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Metabolites
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Effect of Tryptophan Metabolism on Neuropsychiatry and Cancer Immunotherapy
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Effect of Tryptophan Metabolism on Neuropsychiatry and Cancer Immunotherapy

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (1 February 2023) | Viewed by 14154

Special Issue Editor

Dr. Ian Davis

E-Mail Website
Guest Editor
Department of Chemistry, The University of Texas at San Antonio, San Antonio, TX 78249, USA
Interests: metalloenzymology; enzyme mechanisms; structure–function relationship; tryptophan metabolism; EPR spectroscopy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The metabolism of amino acids, especially tryptophan, produces various metabolites that affect human health. Serotonin and melatonin are involved in regulating mood and sleep, and many intermediates of the kynurenine pathway have neuroprotective or neurodegenerative effects. The kynurenine pathway provides the precursor for NAD biosynthesis, is a key regulator of the immune system, and is hijacked by many cancers to evade the innate immune response. The aim of this Special Issue is to highlight how the metabolic pathways for tryptophan affect disease states related to neuropsychiatry and immunotherapy for treating cancer. Specific areas include, but are not limited to, the identification or detection of biomarkers, mechanistic studies of metabolic enzymes, the effects of metabolites or enzyme expression on cells, tissues, or organisms, and bioinformatics.

Dr. Ian Davis
Guest Editor

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Keywords

  • kynurenine pathway
  • depression
  • immune suppression
  • NAD biosynthesis
  • oxidative stress

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Published Papers (5 papers)

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Research

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11 pages, 791 KiB  
Article
Investigation of Genetic Variants Associated with Tryptophan Metabolite Levels via Serotonin and Kynurenine Pathways in Patients with Bipolar Disorder
by Claudia Pisanu, Alessio Squassina, Pasquale Paribello, Stefano Dall’Acqua, Stefania Sut, Sofia Nasini, Antonella Bertazzo, Donatella Congiu, Anna Meloni, Mario Garzilli, Beatrice Guiso, Federico Suprani, Vittoria Pulcinelli, Maria Novella Iaselli, Ilaria Pinna, Giulia Somaini, Laura Arru, Carolina Corrias, Federica Pinna, Bernardo Carpiniello, Stefano Comai and Mirko Manchiaadd Show full author list remove Hide full author list
Metabolites 2022, 12(11), 1127; https://doi.org/10.3390/metabo12111127 - 17 Nov 2022
Cited by 4 | Viewed by 2139
Abstract
The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine [...] Read more.
The kynurenine pathway (KP) may play a role in the pathophysiology of bipolar disorder (BD). We conducted a genome-wide association study (GWAS) to identify genetic variants associated with the plasma levels of the metabolites of tryptophan (TRP) via the serotonin (5-HT) and kynurenine (KYN) pathways in 44 patients with BD and 45 healthy controls. We assessed whether variants that were differentially associated with metabolite levels based on the diagnostic status improved the prediction accuracy of BD using penalized regression approaches. We identified several genetic variants that were significantly associated with metabolites (5-HT, 5-hydroxytryptophan (5-HTP), TRP, and quinolinic acid (QA) or metabolite ratios (5-HTP/TRP and KYN/TRP) and for which the diagnostic status exerted a significant effect. The inclusion of genetic variants led to increased accuracy in the prediction of the BD diagnostic status. Specifically, we obtained an accuracy of 0.77 using Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictors retained as informative in this model included body mass index (BMI), the levels of TRP, QA, and 5-HT, the 5-HTP/TRP ratio, and genetic variants associated with the levels of QA (rs6827515, rs715692, rs425094, rs4645874, and rs77048355) and TRP (rs292212) or the 5-HTP/TRP ratio (rs7902231). In conclusion, our study identified statistically significant associations between metabolites of TRP via the 5-HT and KYN pathways and genetic variants at the genome-wide level. The discriminative performance of penalized regression models incorporating clinical, genetic, and metabolic predictors warrants a follow-up analysis of this panel of determinants. Full article
(This article belongs to the Special Issue Effect of Tryptophan Metabolism on Neuropsychiatry and Cancer Immunotherapy)
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16 pages, 2323 KiB  
Article
Bioinformatic Analysis of Kynurenine Pathway Enzymes and Their Relationship with Glioma Hallmarks
by Gustavo Ignacio Vázquez Cervantes, Javier Ángel Navarro Cossio, Gonzalo Pérez de la Cruz, Aleli Salazar, Verónica Pérez de la Cruz and Benjamin Pineda
Metabolites 2022, 12(11), 1054; https://doi.org/10.3390/metabo12111054 - 2 Nov 2022
Cited by 2 | Viewed by 1837
Abstract
Indoleamine dioxygenase (IDO), a rate limiting enzyme of the tryptophan catabolism through the kynurenine pathway (KP), has been related with a lower survival and a poor patient prognosis on several solid tumors, including gliomas. However, the use of IDO inhibitors as a therapeutic [...] Read more.
Indoleamine dioxygenase (IDO), a rate limiting enzyme of the tryptophan catabolism through the kynurenine pathway (KP), has been related with a lower survival and a poor patient prognosis on several solid tumors, including gliomas. However, the use of IDO inhibitors as a therapeutic strategy for tumor treatment remains controversial in clinical trials and the role of other KP enzymes on tumor progression has remained poorly understood so far. Recently, different studies on different types of cancer have pointed out the importance of KP enzymes downstream IDO. Because of this, we conducted a bioinformatic analysis of the expression of different KP enzymes and their correlation with the gene expression of molecules related to the hallmarks of cancer in transcriptomic datasets from patients with different types of brain tumors including low grade gliomas, glioblastoma multiforme, neuroblastoma, and paraganglioma and pheochromocytoma. We found that KP enzymes that drive to NAD+ synthesis are overexpressed on different brain tumors compared to brain cortex data. Moreover, these enzymes presented positive correlations with the expression of genes related to immune response modulation, angiogenesis, Signal Transducer and Activator of Transcription (STAT) signaling, and Rho GTPase expression. These correlations suggest the relevance of the expression of the KP enzymes in brain tumor pathogenesis. Full article
(This article belongs to the Special Issue Effect of Tryptophan Metabolism on Neuropsychiatry and Cancer Immunotherapy)
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Review

