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Tryptophan Metabolism as the Therapeutic and Biomarker Target
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Tryptophan Metabolism as the Therapeutic and Biomarker Target

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (24 March 2023) | Viewed by 20818

Special Issue Editor

Dr. Magdalena Staniszewska

E-Mail Website
Guest Editor
Laboratory of Separation and Spectroscopic Method Applications, Centre for Interdisciplinary Research, The John Paul II Catholic University of Lublin, 1J Konstantynów Str., 20-708 Lublin, Poland
Interests: kynurenine pathway; tryptophan metabolites; indoleamine-2,3-dioxygenase; tryptophan-2,3-dioxygenase; immune regulation; cancer development and biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tryptophan (Trp) metabolism has obtained great interest due to its wide involvement in the regulation of immune response and mechanisms of several diseases. The process is associated with immune regulation, cancer, neuropsychology, and maternal tolerance during fetus implantation.

Tryptophan is an essential amino acid serving as a building block in protein structures. On the other hand, the remaining majority of Trp is catabolized along four pathways of which the kynurenine pathway (KP) converts most of the available free L-tryptophan. The kynurenine pathway is a source of several biomolecules and is initiated by hepatic tryptophan-2-3-dioxygenase enzyme or the tissues-specific counterparts (indoleamine-2-3-dioxygenases). Several other KP enzymes contribute to generation of biologically relevant metabolites collectively called “kynurenines”, finally leading to NAD+ production. Some of the molecules generated through KP show cytotoxic properties (kynurenine, 3-hydroxykynurenie), while others (kynurenic acid) are associated with positive effects. The other pathways of tryptophan metabolism in human organism generate serotonin, 5-hydroxytryptamine, and melatonin that play important role in nervous system homeostasis and contribute to neuropsychological effects. 

KP enzymes present attractive pharmacological targets for developing inhibitors to control cancer, immune, and psychiatric diseases and modulate homeostasis. Learning about accumulation of Trp metabolites can result in the useful biomarker tools for monitoring of disease progression. The presented Pharmaceuticals Special Issue aims to collect recent scientific achievements in development of novel pharmaceuticals aimed as inhibitors of KP enzymes, encompassing issues with inhibitor synthesis, pharmacology, and biological properties. The other welcomed aspects include the bioavailability of Trp metabolites, enzyme regulation and activity, association of Trp metabolites with cancer progression, immune regulation, and psychiatric disfunctions as well as developments in analytical methods for determination of Trp metabolites

Dr. Magdalena Staniszewska
Guest Editor

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Keywords

  • Kynureninepathway
  • tryptophanmetabolites
  • kynurenine
  • indoleamine-2,3-dioxygenase
  • tryptophan-2,3-dioxygenase
  • immune suppression
  • cancer microenvironment
  • analysis of pharmaceuticals
  • determination of tryptophan metabolites
  • analysis of biological fluids
  • metabolic biomarkers

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Published Papers (7 papers)

