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Ariel Lewis-Ballester, Farhad Forouhar, Sung-Mi Kim, Scott Lew, YongQiang Wang, Shay Karkashon, Jayaraman Seetharaman, Dipanwita Batabyal, Bing-Yu Chiang, Munif Hussain, Maria Almira Correia, Syun-Ru Yeh, Liang Tong
Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) play a central role in tryptophan metabolism and are involved in many cellular and disease processes. Here we report the crystal structure of human TDO (hTDO) in a ternary complex with the substrates L-Trp and O2 and in a binary complex with the product N-formylkynurenine (NFK), defining for the first time the binding modes of both substrates and the product of this enzyme. The structure indicates that the dioxygenation reaction is initiated by a direct attack of O2 on the C2 atom of the L-Trp indole ring...
October 20, 2016: Scientific Reports
Tatiane da Silva Araújo, Adriano Jose Maia Chaves Filho, Aline Santos Monte, Ana Isabelle de Góis Queiroz, Rafaela Carneiro Cordeiro, Michel de Jesus Souza Machado, Ricardo de Freitas Lima, David Freitas de Lucena, Michael Maes, Danielle Macêdo
Immune dysregulation observed in schizophrenia alters tryptophan metabolism. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Tryptophan is converted to quinolinic acid, a potent neurotoxin, and to kynurenic acid, an NMDA antagonist. 1-Methyl-D-tryptophan (MDT) inhibits IDO. Melatonin is metabolized by IDO while inhibiting TDO. We evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice by the administration of MDT (20 or 40 mg/kg, i...
September 21, 2016: Journal of Psychiatric Research
Mads Hald Andersen
Our initial understanding of immune-regulatory cells was based on the discovery of suppressor cells that assure peripheral T-cell tolerance and promote immune homeostasis. Research has particularly focused on the importance of regulatory T cells (Tregs) for immune modulation, e.g. directing host responses to tumours or inhibiting autoimmunity development. However, recent studies report the discovery of self-reactive pro-inflammatory T cells-termed anti-regulatory T cells (anti-Tregs)-that target immune-suppressive cells...
September 27, 2016: Seminars in Immunopathology
Elina Timosenko, Hemza Ghadbane, Jonathan D Silk, Dawn Shepherd, Uzi Gileadi, Lauren J Howson, Robert Laynes, Qi Zhao, Robert L Strausberg, Lars R Olsen, Stephen Taylor, Francesca M Buffa, Richard Boyd, Vincenzo Cerundolo
Tryptophan degradation is an immune escape strategy shared by many tumors. However, cancer cells' compensatory mechanisms remain unclear. We demonstrate here that a shortage of tryptophan caused by expression of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) resulted in ATF4-dependent upregulation of several amino acid transporters, including SLC1A5 and its truncated isoforms. which in turn enhanced tryptophan and glutamine uptake. Importantly, SLC1A5 failed to be up-regulated in resting human T cells kept under low tryptophan conditions, but was enhanced upon cognate antigen T cell receptor engagement...
September 20, 2016: Cancer Research
Olga Novikov, Zhongyan Wang, Elizabeth A Stanford, Ashley J Parks, Alejandra Ramirez-Cardenas, Esther Landesman, Israa Laklouk, Carmen Sarita-Reyes, Daniel Gusenleitner, Amy Li, Stefano Monti, Sara Manteiga, Kyongbum Lee, David H Sherr
The endogenous ligand-activated aryl hydrocarbon receptor (AHR) plays an important role in numerous biologic processes. As the known number of AHR-mediated processes grows, so too does the importance of determining what endogenous AHR ligands are produced, how their production is regulated, and what biologic consequences ensue. Consequently, our studies were designed primarily to determine whether ER(-)/PR(-)/Her2(-) breast cancer cells have the potential to produce endogenous AHR ligands and, if so, how production of these ligands is controlled...
November 2016: Molecular Pharmacology
Frank Elbers, Claudia Woite, Valentina Antoni, Sara Stein, Hiroshi Funakoshi, Toshikazu Nakamura, Gereon Schares, Walter Däubener, Silvia K Eller
Tryptophan is an essential amino acid for hosts and pathogens. The liver enzyme tryptophan 2,3-dioxygenase (TDO) provokes, by its ability to degrade tryptophan to N-formylkynurenine, the precursor of the immune-relevant kynurenines, direct and indirect antimicrobial and immunoregulatory states. Up to now these TDO-mediated broad-spectrum effector functions have never been observed under hypoxia in vitro, although physiologic oxygen concentrations in liver tissue are low, especially in case of infection. Here we analysed recombinant expressed human TDO and ex vivo murine TDO functions under different oxygen conditions and show that TDO-induced restrictions of clinically relevant pathogens (bacteria, parasites) and of T cell proliferation are abrogated under hypoxic conditions...
