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Tryptophan catabolism

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https://www.readbyqxmd.com/read/29679555/mass-spectrometric-measurement-of-urinary-kynurenine-to-tryptophan-ratio-in-children-with-and-without-urinary-tract-infection
#1
Melanie L Yarbrough, Kelleigh E Briden, John V Mitsios, Annette L Weindel, Cindy M Terrill, David A Hunstad, Dennis J Dietzen
BACKGROUND: Indoleamine-2,3-dioxygenase (IDO) catalyzes the first step of tryptophan (Trp) catabolism, yielding kynurenine (Kyn) metabolites. The kynurenine-to-tryptophan (K/T) ratio is used as a surrogate for biological IDO enzyme activity. IDO expression is increased during Escherichia coli urinary tract infection (UTI). Thus, our objective was to develop a method for measurement of Kyn/Trp ratio in human blood and urine and evaluate its use as a biomarker of UTI. METHODS: A mass spectrometric method was developed to measure Trp and Kyn in serum and urine specimens...
April 18, 2018: Clinical Biochemistry
https://www.readbyqxmd.com/read/29667084/investigation-of-the-aryl-hydrocarbon-receptor-and-the-intrinsic-tumoral-component-of-the-kynurenine-pathway-of-tryptophan-metabolism-in-primary-brain-tumors
#2
Anthony R Guastella, Sharon K Michelhaugh, Neil V Klinger, Hassan A Fadel, Sam Kiousis, Rouba Ali-Fehmi, William J Kupsky, Csaba Juhász, Sandeep Mittal
INTRODUCTION: There is mounting evidence supporting the role of tryptophan metabolism via the kynurenine pathway (KP) in the pathogenesis of primary brain tumors. Under normal physiological conditions, the KP is the major catabolic pathway for the essential amino acid tryptophan. However, in cancer cells, the KP becomes dysregulated, depletes local tryptophan, and contributes to an immunosuppressive tumor microenvironment. METHODS: We examined the protein expression levels (in 73 gliomas and 48 meningiomas) of the KP rate-limiting enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, and tryptophan 2,3-dioxygenase (TDO2), as well as, the aryl hydrocarbon receptor (AhR), a carcinogenic transcription factor activated by KP metabolites...
April 17, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29661920/dhtkd1-deficiency-causes-charcot-marie-tooth-disease-in-mice
#3
Wang-Yang Xu, Houbao Zhu, Yan Shen, Ying-Han Wan, Xiao-Die Tu, Wen-Ting Wu, Lingyun Tang, Hong-Xin Zhang, Shun-Yuan Lu, Xiao-Long Jin, Jian Fei, Zhu-Gang Wang
DHTKD1, a part of 2-ketoadipic acid dehydrogenase complex, is involved in lysine and tryptophan catabolism. Mutations in DHTKD1 block the metabolic pathway and cause 2-aminoadipic and 2-oxoadipic aciduria (AMOXAD), an autosomal recessive inborn metabolic disorder. In addition, a nonsense mutation in DHTKD1 we identified previously causes Charcot-Marie-Tooth disease (CMT) type 2Q, one of the most common inherited neurological disorders affecting the peripheral nerves in the musculature. However, the comprehensive molecular mechanism underlying CMT2Q remains elusive...
April 16, 2018: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29651242/discovery-of-novel-inhibitors-of-indoleamine-2-3-dioxygenase-1-through-structure-based-virtual-screening
#4
Guoqing Zhang, Jing Xing, Yulan Wang, Lihao Wang, Yan Ye, Dong Lu, Jihui Zhao, Xiaomin Luo, Mingyue Zheng, Shiying Yan
Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular monomeric heme-containing enzyme that catalyzes the first and the rate limiting step in catabolism of tryptophan via the kynurenine (KYN) pathway, which plays a significant role in the proliferation and differentiation of T cells. IDO1 has been proven to be an attractive target for anticancer therapy and chronic viral infections. In the present study, a class of IDO1 inhibitors with novel scaffolds were identified by virtual screening and biochemical validation, in which the compound DC-I028 shows moderate IDO1 inhibitory activity with an IC50 of 21...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29615752/endothelial-indoleamine-2-3-dioxygenase-1-regulates-the-placental-vascular-tone-and-is-deficient-in-intrauterine-growth-restriction-and-pre-eclampsia
#5
Pablo Zardoya-Laguardia, Astrid Blaschitz, Birgit Hirschmugl, Ingrid Lang, Sereina A Herzog, Liudmila Nikitina, Martin Gauster, Martin Häusler, Mila Cervar-Zivkovic, Eva Karpf, Ghassan J Maghzal, Chris P Stanley, Roland Stocker, Christian Wadsack, Saša Frank, Peter Sedlmayr
Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L-Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE)...