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Research

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29 pages, 4578 KiB  
Article
Brain Kynurenine Pathway Metabolite Levels May Reflect Extent of Neuroinflammation in ALS, FTD and Early Onset AD
by Annelies Heylen, Yannick Vermeiren, Ido P. Kema, Martijn van Faassen, Claude van der Ley, Debby Van Dam and Peter P. De Deyn
Pharmaceuticals 2023, 16(4), 615; https://doi.org/10.3390/ph16040615 - 19 Apr 2023
Cited by 1 | Viewed by 2397
Abstract
Objectives: Despite distinct clinical profiles, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients share a remarkable portion of pathological features, with a substantial percentage of patients displaying a mixed disease phenotype. Kynurenine metabolism seems to play a role in dementia-associated neuroinflammation and [...] Read more.
Objectives: Despite distinct clinical profiles, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients share a remarkable portion of pathological features, with a substantial percentage of patients displaying a mixed disease phenotype. Kynurenine metabolism seems to play a role in dementia-associated neuroinflammation and has been linked to both diseases. We aimed to explore dissimilarities in kynurenine pathway metabolites in these early onset neurodegenerative disorders in a brain-region-specific manner. Methods: Using liquid chromatography mass spectrometry (LC-MS/MS), kynurenine metabolite levels were determined in the brain samples of 98 healthy control subjects (n = 20) and patients with early onset Alzheimer’s disease (EOAD) (n = 23), ALS (n = 20), FTD (n = 24) or a mixed FTD–ALS (n = 11) disease profile. Results: Overall, the kynurenine pathway metabolite levels were significantly lower in patients with ALS compared to FTD, EOAD and control subjects in the frontal cortex, substantia nigra, hippocampus and neostriatum. Anthranilic acid levels and kynurenine-to-tryptophan ratios were consistently lower in all investigated brain regions in ALS compared to the other diagnostic groups. Conclusions: These results suggest that the contribution of kynurenine metabolism in neuroinflammation is lower in ALS than in FTD or EOAD and may also be traced back to differences in the age of onset between these disorders. Further research is necessary to confirm the potential of the kynurenine system as a therapeutic target in these early onset neurodegenerative disorders. Full article
(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)
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10 pages, 256 KiB  
Article
The Kynurenine Pathway in Healthy Subjects and Subjects with Obesity, Depression and Chronic Obstructive Pulmonary Disease
by Per G. Farup, Håvard Hamarsland, Knut Sindre Mølmen, Stian Ellefsen and Knut Hestad
Pharmaceuticals 2023, 16(3), 351; https://doi.org/10.3390/ph16030351 - 25 Feb 2023
Cited by 7 | Viewed by 3052
Abstract
Background: Changes in tryptophan metabolism through the kynurenine pathway (KP) are observed in several disorders and coupled with pathophysiological deviations. Methods: This study retrospectively compared the KP in serum in healthy subjects (108) with subjects with obesity (141), depression (49), and chronic obstructive [...] Read more.
Background: Changes in tryptophan metabolism through the kynurenine pathway (KP) are observed in several disorders and coupled with pathophysiological deviations. Methods: This study retrospectively compared the KP in serum in healthy subjects (108) with subjects with obesity (141), depression (49), and chronic obstructive pulmonary disease (COPD) (22) participating in four clinical studies and explored predictors of the changes in the KP metabolites. Results: Compared with the healthy group, the KP was upregulated in the disease groups with high kynurenine, quinolinic acid (QA), kynurenine/tryptophan-ratio and QA/xanthurenic acid-ratio and low kynurenic acid/QA-ratio. Tryptophan and xanthurenic acid were upregulated in the depressed group compared with the groups with obesity and COPD. The covariates BMI, smoking, diabetes, and C-reactive protein explained the significant differences between the healthy group and the group with obesity but not between the healthy group and the groups with depression and COPD, indicating that different pathophysiological conditions result in the same changes in the KP. Conclusions: The KP was significantly upregulated in the disease groups compared with the healthy group, and there were significant differences between the disease groups. Different pathophysiological abnormalities seemed to result in the same deviations in the KP. Full article
(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)
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9 pages, 956 KiB  
Article
The Influence of Exercise Intensity on Tryptophan Metabolites in Thoroughbred Horses
by Magdalena Staniszewska, Sylwester Kowalik, Ilona Sadok and Witold Kędzierski
Pharmaceuticals 2023, 16(1), 107; https://doi.org/10.3390/ph16010107 - 11 Jan 2023
Cited by 2 | Viewed by 1989
Abstract
Catabolism of tryptophan (Trp) is modulated by physical activity and provides a pool of active compounds: Trp is considered a calmative agent, kynurenine (Kyn) and 3-hydroxykynurenine (3-HKyn) show neurotoxic effects, kynurenic acid (Kyna) and xanthurenic acid (XA) have neuroprotective properties like nicotinamide (NAm), [...] Read more.
Catabolism of tryptophan (Trp) is modulated by physical activity and provides a pool of active compounds: Trp is considered a calmative agent, kynurenine (Kyn) and 3-hydroxykynurenine (3-HKyn) show neurotoxic effects, kynurenic acid (Kyna) and xanthurenic acid (XA) have neuroprotective properties like nicotinamide (NAm), while serotonin is the neurotransmitter. The study was conducted to investigate the dependence of exercise intensity, measured by plasma lactic acid (LA) concentration, on the level of Trp, its catabolites (serotonin, Kyn, 3-HKyn, Kyna and XA), and NAm in Thoroughbred horses. A total of 18 young race Thoroughbred horses were investigated during exercise tests. Blood samples for analysis were collected: at rest, 10 min after the end of the exercise, and 60 min after the end of the exercise. Plasma LA was determined by the enzymatic method, Trp, and other metabolites using liquid chromatography coupled with mass spectrometry. In horses performing intense exercise, the concentration of LA, Kyn, XA and NAm was increased, while Trp was decreased. Significant correlations were detected for exercise-induced increase in LA and 3-HKyn, XA, and NAm. Considering the scope of changes in analyzed data, there is an expected neutral effect on the health status of exercised horses. Full article