2016: Mediators of Inflammation
Abdulla A-B Badawy, Samina Bano
Rat liver tryptophan (Trp), kynurenine pathway metabolites, and enzymes deduced from product/substrate ratios were assessed following acute and/or chronic administration of kynurenic acid (KA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid (3-HAA), Trp, and the kynureni-nase inhibitors benserazide (BSZ) and carbidopa (CBD). KA activated Trp 2,3-dioxygenase (TDO), possibly by increasing liver 3-HAA, but inhibited kynurenine aminotransferase (KAT) and kynureninase activities with 3-HK as substrate. 3-HK inhibited kynureninase activity from 3-HK...
2016: International Journal of Tryptophan Research: IJTR
Abdulla A-B Badawy, Donald M Dougherty
Tryptophan (Trp) metabolism via the kynurenine pathway (KP) was assessed in normal healthy US volunteers at baseline and after acute Trp depletion (ATD) and acute Trp loading (ATL) using amino acid formulations. The hepatic KP accounts for ~90% of overall Trp degradation. Liver Trp 2,3-dioxygenase (TDO) contributes ~70% toward Trp oxidation, with the remainder achieved by subsequent rate-limiting enzymes in the KP. TDO is not influenced by a 1.15 g Trp load, but is maximally activated by a 5.15 g dose. We recommend a 30 mg/kg dose for future ATL studies...
2016: International Journal of Tryptophan Research: IJTR
Paul B Larkin, Korrapati V Sathyasaikumar, Francesca M Notarangelo, Hiroshi Funakoshi, Toshikazu Nakamura, Robert Schwarcz, Paul J Muchowski
BACKGROUND: In mammals, the majority of the essential amino acid tryptophan is degraded via the kynurenine pathway (KP). Several KP metabolites play distinct physiological roles, often linked to immune system functions, and may also be causally involved in human diseases including neurodegenerative disorders, schizophrenia and cancer. Pharmacological manipulation of the KP has therefore become an active area of drug development. To target the pathway effectively, it is important to understand how specific KP enzymes control levels of the bioactive metabolites in vivo...
November 2016: Biochimica et Biophysica Acta
Valeriya Navrotskaya, Gregory Oxenkrug, Lyudmila Vorobyova, Paul Summergrad
Exposure to high sugar diet (HSD) is an experimental model of insulin resistance (IR) and type 2 diabetes (T2D) in mammals and insects. In Drosophila, HSD-induced IR delays emergence of pupae from larvae and eclosion of imago from pupae. Understanding of mechanisms of IR/T2D is essential for refining T2D prevention and treatment strategies. Dysregulation of tryptophan (Trp)-kynurenine (Kyn) pathway was suggested as one of the mechanisms of IR/T2D development. Rate-limiting enzyme of Trp-Kyn pathway in Drosophila is Trp 2,3-dioxygenase (TDO), an evolutionary conserved ortholog of human TDO...
March 2016: Integrative Obesity and Diabetes
Yoshiji Ohta, Hisako Kubo, Koji Yashiro, Koji Ohashi, Yuji Tsuzuki, Naoya Wada, Yasuko Yamamoto, Kuniaki Saito
The aim of this study was to clarify the effect of water-immersion restraint stress (WIRS) on tryptophan (Trp) catabolism through the kynurenine (Kyn) pathway in rat tissues. The tissues of rats subjected to 6 h of WIRS (+WIRS) had increased tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) activities and increased TDO and IDO1 (one of two IDO isozymes in mammals) mRNA expression levels, with decreased Trp and increased Kyn contents in the liver. +WIRS rats had unchanged TDO and IDO activities in the kidney, decreased TDO activity and unchanged IDO activity in the brain, and unchanged IDO activity in the lung and spleen, with increased Kyn content in all of these tissues...
June 30, 2016: Journal of Physiological Sciences: JPS
Abdulla A-B Badawy, Aryan M A Namboodiri, John R Moffett
We hypothesize that: (1) L-tryptophan (Trp) is greatly utilized and not depleted in pregnancy; (2) fetal tolerance is achieved in part through immunosuppressive kynurenine (Kyn) metabolites produced by the flux of plasma free (non-albumin-bound) Trp down the Kyn pathway; (3) the role of indoleamine 2,3-dioxygenase (IDO) in infection is not related to limitation of an essential amino acid, but is rather associated with stress responses and the production of Kyn metabolites that regulate the activities of antigen presenting cells and T-cells, as well as increased NAD(+) synthesis in IDO-expressing cells; (4) Trp depletion is not a host defence mechanism, but is a consequence of Trp utilization...
