (32:1) and low expression of tryptophan, kynurenine, taurine and 25-hydroxyvitamin D in MDD patients. Creatinine, tryptophan, kynurenic acid, leucine, uronic acid, taurine and histidine levels were lower in MDD patients not taking antidepressants (AF-MDD) compared to controls. Patients with MDD treated with antidepressants (AT-MDD) had lower levels of glycine, hypoxanthine, kynurenine quinolinic acid, asparagine, glutamine, serine, and tryptophan. The results showed a sustained downregulation of L-tryptophan and kynurenine quinolinic acid, independent of the presence or absence of antidepressants. Disease severity was significantly negatively correlated with L-tryptophan, suggesting that patients with higher depression scores may have lower L-tryptophan levels.

A simplified schematic diagram of the altered metabolic pathways in the blood of patients with MDD ⁽¹⁾

Finally, the differential metabolites of the three groups (MDD, AF-MDD and AT-MDD) were analyzed in raw letter. This study systematically reveals metabolic changes in peripheral blood (serum or plasma samples) associated with MDD, particularly a decrease in tryptophan and kynurenine acid, as well as alterations in tryptophan-kynurenine and fatty acid metabolic pathways. This study contributes to the development of biomarkers and the elucidation of the molecular mechanisms of MDD.

Case 2. Tryptophan metabolism regulates iron death plasticity in tumor cells ⁽²⁾

Methionine is converted to cysteine via transamination to protect tumors from iron death, but whether other amino acids can regulate iron death independently of the cysteine pathway remains largely unknown. Tryptophan metabolism has two pathways, the serotonin pathway and the kynurenine pathway, which produce two metabolites, serotonin (5-HT) and 3-hydroxy-o-aminobenzoic acid (3-HA), respectively. Both 5-HT and 3-HA are potential free radical-trapping antioxidants that reduce lipid peroxidation by trapping free radicals, thereby inhibiting cellular iron death. Monoamine oxidase (MAOA) can greatly abrogate the protective effect of 5-HT by reducing 5-HT. MAOA deficiency can confer tolerance to iron death in cancer cells. Kynurenine enzyme (KYNU) plays a key role in 3-HA production, while 3-hydroxy-o-aminobenzoate 3,4-dioxygenase (HAAO) eliminates its mediated iron death resistance by degrading 3-HA. expression of HAAO positively correlates with lipid peroxidation and clinical regression. Studies suggest that tryptophan metabolites promote tumor cell growth through the iron death resistance pathway, and targeting this pathway will hopefully be a new cancer treatment.

Identification and validation of tryptophan metabolites as potent ferroptosis inhibitor ⁽²⁾.

References

Pu, Juncai, et al. "An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder." Molecular psychiatry 26.8 (2021): 4265-4276.
Liu, Dong, et al. "Tryptophan Metabolism Acts as a New Anti‐Ferroptotic Pathway to Mediate Tumor Growth." Advanced Science (2023): 2204006.

* For Research Use Only. Not for use in diagnostic procedures.

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