(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)
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19 pages, 10795 KiB  
Article
Evaluation of Novel Inhibitors of Tryptophan Dioxygenases for Enzyme and Species Selectivity Using Engineered Tumour Cell Lines Expressing Either Murine or Human IDO1 or TDO2
by Sofian M Tijono, Brian D. Palmer, Petr Tomek, Jack U. Flanagan, Kimiora Henare, Swarna Gamage, Lukas Braun and Lai-Ming Ching
Pharmaceuticals 2022, 15(9), 1090; https://doi.org/10.3390/ph15091090 - 31 Aug 2022
Cited by 2 | Viewed by 2110
Abstract
Indoleamine 2, 3-dioxygenase 1 (IDO1) is commonly expressed by cancers as a mechanism for evading the immune system. Preclinical and clinical studies have indicated the potential of combining IDO1 inhibitors with immune therapies for the treatment of cancer, strengthening an interest in the [...] Read more.
Indoleamine 2, 3-dioxygenase 1 (IDO1) is commonly expressed by cancers as a mechanism for evading the immune system. Preclinical and clinical studies have indicated the potential of combining IDO1 inhibitors with immune therapies for the treatment of cancer, strengthening an interest in the discovery of novel dioxygenase inhibitors for reversing tumour-mediated immune suppression. To facilitate the discovery, development and investigation of novel small molecule inhibitors of IDO1 and its hepatic isozyme tryptophan dioxygenase (TDO2), murine tumour cells were engineered to selectively express either murine or human IDO1 and TDO2 for use as tools to dissect both the species specificity and isoenzyme selectivity of newly discovered inhibitors. Lewis lung carcinoma (LLTC) lines were engineered to express either murine or human IDO1 for use to test species selectivity of the novel inhibitors; in addition, GL261 glioma lines were engineered to express either human IDO1 or human TDO2 and used to test the isoenzyme selectivity of individual inhibitors in cell-based assays. The 20 most potent inhibitors against recombinant human IDO1 enzyme, discovered from a commissioned screening of 40,000 compounds in the Australian WEHI compound library, returned comparable IC50 values against murine or human IDO1 in cell-based assays using the LLTC-mIDO1 and LLTC-hIDO1 line, respectively. To test the in vivo activity of the hits, transfected lines were inoculated into syngeneic C57Bl/6 mice. Individual LLTC-hIDO1 tumours showed variable expression of human IDO1 in contrast to GL261-hIDO1 tumours which were homogenous in their IDO1 expression and were subsequently used for in vivo studies. W-0019482, the most potent IDO1 inhibitor identified from cell-based assays, reduced plasma and intratumoural ratios of kynurenine to tryptophan (K:T) and delayed the growth of subcutaneous GL261-hIDO1 tumours in mice. Synthetic modification of W-0019482 generated analogues with dual IDO1/TDO2 inhibitory activity, as well as inhibitors that were selective for either TDO2 or IDO1. These results demonstrate the versatility of W-0019482 as a lead in generating all three subclasses of tryptophan dioxygenase inhibitors which can be applied for investigating the individual roles and interactions between IDO1 and TDO2 in driving cancer-mediated immune suppression. Full article
(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)
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13 pages, 1074 KiB  
Article
Tryptophan Challenge in Healthy Controls and People with Schizophrenia: Acute Effects on Plasma Levels of Kynurenine, Kynurenic Acid and 5-Hydroxyindoleacetic Acid
by Korrapati V. Sathyasaikumar, Francesca M. Notarangelo, Deanna L. Kelly, Laura M. Rowland, Stephanie M. Hare, Shuo Chen, Chen Mo, Robert W. Buchanan and Robert Schwarcz
Pharmaceuticals 2022, 15(8), 1003; https://doi.org/10.3390/ph15081003 - 15 Aug 2022
Cited by 9 | Viewed by 3778
Abstract
The pivotal tryptophan (TRP) metabolite kynurenine is converted to several neuroactive compounds, including kynurenic acid (KYNA), which is elevated in the brain and cerebrospinal fluid of people with schizophrenia (SZ) and may contribute to cognitive abnormalities in patients. A small proportion of TRP [...] Read more.
The pivotal tryptophan (TRP) metabolite kynurenine is converted to several neuroactive compounds, including kynurenic acid (KYNA), which is elevated in the brain and cerebrospinal fluid of people with schizophrenia (SZ) and may contribute to cognitive abnormalities in patients. A small proportion of TRP is metabolized to serotonin and further to 5-hydroxyindoleacetic acid (5-HIAA). Notably, KP metabolism is readily affected by immune stimulation. Here, we assessed the acute effects of an oral TRP challenge (6 g) on peripheral concentrations of kynurenine, KYNA and 5-HIAA, as well as the cytokines interferon-γ, TNF-α and interleukin-6, in 22 participants with SZ and 16 healthy controls (HCs) using a double-blind, placebo-controlled, crossover design. TRP raised the levels of kynurenine, KYNA and 5-HIAA in a time-dependent manner, causing >20-fold, >130-fold and 1.5-fold increases in kynurenine, KYNA and 5-HIAA concentrations, respectively, after 240 min. According to multivariate analyses, neither baseline levels nor the stimulating effects of TRP differed between participants with SZ and HC. Basal cytokine levels did not vary between groups, and remained unaffected by TRP. Although unlikely to be useful diagnostically, measurements of circulating metabolites following an acute TRP challenge may be informative for assessing the in vivo efficacy of drugs that modulate the neosynthesis of KYNA and other products of TRP degradation. Full article
(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)
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Review