April 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29607498/1-l-mt-an-ido-inhibitor-prevented-colitis-associated-cancer-by-inducing-cdc20-inhibition-mediated-mitotic-death-of-colon-cancer-cells
#6
Xiuting Liu, Wei Zhou, Xin Zhang, Yang Ding, Qianming Du, Rong Hu
Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells...
April 1, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29565744/il-27-expression-and-responsiveness-in-human-uterine-epithelial-cells-and-fibroblasts-in-vitro-and-the-role-of-estradiol
#7
Mickey V Patel, Zheng Shen, Richard M Rossoll, Charles R Wira
Interleukin (IL)-27 is a pleiotropic cytokine that regulates multiple aspects of innate and adaptive immunity, but whose role in immune protection of the female reproductive tract is unknown. Although not constitutively expressed by human uterine epithelial cells and fibroblasts in culture, IL-27 secretion was upregulated after treatment with the viral ligand poly (I:C) in a type I interferon (IFN)-dependent manner, with higher levels measured in fibroblasts than epithelial cells. Estradiol increased poly (I:C)-induced IL-27 production by fibroblasts, but not epithelial cells...
March 2018: Journal of Interferon & Cytokine Research
https://www.readbyqxmd.com/read/29563329/deficiency-of-immunoregulatory-indoleamine-2-3-dioxygenase-1in-juvenile-diabetes
#8
Ciriana Orabona, Giada Mondanelli, Maria T Pallotta, Agostinho Carvalho, Elisa Albini, Francesca Fallarino, Carmine Vacca, Claudia Volpi, Maria L Belladonna, Maria G Berioli, Giulia Ceccarini, Susanna Mr Esposito, Raffaella Scattoni, Alberto Verrotti, Alessandra Ferretti, Giovanni De Giorgi, Sonia Toni, Marco Cappa, Maria C Matteoli, Roberta Bianchi, Davide Matino, Alberta Iacono, Matteo Puccetti, Cristina Cunha, Silvio Bicciato, Cinzia Antognelli, Vincenzo N Talesa, Lucienne Chatenoud, Dietmar Fuchs, Luc Pilotte, Benoît Van den Eynde, Manuel C Lemos, Luigina Romani, Paolo Puccetti, Ursula Grohmann
A defect in indoleamine 2,3-dioxygenase 1 (IDO1), which is responsible for immunoregulatory tryptophan catabolism, impairs development of immune tolerance to autoantigens in NOD mice, a model for human autoimmune type 1 diabetes (T1D). Whether IDO1 function is also defective in T1D is still unknown. We investigated IDO1 function in sera and peripheral blood mononuclear cells (PBMCs) from children with T1D and matched controls. These children were further included in a discovery study to identify SNPs in IDO1 that might modify the risk of T1D...
March 22, 2018: JCI Insight
https://www.readbyqxmd.com/read/29543650/tryptophan-catabolites-along-the-indoleamine-2-3-dioxygenase-pathway-as-a-biological-link-between-depression-and-cancer
#9
Francisco S Barreto, Adriano J M Chaves Filho, Márcia C C R de Araújo, Manoel O de Moraes, Maria E A de Moraes, Michael Maes, David F de Lucena, Danielle S Macedo
Both depression and cancer are related to a dysregulation of inflammatory and immune pathways. Indeed, depression is associated with increased expression of interferon-γ, interleukin-1β, and tumor necrosis factor α (TNF-α). In contrast, reductions of the activity of major histocompatibility complex protein molecules - class I and class II and natural killer cells are also observed. Similarly, cancers present elevated levels of TNF-α, reduced major histocompatibility complex class I and II, and natural killer cells...
April 2018: Behavioural Pharmacology
https://www.readbyqxmd.com/read/29541451/cancer-cell-metabolic-plasticity-allows-resistance-to-nampt-inhibition-but-invariably-induces-dependence-on-ldha
#10
Natthakan Thongon, Chiara Zucal, Vito Giuseppe D'Agostino, Toma Tebaldi, Silvia Ravera, Federica Zamporlini, Francesco Piacente, Ruxanda Moschoi, Nadia Raffaelli, Alessandro Quattrone, Alessio Nencioni, Jean-Francois Peyron, Alessandro Provenzani
Background: Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD+ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance. Methods: We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms...
