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Sapienza J, Agostoni G, Repaci F, Spangaro M, Comai S, Bosia M. Metabolic Syndrome and Schizophrenia: Adding a Piece to the Interplay Between the Kynurenine Pathway and Inflammation. Metabolites 2025; 15:176. [PMID: 40137141 PMCID: PMC11944102 DOI: 10.3390/metabo15030176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 01/29/2025] [Accepted: 02/21/2025] [Indexed: 03/27/2025] Open
Abstract
The biology of schizophrenia is highly complex and multifaceted. Numerous efforts have been made over the years to disentangle the heterogeneity of the disease, gradually leading to a more detailed understanding of its underlying pathogenic mechanisms. Two cardinal elements in the pathophysiology of schizophrenia are neuroinflammation and alterations of neurotransmission. The kynurenine (KYN) pathway (KP) is of particular importance because it is inducted by systemic low-grade inflammation in peripheral tissues, producing metabolites that are neuroactive (i.e., modulating glutamatergic and cholinergic neurotransmission), neuroprotective, or neurotoxic. Consequently, the KP is at the crossroads between two primary systems involved in the pathogenesis of schizophrenia. It bridges the central nervous system (CNS) and the periphery, as KP metabolites can cross the blood-brain barrier and modulate neuronal activity. Metabolic syndrome plays a crucial role in this context, as it frequently co-occurs with schizophrenia, contributing to a sub-inflammatory state able to activate the KP. This narrative review provides valuable insights into these complex interactions, offering a framework for developing targeted therapeutic interventions or precision psychiatry approaches of the disorder.
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Affiliation(s)
- Jacopo Sapienza
- Schizophrenia Research and Clinical Unit, IRCCS San Raffaele Scientific Institute, 20127 Milan, Italy; (J.S.)
- Department of Humanities and Life Sciences, University School for Advanced Studies IUSS, 27100 Pavia, Italy
| | - Giulia Agostoni
- Schizophrenia Research and Clinical Unit, IRCCS San Raffaele Scientific Institute, 20127 Milan, Italy; (J.S.)
| | - Federica Repaci
- Schizophrenia Research and Clinical Unit, IRCCS San Raffaele Scientific Institute, 20127 Milan, Italy; (J.S.)
| | - Marco Spangaro
- Schizophrenia Research and Clinical Unit, IRCCS San Raffaele Scientific Institute, 20127 Milan, Italy; (J.S.)
| | - Stefano Comai
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35123 Padua, Italy
- Division of Neurosciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
- Department of Psychiatry, McGill University, Montreal, QC H3A 0G4, Canada
- Department of Biomedical Sciences, University of Padua, 35123 Padua, Italy
| | - Marta Bosia
- Schizophrenia Research and Clinical Unit, IRCCS San Raffaele Scientific Institute, 20127 Milan, Italy; (J.S.)
- School of Medicine, Vita-Salute San Raffaele University, 20132 Milan, Italy
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Pocivavsek A, Schwarcz R, Erhardt S. Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities. Pharmacol Rev 2024; 76:978-1008. [PMID: 39304346 PMCID: PMC11549936 DOI: 10.1124/pharmrev.124.000239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 09/08/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024] Open
Abstract
Both preclinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurologic and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies. SIGNIFICANCE STATEMENT: Studies have implicated the kynurenine pathway of tryptophan in the pathophysiology of neurologic and psychiatric diseases. Key enzymes of the kynurenine pathway regulate brain metabolism in both health and disease, making them promising targets for treating these disorders. Therefore, understanding the distribution, cellular expression, and regulation of these enzymes and metabolites in the brain is critical for developing effective therapeutic strategies. This review endeavors to describe these processes in detail.
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Affiliation(s)
- Ana Pocivavsek
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina (A.P.); Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland (R.S.); and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.E.)
| | - Robert Schwarcz
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina (A.P.); Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland (R.S.); and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.E.)
| | - Sophie Erhardt
- Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, South Carolina (A.P.); Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland (R.S.); and Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden (S.E.)
