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Decoding the Complex Crossroad of Tryptophan Metabolic Pathways

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 48436

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Special Issue Editors

Dr. Ciriana Orabona

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Guest Editor

Dept. Experimental Medicine, University of Perugia, Perugia, Italy
Interests: immunopharmacology

Dr. Claudia Volpi

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Co-Guest Editor

Dept. Experimental Medicine, University of Perugia, Perugia, Italy
Interests: immunopharmacology

Dr. Giada Mondanelli

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Co-Guest Editor

Department of Medicine and Surgery, Section Pharmacology, University of Perugia, Perugia, Italy
Interests: arginine and tryptophan metabolisms – either as such individually or collectively - by conventional dendritic cells

Special Issue Information

Dear Colleagues,

Tryptophan (Trp) is an essential aromatic amino acid obtained from the dietary intake in humans. It acts as a building block for protein synthesis and represents a crossroad of different metabolic pathways, generating a plethora of metabolites. Trp metabolites are not mere byproducts, but they play relevant physiologic functions, ranging from the neurological to the immunological functions.

In eukaryotic cells, Trp is conveyed in two main pathways, i.e., the serotonin and the kynurenine pathways. The serotonin pathway is responsible for the synthesis of serotonin and melatonin that act as neurotransmitters in both the central and peripheral nervous systems, affecting the mood, stress sensitivity, appetite, and intestinal functions. The kynurenine pathway generates a series of immuno- and neuroactive catabolites, collectively called kynurenines, and leads to downstream nicotinamide adenine dinucleotide (NAD) biosynthesis. A third route of Trp transformation is employed by the gut microbiota that converts Trp into indole derivatives. Many indole metabolites are ligands for the aryl hydrocarbon receptor (AhR) that, by mediating the immune responses at barrier sites, is crucial for the intestinal homeostasis. Beyond the eclectic activity of Trp metabolites on different targets, also the metabolic enzymes involved in Trp transformation are finely modulated at both transcriptional and post-translational levels. Many of them were found overexpressed or defective in several pathological conditions and thus have become attractive therapeutic targets. Overall, the central role of the Trp metabolism in health and human disease requires further advances. Interestingly, deciphering the complex cross-talk between the metabolic pathways active in the host and in the microbiota will improve the understanding of the pathogenesis of several human diseases and thus open innovative therapeutic opportunities.

The current Special Issue offers the opportunity of collecting high-quality publications on various aspects of the Trp metabolism, to provide an interdisciplinary view of the topic that overarches from the methodologic procedure for the specific and quantitative identification of Trp metabolites in different biological samples to experimental observations in different disease models to highlight potential drug targets and therapeutic approaches.

Dr. Ciriana Orabona
Dr. Claudia Volpi
Dr. Giada Mondanelli
Guest Editors

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Keywords

tryptophan
kynurenine
serotonin
indole derivatives
aryl hydrocarbon receptor (AhR)
indoleamine 2,3 dioxygenase 1 (IDO1)
indoleamine 2,3 dioxygenase 2 (IDO2)
tryptophan 2,3 dioxygenase (TDO)
metabolic pathway
essential amino acid

Published Papers (10 papers)

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Editorial

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4 pages, 184 KiB

Open AccessEditorial

Decoding the Complex Crossroad of Tryptophan Metabolic Pathways

by Giada Mondanelli, Claudia Volpi and Ciriana Orabona

Int. J. Mol. Sci. 2022, 23(2), 787; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020787 - 12 Jan 2022

Cited by 7 | Viewed by 1606

Abstract

Among the 20 amino acids needed for protein synthesis, Tryptophan (Trp) is an aromatic amino acid fundamental not only for the synthesis of the major components of living cells (namely, the proteins), but also for the maintenance of cellular homeostasis [...] Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

Research

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14 pages, 1650 KiB

Open AccessArticle

Tryptophan Metabolites Regulate Neuropentraxin 1 Expression in Endothelial Cells

by Romain Vial, Stéphane Poitevin, Nathalie McKay, Stéphane Burtey and Claire Cerini

Int. J. Mol. Sci. 2022, 23(4), 2369; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042369 - 21 Feb 2022