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16 pages, 1989 KiB  
Review
The Engagement of Cytochrome P450 Enzymes in Tryptophan Metabolism
by Anna Haduch, Ewa Bromek, Wojciech Kuban and Władysława Anna Daniel
Metabolites 2023, 13(5), 629; https://doi.org/10.3390/metabo13050629 - 5 May 2023
Cited by 11 | Viewed by 4078
Abstract
Tryptophan is metabolized along three main metabolic pathways, namely the kynurenine, serotonin and indole pathways. The majority of tryptophan is transformed via the kynurenine pathway, catalyzed by tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase, leading to neuroprotective kynurenic acid or neurotoxic quinolinic acid. Serotonin synthesized by tryptophan [...] Read more.
Tryptophan is metabolized along three main metabolic pathways, namely the kynurenine, serotonin and indole pathways. The majority of tryptophan is transformed via the kynurenine pathway, catalyzed by tryptophan-2,3-dioxygenase or indoleamine-2,3-dioxygenase, leading to neuroprotective kynurenic acid or neurotoxic quinolinic acid. Serotonin synthesized by tryptophan hydroxylase, and aromatic L-amino acid decarboxylase enters the metabolic cycle: serotonin → N-acetylserotonin → melatonin → 5-methoxytryptamine→serotonin. Recent studies indicate that serotonin can also be synthesized by cytochrome P450 (CYP), via the CYP2D6-mediated 5-methoxytryptamine O-demethylation, while melatonin is catabolized by CYP1A2, CYP1A1 and CYP1B1 via aromatic 6-hydroxylation and by CYP2C19 and CYP1A2 via O-demethylation. In gut microbes, tryptophan is metabolized to indole and indole derivatives. Some of those metabolites act as activators or inhibitors of the aryl hydrocarbon receptor, thus regulating the expression of CYP1 family enzymes, xenobiotic metabolism and tumorigenesis. The indole formed in this way is further oxidized to indoxyl and indigoid pigments by CYP2A6, CYP2C19 and CYP2E1. The products of gut-microbial tryptophan metabolism can also inhibit the steroid-hormone-synthesizing CYP11A1. In plants, CYP79B2 and CYP79B3 were found to catalyze N-hydroxylation of tryptophan to form indole-3-acetaldoxime while CYP83B1 was reported to form indole-3-acetaldoxime N-oxide in the biosynthetic pathway of indole glucosinolates, considered to be defense compounds and intermediates in the biosynthesis of phytohormones. Thus, cytochrome P450 is engaged in the metabolism of tryptophan and its indole derivatives in humans, animals, plants and microbes, producing biologically active metabolites which exert positive or negative actions on living organisms. Some tryptophan-derived metabolites may influence cytochrome P450 expression, affecting cellular homeostasis and xenobiotic metabolism. Full article
(This article belongs to the Special Issue Effect of Tryptophan Metabolism on Neuropsychiatry and Cancer Immunotherapy)
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11 pages, 674 KiB  
Review
The Role of Kynurenine and Its Metabolites in Comorbid Chronic Pain and Depression
by Onella Athnaiel, Charmaine Ong and Nebojsa Nick Knezevic
Metabolites 2022, 12(10), 950; https://doi.org/10.3390/metabo12100950 - 6 Oct 2022
Cited by 9 | Viewed by 2535
Abstract
Chronic pain and depression affect millions of people worldwide, and their comorbidity tends to exacerbate the severity of each individual condition. Intersecting brain regions and molecular pathways could probably explain the unique yet complex bidirectional relationship between these two disorders. Recent studies have [...] Read more.
Chronic pain and depression affect millions of people worldwide, and their comorbidity tends to exacerbate the severity of each individual condition. Intersecting brain regions and molecular pathways could probably explain the unique yet complex bidirectional relationship between these two disorders. Recent studies have found that inflammatory reactions, frequently identified in both chronic pain and depression, stimulate certain enzymes in the kynurenine pathway, while concurrently suppressing others. Kynurenine, a major tryptophan derivative, and its metabolites have been implicated in several inflammation-associated pain syndromes and depressive mood disorders. Due to inflammation, 95% of tryptophan is metabolized via the kynurenine pathway, which drives the reaction towards the production of metabolites that have distinct roles in the pathophysiology of these disorders. Diminished levels of the neuroprotective metabolite, kynurenic acid (KYNA), and elevated levels of the neurotoxic metabolite, quinolinic acid (QUIN), have been frequently identified in human patients formally diagnosed with these disorders, as well as animal models commonly used in medical research. This review not only explores the epidemiology of comorbid chronic pain and depression, but also highlights the involvement of kynurenine and its metabolites, specifically KYNA and QUIN, in these pervasive conditions. Full article
(This article belongs to the Special Issue Effect of Tryptophan Metabolism on Neuropsychiatry and Cancer Immunotherapy)
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Other