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Ren C, Zhang S, Chen Y, Deng K, Kuang M, Gong Z, Zhang K, Wang P, Huang P, Zhou Z, Gong A. Exploring nicotinamide adenine dinucleotide precursors across biosynthesis pathways: Unraveling their role in the ovary. FASEB J 2024; 38:e23804. [PMID: 39037422 DOI: 10.1096/fj.202400453r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 05/31/2024] [Accepted: 06/26/2024] [Indexed: 07/23/2024]
Abstract
Natural Nicotinamide Adenine Dinucleotide (NAD+) precursors have attracted much attention due to their positive effects in promoting ovarian health. However, their target tissue, synthesis efficiency, advantages, and disadvantages are still unclear. This review summarizes the distribution of NAD+ at the tissue, cellular and subcellular levels, discusses its biosynthetic pathways and the latest findings in ovary, include: (1) NAD+ plays distinct roles both intracellularly and extracellularly, adapting its distribution in response to requirements. (2) Different precursors differs in target tissues, synthetic efficiency, biological utilization, and adverse effects. Importantly: tryptophan is primarily utilized in the liver and kidneys, posing metabolic risks in excess; nicotinamide (NAM) is indispensable for maintaining NAD+ levels; nicotinic acid (NA) constructs a crucial bridge between intestinal microbiota and the host with diverse functions; nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) increase NAD+ systemically and can be influenced by delivery route, tissue specificity, and transport efficiency. (3) The biosynthetic pathways of NAD+ are intricately intertwined. They provide multiple sources and techniques for NAD+ synthesis, thereby reducing the dependence on a single molecule to maintain cellular NAD+ levels. However, an excess of a specific precursor potentially influencing other pathways. In addition, Protein expression analysis suggest that ovarian tissues may preferentially utilize NAM and NMN. These findings summarize the specific roles and potential of NAD+ precursors in enhancing ovarian health. Future research should delve into the molecular mechanisms and intervention strategies of different precursors, aiming to achieve personalized prevention or treatment of ovarian diseases, and reveal their clinical application value.
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Affiliation(s)
- Caifang Ren
- School of Medicine, Jiangsu University, Zhenjiang, China
- Hematological Disease Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
| | - Shuang Zhang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yanyan Chen
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Kaiping Deng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Meiqian Kuang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zihao Gong
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ke Zhang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Panqi Wang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Pan Huang
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhengrong Zhou
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Aihua Gong
- School of Medicine, Jiangsu University, Zhenjiang, China
- Hematological Disease Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, China
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Wujieti B, Feng X, Liu E, Li D, Hao M, Zhou L, Cui W. A theoretical study on the activity and selectivity of IDO/TDO inhibitors. Phys Chem Chem Phys 2024; 26:16747-16764. [PMID: 38818624 DOI: 10.1039/d3cp06036e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2024]
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO) is a tryptophan (Trp) metabolic enzyme along the kynurenine (NFK) pathway. Under pathological conditions, IDO overexpressed by tumor cells causes depletion of tryptophan and the accumulation of metabolic products, which inhibit the local immune response and form immune escape. Therefore, the suppression of IDO activity is one of the strategies for tumor immunotherapy, and drug design for this target has been the focus of research for more than two decades. Apart from IDO, tryptophan dioxygenase (TDO) of the same family can also catalyze the same biochemical reaction in the human body, but it has different tissue distribution and substrate selectivity from IDO. Based on the principle of drug design with high potency and low cross-reactivity to specific targets, in this subject, the activity and selectivity of IDO and TDO toward small molecular inhibitors were studied from the perspective of thermodynamics and kinetics. The aim was to elucidate the structural requirements for achieving favorable biological activity and selectivity of IDO and TDO inhibitors. Specifically, the interactions of inhibitors from eight families with IDO and TDO were initially investigated through molecular docking and molecular dynamics simulations, and the thermodynamic data for binding of inhibitors were predicted by the molecular mechanics/generalized Born surface area (MM/GBSA) method. Secondly, we explored the free energy landscape of JKloops, the kinetic control element of IDO/TDO, using temperature replica exchange molecular dynamics (T-REMD) simulations and elucidated the connection between the rules of IDO/TDO conformational changes and the inhibitor selectivity mechanism. Furthermore, the binding and dissociation processes of the C1 inhibitor (NLG919) were simulated by the adaptive steering molecular dynamics (ASMD) method, which not only addressed the possible stable, metastable, and transition states for C1 inhibitor-IDO/TDO interactions, but also accurately predicted kinetic data for C1 inhibitor binding and dissociation. In conclusion, we have constructed a complete process from enzyme (IDO/TDO) conformational activation to inhibitor binding/dissociation and used the thermodynamic and kinetic data of each link as clues to verify the control mechanism of IDO/TDO on inhibitor selectivity. This is of great significance for us to understand the design principles of tumor immunotherapy drugs and to avoid drug resistance of immunotherapy drugs.
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Affiliation(s)
- Baerlike Wujieti
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China.
| | - Xinping Feng
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China.
| | - Erxia Liu
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China.
| | - Deqing Li
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China.
| | - Mingtian Hao
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China.
| | - Luqi Zhou
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China.
| | - Wei Cui
- School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, China.