Cited by 2 | Viewed by 1957

Abstract

In patients with chronic kidney disease (CKD) and in animal models of CKD, the transcription factor Aryl Hydrocabon Receptor (AhR) is overactivated. In addition to the canonical AhR targets constituting the AhR signature, numerous other genes are regulated by this factor. We identified neuronal pentraxin 1 (NPTX1) as a new AhR target. Belonging to the inflammatory protein family, NPTX1 seems of prime interest regarding the inflammatory state observed in CKD. Endothelial cells were exposed to tryptophan-derived toxins, indoxyl sulfate (IS) and indole-3-acetic acid (IAA). The adenine mouse model of CKD was used to analyze NPTX1 expression in the burden of uremia. NPTX1 expression was quantified by RT-PCR and western blot. AhR involvement was analyzed using silencing RNA. We found that IS and IAA upregulated NPTX1 expression in an AhR-dependent way. Furthermore, this effect was not restricted to uremic indolic toxins since the dioxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) do the same. In CKD mice, NPTX1 expression was increased in the aorta. Therefore, NPTX1 is a new target of AhR and further work is necessary to elucidate its exact role during CKD. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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14 pages, 1665 KiB

Open AccessArticle

Human Indoleamine 2,3-dioxygenase 1 (IDO1) Expressed in Plant Cells Induces Kynurenine Production

by Michele Bellucci, Andrea Pompa, Carine De Marcos Lousa, Eleonora Panfili, Elena Orecchini, Elisa Maricchiolo, Daniele Fraternale, Ciriana Orabona, Francesca De Marchis and Maria Teresa Pallotta

Int. J. Mol. Sci. 2021, 22(10), 5102; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105102 - 12 May 2021

Cited by 1 | Viewed by 2158

Abstract

Genetic engineering of plants has turned out to be an attractive approach to produce various secondary metabolites. Here, we attempted to produce kynurenine, a health-promoting metabolite, in plants of Nicotiana tabacum (tobacco) transformed by Agrobacterium tumefaciens with the gene, coding for human indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme responsible for the kynurenine production because of tryptophan degradation. The presence of IDO1 gene in transgenic plants was confirmed by PCR, but the protein failed to be detected. To confer higher stability to the heterologous human IDO1 protein and to provide a more sensitive method to detect the protein of interest, we cloned a gene construct coding for IDO1-GFP. Analysis of transiently transfected tobacco protoplasts demonstrated that the IDO1-GFP gene led to the expression of a detectable protein and to the production of kynurenine in the protoplast medium. Interestingly, the intracellular localisation of human IDO1 in plant cells is similar to that found in mammal cells, mainly in cytosol, but in early endosomes as well. To the best of our knowledge, this is the first report on the expression of human IDO1 enzyme capable of secreting kynurenines in plant cells. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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14 pages, 2345 KiB

Open AccessArticle

Kynurenine/Tryptophan Ratio as a Potential Blood-Based Biomarker in Non-Small Cell Lung Cancer

by Martina Mandarano, Elena Orecchini, Guido Bellezza, Jacopo Vannucci, Vienna Ludovini, Sara Baglivo, Francesca Romana Tofanetti, Rita Chiari, Elisabetta Loreti, Francesco Puma, Angelo Sidoni and Maria Laura Belladonna

Int. J. Mol. Sci. 2021, 22(9), 4403; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094403 - 22 Apr 2021

Cited by 22 | Viewed by 2627

Abstract

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrade tryptophan (Trp) into kynurenine (Kyn) at the initial step of an enzymatic pathway affecting T cell proliferation. IDO1 is highly expressed in various cancer types and associated with poor prognosis. Nevertheless, the serum Kyn/Trp concentration ratio has been suggested as a marker of cancer-associated immune suppression. We measured Kyn and Trp in blood samples of a wide cohort of non-small-cell lung cancer (NSCLC) patients, before they underwent surgery, and analyzed possible correlations of the Kyn/Trp ratio with either IDO1 expression or clinical–pathological parameters. Low Kyn/Trp significantly correlated with low IDO1 expression and never-smoker patients; while high Kyn/Trp was significantly associated with older (≥68 years) patients, advanced tumor stage, and squamous cell carcinoma (Sqcc), rather than the adenocarcinoma (Adc) histotype. Moreover, high Kyn/Trp was associated, among the Adc group, with higher tumor stages (II and III), and, among the Sqcc group, with a high density of tumor-infiltrating lymphocytes. A trend correlating the high Kyn/Trp ratio with the probability of recurrences from NSCLC was also found. In conclusion, high serum Kyn/Trp ratio, associated with clinical and histopathological parameters, may serve as a serum biomarker to optimize risk stratification and therapy of NSCLC patients. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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12 pages, 1574 KiB

Open AccessArticle

Tryptophan Pathway Abnormalities in a Murine Model of Hereditary Glaucoma

by Michal Fiedorowicz, Tomasz Choragiewicz, Waldemar A. Turski, Tomasz Kocki, Dominika Nowakowska, Kamila Wertejuk, Agnieszka Kamińska, Teresio Avitabile, Marlena Wełniak-Kaminska, Pawel Grieb, Sandrine Zweifel, Robert Rejdak and Mario Damiano Toro

Int. J. Mol. Sci. 2021, 22(3), 1039; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031039 - 21 Jan 2021

