Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism

Abstract

Tryptophan is metabolized along the kynurenine and serotonin pathways, resulting in formation of kynurenine metabolites, neuroactive serotonin and melatonin. Each pathway is critical for maintaining healthy homeostasis. However, the two pathways are extremely unequal in their ability to degrade tryptophan, and little is known about the mechanisms maintaining the balance between them. Here, we demonstrated that in PC12 cells, a change of expression of key genes of one pathway resulted in a change of expression of key genes of the other. Melatonin, the end product of the serotonin pathway, played an important role in tryptophan metabolism by affecting both key enzymes of the two pathways. Melatonin treatment induced the expression of indole-2,3-dioxygenase 1 (IDO1) and enhanced the activity of the IDO1 promoter while decreasing the expression of arylalkylamine N-acetyl transferase. Melatonin treatment up-regulated the expression of forkhead box protein O1 (FoxO1) and enhanced the binding of FoxO1 to the IDO1 promoter. FoxO1 was shown to be a new regulator for IDO1 expression. Melatonin treatment decreased the phosphorylation of FoxO1 by extracellular signal-regulated kinases 1 and 2 and protein kinase B (Akt) and increased the phosphorylation of binding protein 14-3-3 by c-Jun N-terminal kinase (JNK), and thus the complex of FoxO1-14-3-3 in the cytoplasm was disassembled and FoxO1 was relocated to the nucleus to induce IDO1 expression. The JNK signaling pathway played an important role in melatonin-induced IDO1 up-regulation. In conclusion, this study suggests a link between melatonin, JNK, FoxO1 and IDO1 that acts as a potential balance regulator of tryptophan metabolism, and offers a new approach to treat diseases related to dysregulation of tryptophan metabolism.

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“…This may also imply decreased melatonin levels which are associated with circadian malfunctioning and can increase the risk of mood disorders (Quera-Salva et al, 2011). Interestingly, melatonin appears to promote the expression of IDO, suggesting a negative feedback loop through which melatonin regulates the balance between kynurenine and 5-HT pathways (Li et al, 2017).…”

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“…It plays an important role in tryptophan metabolism by affecting both key enzymes of the two pathways. In particular, it has been demonstrated that melatonin treatment induces the expression of indole-2,3-dioxygenase 1 (IDO1) and enhances the activity of the IDO1 promoter while decreasing the expression of arylalkyl amine N-acetyl-transaminase (AANAT), the enzyme responsible for 5-HT catabolism [ 140 ].…”

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“…Serotonin [5-hydroxytryptamine (5-HT)] synthesis is one of the most important Trp pathways(107). Note that 3% of dietary Trp is used for 5-HT synthesis throughout the body, while only 1% of dietary Trp is used for 5-HT synthesis in the brain(108), where Trp is primarily involved in melatonin synthesis(Figure 2)(109).…”