Tryptophan Metabolism: Implications in Health, Disease, and Cancer

What is Tryptophan (Trp)?

Tryptophan (Trp) is the only amino acid that contains an indole structure. It is an essential amino acid, meaning it can only be obtained through diet, and it predominantly exists in the L-form in both human and animal bodies. Tryptophan is absorbed from food through the intestinal epithelium and then enters the bloodstream. Most of the Trp in the blood is bound to albumin, with a small amount remaining in a free state. It plays a crucial role in protein biosynthesis and serves as a precursor for the synthesis of various important bioactive compounds.

The level of tryptophan in the human body depends on dietary intake and the activity of several tryptophan metabolic pathways. Tryptophan metabolism primarily involves three pathways: the kynurenine (Kyn) pathway, the serotonin (5-HT) pathway (or serotonin pathway), and the indole pathway.

What is Tryptophan (Trp) Metabolism?

Tryptophan (Trp) metabolism primarily involves the kynurenine pathway, serotonin (5-HT) pathway, and the indole pathway. Various bioactive compounds produced through tryptophan metabolism can regulate multiple physiological functions, including inflammation, metabolism, immune response, and neural functions. Emerging evidence supports a close relationship between disruptions in tryptophan (Trp) metabolism and various diseases. The levels or ratios of tryptophan metabolism products are significantly correlated with many clinical features. Additionally, research suggests that disease progression can be controlled by modulating tryptophan metabolism. Indoleamine-2,3-dioxygenase, tryptophan-2,3-dioxygenase, kynurenine-3-monooxygenase, and tryptophan hydroxylase are crucial rate-limiting enzymes in tryptophan metabolism. Targeting these key regulatory enzymes holds potential for treating various diseases, including tumors, providing new insights into disease treatment.

Tryptophan (Trp) Metabolism: Three Key Pathways

(1) Kynurenine Pathway

The Kynurenine (Kyn) pathway is the major metabolic pathway, primarily occurring in the liver. Through this pathway, over 95% of tryptophan is degraded into various bioactive compounds. Key rate-limiting enzymes include tryptophan-2,3-dioxygenase (TDO), indoleamine-2,3-dioxygenase 1 (IDO1), and IDO2. This pathway is involved in inflammation, immune response, and excitatory neurotransmission. Metabolites include kynurenine, quinolinic acid, quinolinic acid, picolinic acid, cinnabarinic acid, and xanthurenic acid.

(2) 5-HT Pathway

Tryptophan is converted to serotonin (5-HT) through the 5-HT pathway by the action of various enzymes. 5-HT, also known as serotonin, is a monoamine neurotransmitter in the human central nervous system. When present in the bloodstream, 5-HT causes smooth muscle contraction. 5-HT can further be converted to 5-HIAA, another important monoamine neurotransmitter that regulates mood and anxiety behavior. 5-HT can also be further converted to melatonin, thereby regulating the sleep-wake cycle. Metabolites include serotonin, 5-hydroxytryptophan, N-acetyl-5-hydroxytryptamine, melatonin, and others.

(3) Indole Pathway

Tryptophan, under the influence of intestinal microbiota, can be converted into indole substances such as indole propionic acid, indole-3-acetic acid (IAA), indole-3-propionic acid (IPA), indole-3-acetaldehyde (3-IAld), and skatole. Bacteria involved mainly include anaerobic bacteria, Bacteroides, Clostridium, and bifidobacteria. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that can be activated by indole, indole derivatives, and kynurenine. Activated AhR is involved in immune regulation and various cellular processes. Activated AhR can promote the release of cytokines, including IL-6, IL-17, and IL-22, thereby regulating intestinal homeostasis.

Tryptophan catabolism, key therapeutic targets and drugs in development (Platten et al., 2019).

Tryptophan in Health and Disease

Disruptions in tryptophan (Trp) metabolism can lead to various diseases in the digestive, nervous, respiratory, and blood systems. The levels of tryptophan in tumor cells are significantly elevated, while certain cancers, such as gliomas, colorectal cancer, lung cancer, and hematologic malignancies, exhibit lower Trp levels. The levels of tryptophan metabolites are closely associated with clinical features of multiple diseases, including those affecting the digestive system, nervous system, and cancer-related disorders.

Digestive System Diseases:

Inflammatory Bowel Disease (IBD): Changes in Trp and its metabolites are closely related to clinical features, disease activity, and inflammation severity in IBD. Metabolites from the Kyn pathway regulate the progression of IBD by activating Aryl hydrocarbon receptor (AhR). Compounds like kynurenic acid (KYNA) and xanthurenic acid (XA) promote the proliferation of intestinal epithelial cells (IECs) through AhR interaction and increased IL-22 levels. KYNA and XA also improve mitochondrial respiration in IECs and glycolysis in T cells, thereby alleviating intestinal inflammation. Intestinal microbiota play a crucial role in IBD development through interaction with Trp metabolites.

Nervous System Diseases:

Depression: The serotonin (5-HT) pathway is involved in the development of depression, with significantly lower Trp and 5-HT levels in the plasma of severe depression patients. Supplementing with tryptophan in mouse models downregulates levels of TNF-α, IL-6, IL-1b, and TLR-4, reducing neuroinflammation. Inhibition of indoleamine-2,3-dioxygenase (IDO) improves depression-like behavior in diabetic mice, suggesting IDO as a potential therapeutic target for depression.

Alzheimer's Disease (AD): AD is associated with the deposition of beta-amyloid (Aβ). AD patients show lower levels of Trp, KYNA, and 5-HT in plasma, and higher levels of IDO-1, quinolinic acid (QA), tryptophan-2,3-dioxygenase (TDO), and 3-hydroxykynurenine (3-HKYN). Trp metabolism is related to the decrease in Aβ1-42 levels and the increase in tau protein levels. QA displays neurotoxic potential in the development of various nervous system disorders.

Cancer:

Liver Cancer: Expression of IDO, TDO, kynurenine monooxygenase (KMO), and 5-HT1D is associated with poor prognosis in hepatocellular carcinoma (HCC) patients. TDO2 increases Kyn levels, activating AhR in HCC. AhR activation stimulates tumor cell proliferation and epithelial-mesenchymal transition via STAT3 and NF-kB/TIM4 pathways. Knockdown of TDO2 inhibits migration and invasion capabilities of HCC cells. Exogenous 3-hydroxyanthranilic acid (3-HAA) induces apoptosis by binding to Yin Yang 1 (YY1) in HCC cells.

List of Metabolites Associated with Disease

Reference

1. Platten, Michael, et al. "Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond." Nature reviews Drug discovery 18.5 (2019): 379-401.

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