Cited by 11 | Viewed by 2267

Abstract

Background: It has been shown that a possible pathogenetic mechanism of neurodegeneration in the mouse model of glaucoma (DBA/2J) may be an alteration of kynurenic acid (KYNA) in the retina. This study aimed to verify the hypothesis that alterations of tryptophan (TRP) metabolism in DBA/2J mice is not limited to the retina. Methods: Samples of the retinal tissue and serum were collected from DBA/2J mice (6 and 10 months old) and control C57Bl/6 mice of the same age. The concentration of TRP, KYNA, kynurenine (KYN), and 3-hydroxykynurenine (3OH-K) was measured by HPLC. The activity of indoleamine 2,3-dioxygenase (IDO) was also determined as a KYN/TRP ratio. Results: TRP, KYNA, L-KYN, and 3OH-K concentration were significantly lower in the retinas of DBA/2J mice than in C57Bl/6 mice. 3OH-K concentration was higher in older mice in both strains. Serum TRP, L-KYN, and KYNA concentrations were lower in DBA/2J than in age-matched controls. However, serum IDO activity did not differ significantly between compared groups and strains. Conclusions: Alterations of the TRP pathway seem not to be limited to the retina in the murine model of hereditary glaucoma. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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16 pages, 2716 KiB

Open AccessArticle

Maternal Tryptophan Supplementation Protects Adult Rat Offspring against Hypertension Programmed by Maternal Chronic Kidney Disease: Implication of Tryptophan-Metabolizing Microbiome and Aryl Hydrocarbon Receptor

by Chien-Ning Hsu, I-Chun Lin, Hong-Ren Yu, Li-Tung Huang, Mao-Meng Tiao and You-Lin Tain

Int. J. Mol. Sci. 2020, 21(12), 4552; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124552 - 26 Jun 2020

Cited by 20 | Viewed by 2774

Abstract

Hypertension and chronic kidney disease (CKD) can originate during early-life. Tryptophan metabolites generated by different pathways have both detrimental and beneficial effects. In CKD, uremic toxins from the tryptophan-generating metabolites are endogenous ligands of the aryl hydrocarbon receptor (AHR). The interplay between AHR, nitric oxide (NO), the renin–angiotensin system (RAS), and gut microbiota is involved in the development of hypertension. We examined whether tryptophan supplementation in pregnancy can prevent hypertension and kidney disease programmed by maternal CKD in adult offspring via the aforementioned mechanisms. Sprague–Dawley (SD) female rats received regular chow or chow supplemented with 0.5% adenine for 3 weeks to induce CKD before pregnancy. Pregnant controls or CKD rats received vehicle or tryptophan 200 mg/kg per day via oral gavage during pregnancy. Male offspring were divided into four groups (n = 8/group): control, CKD, tryptophan supplementation (Trp), and CKD plus tryptophan supplementation (CKDTrp). All rats were sacrificed at the age of 12 weeks. We found maternal CKD induced hypertension in adult offspring, which tryptophan supplementation prevented. Maternal CKD-induced hypertension is related to impaired NO bioavailability and non-classical RAS axis. Maternal CKD and tryptophan supplementation differentially shaped distinct gut microbiota profile in adult offspring. The protective effect of tryptophan supplementation against maternal CKD-induced programmed hypertension is relevant to alterations to several tryptophan-metabolizing microbes and AHR signaling pathway. Our findings support interplay among tryptophan-metabolizing microbiome, AHR, NO, and the RAS in hypertension of developmental origins. Furthermore, tryptophan supplementation in pregnancy could be a potential approach to prevent hypertension programmed by maternal CKD. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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Review

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14 pages, 3503 KiB

Open AccessReview

Tryptophan Metabolites at the Crossroad of Immune-Cell Interaction via the Aryl Hydrocarbon Receptor: Implications for Tumor Immunotherapy

by Marco Gargaro, Giorgia Manni, Giulia Scalisi, Paolo Puccetti and Francesca Fallarino

Int. J. Mol. Sci. 2021, 22(9), 4644; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094644 - 28 Apr 2021

Cited by 26 | Viewed by 3069

Abstract

The Aryl hydrocarbon receptor (AhR) is a critical regulator of both innate and adaptive immune responses, with potent immunomodulatory effects that makes this receptor an attractive molecular target for novel therapeutics. Accumulating evidence indicates that diverse—both host’s and microbial—tryptophan metabolites profoundly regulate the immune system in the host via AhR, promoting either tolerance or immunity, largely as a function of the qualitative and quantitative nature of the metabolites being contributed by either source. Additional findings indicate that host and microbiota-derived tryptophan metabolic pathways can influence the outcome of immune responses to tumors. Here, we review recent studies on the role and modalities of AhR activation by various ligands, derived from either host-cell or microbial-cell tryptophan metabolic pathways, in the regulation of immune responses. Moreover, we highlight potential implications of those ligands and pathways in tumor immunotherapy, with particular relevance to checkpoint-blockade immune intervention strategies. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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23 pages, 1534 KiB