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13 pages, 3881 KiB  
Hypothesis
Kynurenine Pathway Regulation at Its Critical Junctions with Fluctuation of Tryptophan
by Ashley Newton, Luree McCann, Lu Huo and Aimin Liu
Metabolites 2023, 13(4), 500; https://doi.org/10.3390/metabo13040500 - 30 Mar 2023
Cited by 3 | Viewed by 2443
Abstract
The kynurenine pathway (KP) is the primary route for the catabolism of the essential amino acid tryptophan. The central KP metabolites are neurologically active molecules or biosynthetic precursors to critical molecules, such as NAD+. Within this pathway are three enzymes of [...] Read more.
The kynurenine pathway (KP) is the primary route for the catabolism of the essential amino acid tryptophan. The central KP metabolites are neurologically active molecules or biosynthetic precursors to critical molecules, such as NAD+. Within this pathway are three enzymes of interest, HAO, ACMSD, and AMSDH, whose substrates and/or products can spontaneously cyclize to form side products such as quinolinic acid (QA or QUIN) and picolinic acid. Due to their unstable nature for spontaneous autocyclization, it might be expected that the levels of these side products would be dependent on tryptophan intake; however, this is not the case in healthy individuals. On top of that, the regulatory mechanisms of the KP remain unknown, even after a deeper understanding of the structure and mechanism of the enzymes that handle these unstable KP metabolic intermediates. Thus, the question arises, how do these enzymes compete with the autocyclization of their substrates, especially amidst increased tryptophan levels? Here, we propose the formation of a transient enzyme complex as a regulatory mechanism for metabolite distribution between enzymatic and non-enzymatic routes during periods of increased metabolic intake. Amid high levels of tryptophan, HAO, ACMSD, and AMSDH may bind together, forming a tunnel to shuttle the metabolites through each enzyme, consequently regulating the autocyclization of their products. Though further research is required to establish the formation of transient complexation as a solution to the regulatory mysteries of the KP, our docking model studies support this new hypothesis. Full article
(This article belongs to the Special Issue Effect of Tryptophan Metabolism on Neuropsychiatry and Cancer Immunotherapy)
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