2018: Cancer & Metabolism
https://www.readbyqxmd.com/read/29532751/ischemic-stroke-and-kynurenines-medicinal-chemistry-aspects
#11
Peter Hertelendy, Jozsef Toldi, Ferenc Fulop, Laszlo Vecsei
Ischemic stroke is one of the leading causes of mortality and permanent disability in developed countries. Stroke induces massive glutamate release, which in turn causes N-Methyl-D-aspartate (NMDA) receptor over-excitation and thus calcium overload in neurons leading to cell death via apoptotic cascades. The kynurenine pathway is a complex enzymatic cascade of tryptophan catabolism, generating various neuroactive metabolites. One metabolite, kynurenic acid (KYNA), is a potent endogenous NMDA glutamate receptor antagonist, making it a possible therapeutic tool to decrease excitotoxicity and neuroinflammation...
March 12, 2018: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29495953/voglibose-mediated-alterations-in-neurometabolomic-profiles-in-the-hypothalamus-of-high-fat-diet-fed-mice
#12
Soo Jin Yang, Hyun Ju Do, Youngae Jung, Geum-Sook Hwang, Min-Jeong Shin
The alpha-glucosidase inhibitor voglibose (VO) was recently reported to have a protective effect against weight gain as well as affect various metabolic changes related to food intake and gut-brain signaling. We hypothesized that VO prevents weight gain by altering neurometabolome profiles in the hypothalamus to reduce food intake. To test this hypothesis, we assessed metabolite profiles in the hypothalamus of standard diet- or high-fat (HF) diet-fed mice in the absence or presence of VO. In total, 29 male C57BL/6 mice were divided into 3 groups: (1) lean control, (2) HF, and (3) HF + VO...
March 1, 2018: Nutritional Neuroscience
https://www.readbyqxmd.com/read/29437277/identification-of-native-and-post-translationally-modified-hla-b-57-01-restricted-hiv-envelope-derived-epitopes-using-immunoproteomics
#13
Sri H Ramarathinam, Stephanie Gras, Sheilajen Alcantara, Amanda W S Yeung, Nicole A Mifsud, Secondo Sonza, Patricia T Illing, Elias N Glaros, Robert J Center, Shane Thomas, Stephen J Kent, Nicola Ternette, Damian F J Purcell, Jamie Rossjohn, Anthony W Purcell
The recognition of pathogen-derived peptides by T lymphocytes is the cornerstone of adaptive immunity, whereby intracellular antigens are degraded in the cytosol and short peptides assemble with class I human leukocyte antigen (HLA) molecules in the endoplasmic reticulum (ER). These peptide-HLA complexes egress to the cell surface and are scrutinized by cytotoxic CD8+ T-cells leading to the eradication of the infected cell. Here we identify naturally presented HLA-B*57:01 bound peptides derived from the envelope protein of the human immunodeficiency virus (HIVenv)...
February 13, 2018: Proteomics
https://www.readbyqxmd.com/read/29415228/plasma-tryptophan-kynurenine-metabolites-are-altered-in-hiv-infection-and-associated-with-progression-of-carotid-artery-atherosclerosis
#14
Qibin Qi, Simin Hua, Clary B Clish, Justin M Scott, David B Hanna, Tao Wang, Sabina A Haberlen, Sanjiv J Shah, Marshall J Glesby, Jason M Lazar, Robert D Burk, Howard N Hodis, Alan L Landay, Wendy S Post, Kathryn Anastos, Robert C Kaplan
Background: It is unknown whether disrupted tryptophan catabolism is associated with cardiovascular disease (CVD) in HIV-infected individuals. Methods: Plasma tryptophan and kynurenic acid were measured among 737 women and men (520 HIV+, 217 HIV-) from the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. Repeated B-mode carotid artery ultrasound imaging was obtained among these participants in 2004-2013. We examined associations of baseline plasma tryptophan, kynurenic acid, and kynurenic acid-to-tryptophan (KYNA/TRP) ratio, a measure of tryptophan catabolism, with risk of carotid artery plaque...
February 3, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
https://www.readbyqxmd.com/read/29413890/indoleamine-2-3-dioxygenase-and-its-therapeutic-inhibition-in-cancer
#15
George C Prendergast, William J Malachowski, Arpita Mondal, Peggy Scherle, Alexander J Muller
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression. Lastly, emerging evidence suggests that the IDO1-related enzyme IDO2 may support IDO1-mediated iTreg and contribute to B-cell inflammed states in certain cancers...