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12 pages, 1158 KiB  
Review
Kynurenine Pathway Metabolites as Potential Biomarkers in Chronic Pain
by Andrew Auyeung, Hank C. Wang, Kannan Aravagiri and Nebojsa Nick Knezevic
Pharmaceuticals 2023, 16(5), 681; https://doi.org/10.3390/ph16050681 - 2 May 2023
Cited by 6 | Viewed by 2810
Abstract
Chronic pain is a pressing medical and socioeconomic issue worldwide. It is debilitating for individual patients and places a major burden on society in the forms of direct medical costs and lost work productivity. Various biochemical pathways have been explored to explain the [...] Read more.
Chronic pain is a pressing medical and socioeconomic issue worldwide. It is debilitating for individual patients and places a major burden on society in the forms of direct medical costs and lost work productivity. Various biochemical pathways have been explored to explain the pathophysiology of chronic pain in order to identify biomarkers that can potentially serve as both evaluators of and guides for therapeutic effectiveness. The kynurenine pathway has recently been a source of interest due to its suspected role in the development and sustainment of chronic pain conditions. The kynurenine pathway is the primary pathway responsible for the metabolization of tryptophan and generates nicotinamide adenine dinucleotide (NAD+), in addition to the metabolites kynurenine (KYN), kynurenic acid (KA), and quinolinic acid (QA). Dysregulation of this pathway and changes in the ratios of these metabolites have been associated with numerous neurotoxic and inflammatory states, many of which present simultaneously with chronic pain symptoms. While further studies utilizing biomarkers to elucidate the kynurenine pathway’s role in chronic pain are needed, the metabolites and receptors involved in its processes nevertheless present researchers with promising sources of novel and personalized disease-modifying treatments. Full article
(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)
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29 pages, 4200 KiB  
Review
Changes in Tryptophan-Kynurenine Metabolism in Patients with Depression Undergoing ECT—A Systematic Review
by Tore Ivar Malmei Aarsland, Johanne Telnes Instanes, Maj-Britt Rocio Posserud, Arve Ulvik, Ute Kessler and Jan Haavik
Pharmaceuticals 2022, 15(11), 1439; https://doi.org/10.3390/ph15111439 - 19 Nov 2022
Cited by 4 | Viewed by 3220
Abstract
The kynurenine pathway of tryptophan (Trp) metabolism generates multiple biologically active metabolites (kynurenines) that have been implicated in neuropsychiatric disorders. It has been suggested that modulation of kynurenine metabolism could be involved in the therapeutic effect of electroconvulsive therapy (ECT). We performed a [...] Read more.
The kynurenine pathway of tryptophan (Trp) metabolism generates multiple biologically active metabolites (kynurenines) that have been implicated in neuropsychiatric disorders. It has been suggested that modulation of kynurenine metabolism could be involved in the therapeutic effect of electroconvulsive therapy (ECT). We performed a systematic review with aims of summarizing changes in Trp and/or kynurenines after ECT and assessing methodological issues. The inclusion criterium was measures of Trp and/or kynurenines before and after ECT. Animal studies and studies using Trp administration or Trp depletion were excluded. Embase, MEDLINE, PsycInfo and PubMed were searched, most recently in July 2022. Outcomes were levels of Trp, kynurenines and ratios before and after ECT. Data on factors affecting Trp metabolism and ECT were collected for interpretation and discussion of the reported changes. We included 17 studies with repeated measures for a total of 386 patients and 27 controls. Synthesis using vote counting based on the direction of effect found no evidence of effect of ECT on any outcome variable. There were considerable variations in design, patient characteristics and reported items. We suggest that future studies should include larger samples, assess important covariates and determine between- and within-subject variability. PROSPERO (CRD42020187003). Full article
(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)
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