August 1, 2016: Clinical Science (1979-)
Lay Khoon Too, Kong M Li, Cacang Suarna, Ghassan J Maghzal, Roland Stocker, Iain S McGregor, Nicholas H Hunt
Tryptophan, an amino acid involved in routine energy metabolism, is a key modulator of sickness behaviors associated with inflammatory states and also plays roles in some psychiatric disorders. Tissue concentrations of tryptophan are regulated primarily by the enzymes indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO, encoded by TDO2). Altered IDO1 and TDO activities have been linked to the perturbed serotonergic neurotransmission that may underlie certain psychopathologies. Here we assessed mice genetically modified to be deficient in IDO1, IDO2 or TDO2 for their behavior and cognitive function using an automated home cage system, the IntelliCage™...
October 1, 2016: Behavioural Brain Research
Saurav Paul, Ashalata Roy, Suman Jyoti Deka, Subhankar Panda, Vishal Trivedi, Debasis Manna
Tryptophan metabolism through the kynurenine pathway is considered as a crucial mechanism in immune tolerance. Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in tryptophan catabolism in the immune system and it is also considered as an important therapeutic target for the treatment of cancer and other diseases that are linked with kynurenine pathway. In this study, a series of nitrobenzofurazan derivatives of N'-hydroxybenzimidamides (1) and N'-hydroxy-2-phenylacetimidamides (2) were synthesized and their inhibitory activities against human IDO1 enzyme were tested using in-vitro and cellular enzyme activity assay...
October 4, 2016: European Journal of Medicinal Chemistry
S M Balaji
BACKGROUND: Distraction osteogenesis (DO) is a recognized technique for the bone lengthening and correction of various mandibular deformities. It has an aided advantage of both osteogenesis and histiogenesis in achieving a bone supported mandibular ridge covered with attached gingiva, forming an appropriate vestibule. AIM: The aim of this study was to present our clinical experience in using transport DO technique (TDO) for treating mandibular bony defects following tumor ablation in both benign and malignant tumor cases...
March 2016: Indian Journal of Dental Research: Official Publication of Indian Society for Dental Research
Katsumi Shibata, Tsutomu Fukuwatari
The aim of this article is to report the organ-specific correlation with tryptophan (Trp) metabolism obtained by analyses of tryptophan 2,3-dioxygenase knockout (TDO-KO) and quinolinic acid phosphoribosyltransferase knockout (QPRT-KO) mice models. We found that TDO-KO mice could biosynthesize the necessary amount of nicotinamide (Nam) from Trp, resulting in the production of key intermediate, 3-hydroxyanthranilic acid. Upstream metabolites, such as kynurenic acid and xanthurenic acid, in the urine were originated from nonhepatic tissues, and not from the liver...
2016: International Journal of Tryptophan Research: IJTR
Carlo Breda, Korrapati V Sathyasaikumar, Shama Sograte Idrissi, Francesca M Notarangelo, Jasper G Estranero, Gareth G L Moore, Edward W Green, Charalambos P Kyriacou, Robert Schwarcz, Flaviano Giorgini
Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
Georgios Pantouris, James Loudon-Griffiths, Christopher G Mowat
Tryptophan 2,3-dioxygenase (TDO) is a cytosolic protein with a proven immunomodulatory function that promotes tumoral immune resistance and proliferation. Despite the interest in TDO as a therapeutic target in cancer treatment, the number of biologically useful inhibitors is limited. Herein, we report isatin derivatives as a new class of TDO inhibitors. Through structure-activity relationships and molecular docking studies, we optimized the inhibition potency of isatin derivatives by >130-fold and elucidated the mechanistic details that control their mode of action...
April 20, 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Cheng-Peng Yu, Ze-Zheng Pan, Da-Ya Luo
Tryptophan-2, 3-dioxygenase (TDO) is a heme-containing protein catalyzing the first reaction in the kynurenine pathway, which incorporates oxygen into the indole moiety of tryptophan and catalyzes it into kynurenine (KYN). The activation of TDO results in the depletion of tryptophan and the accumulation of kynurenine and its metabolites. These metabolites can affect the function of neurons and inhibit the proliferation of T cells. Increasing evidence demonstrates that TDO is a potential therapeutic target in the treatment of brain diseases as well as in the antitumor and transplant fields...
August 2016: Metabolic Brain Disease
MyungGu Yeo, Ji-Seon Lee, Wook Chun, Geun Hyung Kim
Three-dimensional (3D) cell printing processes have been used widely in various tissue engineering applications due to the efficient embedding of living cells in appropriately designed micro- or macro-structures. However, there are several issues to overcome, such as the limited choice of bioinks and tailor-made fabricating strategies. Here, we suggest a new, innovative cell-printing process, supplemented with a core-sheath nozzle and an aerosol cross-linking method, to obtain multilayered cell-laden mesh structure and a newly considered collagen-based cell-laden bioink...
April 11, 2016: Biomacromolecules
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