2018: International Review of Cell and Molecular Biology
https://www.readbyqxmd.com/read/29413421/inflammatory-reprogramming-with-ido1-inhibitors-turning-immunologically-unresponsive-cold-tumors-hot
#16
REVIEW
George C Prendergast, Arpita Mondal, Souvik Dey, Lisa D Laury-Kleintop, Alexander J Muller
We discuss how small-molecule inhibitors of the tryptophan (Trp) catabolic enzyme indoleamine 2,3-dioxygenase (IDO) represent a vanguard of new immunometabolic adjuvants to safely enhance the efficacy of cancer immunotherapy, radiotherapy, or 'immunogenic' chemotherapy by leveraging responses to tumor neoantigens. IDO inhibitors re-program inflammatory processes to help clear tumors by blunting tumor neovascularization and restoring immunosurveillance. Studies of regulatory and effector pathways illuminate IDO as an inflammatory modifier...
January 2018: Trends in Cancer
https://www.readbyqxmd.com/read/29406815/dysregulation-of-tryptophan-catabolism-in-metabolic-syndrome
#17
Neila Hiraishi Mallmann, Emerson Silva Lima, Pritesh Lalwani
OBJECTIVE: Obesity and metabolic syndrome are preventable complex-multifactorial disorders that severely increase risk of cardiovascular disease (CVD). Indoleamine 2,3-dioxygenase (IDO) enzyme converts tryptophan (TRP) to kynurenine (KYN); besides, KYN/TRP ratio has been shown to predict major coronary events and all-cause mortality in patients with coronary artery disease. However, their role in metabolic syndrome is not understood. METHODS: In a cross-sectional study (n = 161, mean population age in years = 32 ± 7...
February 6, 2018: Metabolic Syndrome and related Disorders
https://www.readbyqxmd.com/read/29393500/indoleamine-2-3-dioxygenase-regulation-of-immune-response-review
#18
Hao Wu, Jianping Gong, Yong Liu
Indoleamine 2, 3-dioxygenase (IDO) catalyzes the initial and rate‑limiting step in the degradation pathway of the essential amino acid tryptophan and is expressed by professional antigen presenting cells (APCs), epithelial cells, vascular endothelium and tumor cells. IDO‑mediated catabolic products, which are additionally termed 'kynurenines', exerts important immunosuppressive functions primarily via regulating T effector cell anergy and inducing the proliferation of T regulatory cells. This endogenous tolerogenic pathway has a critical effect on mediating the magnitude of immune responses under various stress conditions, including tumor, infection and transplantation...
February 1, 2018: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29335800/enrichment-and-characterization-of-a-bacterial-mixture-capable-of-utilizing-c-mannosyl-tryptophan-as-a-carbon-source
#19
Tanim J Hossain, Shino Manabe, Yukishige Ito, Toshiya Iida, Saori Kosono, Kenji Ueda, Akira Hosomi, Daishi Inoue, Tadashi Suzuki
C-Mannosylation, a protein-modification found in various eukaryotes, involves the attachment of a single mannose molecule to selected tryptophan residues of proteins. Since C-mannosyl tryptophan (CMW) was detected in human urine, it is generally thought that CMW is not catabolized inside our body and instead is excreted via the urine. This paper reports enrichment of a bacterial consortium from soil that degrades CMW. The bacteria grew in minimal medium supplemented with CMW as the carbon source. Interestingly, even after successive clonal picks of individual colonies, several species were still present in each colony as revealed by 16S rRNA gene sequence analysis, indicating that a single species may not be responsible for this activity...
January 15, 2018: Glycoconjugate Journal
https://www.readbyqxmd.com/read/29327354/a-validated-liquid-chromatography-high-resolution-tandem-mass-spectrometry-method-for-the-simultaneous-quantitation-of-tryptophan-kynurenine-kynurenic-acid-and-quinolinic-acid-in-human-plasma
#20
Kathrin Arnhard, Florian Pitterl, Barbara Sperner-Unterweger, Dietmar Fuchs, Therese Koal, Herbert Oberacher
Tryptophan (TRP) catabolism via the kynurenine pathway is considered to represent a major link between inflammation and various diseases, including neurodegenerative disorders, depression, schizophrenia, multiple sclerosis, cardiovascular disease, and cancer. The kynurenine pathway and levels of TRP and its metabolites kynurenine (KYN), kynurenic acid (KYNA) and quinolinic acid (QUIN) are well regulated under physiological conditions but may be altered as part of the activated immune response. A simple, sensitive, and specific liquid chromatography-time of flight mass spectrometry method was developed for determining levels of the four compounds in human plasma samples...
January 12, 2018: Electrophoresis
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