Open AccessReview

Tryptophan Metabolism and Gut-Brain Homeostasis

by William Roth, Kimia Zadeh, Rushi Vekariya, Yong Ge and Mansour Mohamadzadeh

Int. J. Mol. Sci. 2021, 22(6), 2973; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22062973 - 15 Mar 2021

Cited by 135 | Viewed by 20564

Abstract

Tryptophan is an essential amino acid critical for protein synthesis in humans that has emerged as a key player in the microbiota-gut-brain axis. It is the only precursor for the neurotransmitter serotonin, which is vital for the processing of emotional regulation, hunger, sleep, and pain, as well as colonic motility and secretory activity in the gut. Tryptophan catabolites from the kynurenine degradation pathway also modulate neural activity and are active in the systemic inflammatory cascade. Additionally, tryptophan and its metabolites support the development of the central and enteric nervous systems. Accordingly, dysregulation of tryptophan metabolites plays a central role in the pathogenesis of many neurologic and psychiatric disorders. Gut microbes influence tryptophan metabolism directly and indirectly, with corresponding changes in behavior and cognition. The gut microbiome has thus garnered much attention as a therapeutic target for both neurologic and psychiatric disorders where tryptophan and its metabolites play a prominent role. In this review, we will touch upon some of these features and their involvement in health and disease. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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17 pages, 696 KiB

Open AccessReview

The Role of the Kynurenine Signaling Pathway in Different Chronic Pain Conditions and Potential Use of Therapeutic Agents

by Filip Jovanovic, Kenneth D. Candido and Nebojsa Nick Knezevic

Int. J. Mol. Sci. 2020, 21(17), 6045; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176045 - 22 Aug 2020

Cited by 50 | Viewed by 4090

Abstract

Tryptophan (TRP) is an essential, aromatic amino acid catabolized by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) enzymes into kynurenine. The IDO enzyme is expressed in peripheral tissues and the central nervous system. Another enzyme of interest in the kynurenine signaling pathway is kynurenine 3-monooxygenase (KMO). The purpose of this review is to discuss the role of TRP and the kynurenine signaling pathway in different chronic pain patients. The IDO-1, IDO-2, and KMO enzymes and the kynurenine metabolite have been shown to be involved in the pathogenesis of neuropathic pain and other painful conditions (migraine, cluster headache, etc.) as well as depressive behavior. We highlighted the analgesic potential of novel agents targeting the enzymes of the kynurenine signaling pathway to explore their efficacy in both future basic science and transitional studies. Upcoming studies conducted on animal models will need to take into consideration the differences in TRP metabolism between human and non-human species. Since chronic painful conditions and depression have common pathophysiological patterns, and the kynurenine signaling pathway is involved in both of them, future clinical studies should aim to have outcomes targeting not only pain, but also functionality, mood changes, and quality of life. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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21 pages, 1878 KiB

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Pyridoxal 5′-Phosphate-Dependent Enzymes at the Crossroads of Host–Microbe Tryptophan Metabolism

by Barbara Cellini, Teresa Zelante, Mirco Dindo, Marina M. Bellet, Giorgia Renga, Luigina Romani and Claudio Costantini

Int. J. Mol. Sci. 2020, 21(16), 5823; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165823 - 13 Aug 2020

Cited by 22 | Viewed by 6395

Abstract

The chemical processes taking place in humans intersects the myriad of metabolic pathways occurring in commensal microorganisms that colonize the body to generate a complex biochemical network that regulates multiple aspects of human life. The role of tryptophan (Trp) metabolism at the intersection between the host and microbes is increasingly being recognized, and multiple pathways of Trp utilization in either direction have been identified with the production of a wide range of bioactive products. It comes that a dysregulation of Trp metabolism in either the host or the microbes may unbalance the production of metabolites with potential pathological consequences. The ability to redirect the Trp flux to restore a homeostatic production of Trp metabolites may represent a valid therapeutic strategy for a variety of pathological conditions, but identifying metabolic checkpoints that could be exploited to manipulate the Trp metabolic network is still an unmet need. In this review, we put forward the hypothesis that pyridoxal 5′-phosphate (PLP)-dependent enzymes, which regulate multiple pathways of Trp metabolism in both the host and in microbes, might represent critical nodes and that modulating the levels of vitamin B6, from which PLP is derived, might represent a metabolic checkpoint to re-orienteer Trp flux for therapeutic purposes. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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