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Shen J, Zhao W, Cheng J, Cheng J, Zhao L, Dai C, Fu Y, Li B, Chen Z, Shi D, Li H, Deng Y. Lipopolysaccharide accelerates tryptophan degradation in the ovary and the derivative kynurenine disturbs hormone biosynthesis and reproductive performance. JOURNAL OF HAZARDOUS MATERIALS 2023; 458:131988. [PMID: 37418963 DOI: 10.1016/j.jhazmat.2023.131988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Revised: 07/01/2023] [Accepted: 07/01/2023] [Indexed: 07/09/2023]
Abstract
Lipopolysaccharide (LPS), also known as endotoxin, is a component of the outer membrane of gram-negative bacteria. LPS is released into the surrounding environment during bacterial death and lysis. Due to its chemical and thermal stability, LPS can be detected anywhere and easily exposed to humans and animals. Previous studies have shown that LPS causes hormonal imbalances, ovarian failure, and infertility in mammals. However, the potential mechanisms remain unclear. In this study, we investigated the effects and mechanisms of LPS on tryptophan degradation, both in vivo and in vitro. The effects of kynurenine, a tryptophan derivative, on granulosa cell function and reproductive performance were explored. Results showed that p38, NF-κB, and JNK signaling pathways were involved in LPS-induced Ido1 expressions and kynurenine accumulation. Furthermore, the kynurenine decreased estradiol production, but increased granulosa cell proliferation. In vivo, experiments showed that kynurenine decreased estradiol and FSH production and inhibited ovulation and corpus luteum formation. Additionally, pregnancy and offspring survival rates decreased considerably after kynurenine treatment. Our findings suggest that kynurenine accumulation disrupts hormone secretion, ovulation, corpus luteal formation, and reproductive performance in mammals.
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Affiliation(s)
- Jie Shen
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China; Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Weimin Zhao
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Juanru Cheng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Jinhua Cheng
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Lei Zhao
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China; Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Chaohui Dai
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Yanfeng Fu
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Bixia Li
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Zhe Chen
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China
| | - Deshun Shi
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Hui Li
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base of Ministry of Science and Technology, Institute of Animal Science, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China.
| | - Yanfei Deng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Guangxi Key Laboratory of Animal Breeding and Disease Control, College of Animal Science and Technology, Guangxi University, Nanning 530004, China.
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Torres N, Tobón-Cornejo S, Velazquez-Villegas LA, Noriega LG, Alemán-Escondrillas G, Tovar AR. Amino Acid Catabolism: An Overlooked Area of Metabolism. Nutrients 2023; 15:3378. [PMID: 37571315 PMCID: PMC10421169 DOI: 10.3390/nu15153378] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 07/14/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Amino acids have been extensively studied in nutrition, mainly as key elements for maintaining optimal protein synthesis in the body as well as precursors of various nitrogen-containing compounds. However, it is now known that amino acid catabolism is an important element for the metabolic control of different biological processes, although it is still a developing field to have a deeper understanding of its biological implications. The mechanisms involved in the regulation of amino acid catabolism now include the contribution of the gut microbiota to amino acid oxidation and metabolite generation in the intestine, the molecular mechanisms of transcriptional control, and the participation of specific miRNAs involved in the regulation of amino acid degrading enzymes. In addition, molecules derived from amino acid catabolism play a role in metabolism as they are used in the epigenetic regulation of many genes. Thus, this review aims to examine the mechanisms of amino acid catabolism and to support the idea that this process is associated with the immune response, abnormalities during obesity, in particular insulin resistance, and the regulation of thermogenesis.
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Affiliation(s)
| | | | | | | | | | - Armando R. Tovar
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga No 15. Col Belisario Domínguez-Sección XVI, Tlalpan, Mexico City 14080, Mexico; (N.T.); (S.T.-C.); (L.A.V.-V.); (L.G.N.); (G.A.-E.)
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Sung Y, Yu YC, Han JM. Nutrient sensors and their crosstalk. Exp Mol Med 2023; 55:1076-1089. [PMID: 37258576 PMCID: PMC10318010 DOI: 10.1038/s12276-023-01006-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 02/22/2023] [Accepted: 03/13/2023] [Indexed: 06/02/2023] Open
Abstract
The macronutrients glucose, lipids, and amino acids are the major components that maintain life. The ability of cells to sense and respond to fluctuations in these nutrients is a crucial feature for survival. Nutrient-sensing pathways are thus developed to govern cellular energy and metabolic homeostasis and regulate diverse biological processes. Accordingly, perturbations in these sensing pathways are associated with a wide variety of pathologies, especially metabolic diseases. Molecular sensors are the core within these sensing pathways and have a certain degree of specificity and affinity to sense the intracellular fluctuation of each nutrient either by directly binding to that nutrient or indirectly binding to its surrogate molecules. Once the changes in nutrient levels are detected, sensors trigger signaling cascades to fine-tune cellular processes for energy and metabolic homeostasis, for example, by controlling uptake, de novo synthesis or catabolism of that nutrient. In this review, we summarize the major discoveries on nutrient-sensing pathways and explain how those sensors associated with each pathway respond to intracellular nutrient availability and how these mechanisms control metabolic processes. Later, we further discuss the crosstalk between these sensing pathways for each nutrient, which are intertwined to regulate overall intracellular nutrient/metabolic homeostasis.
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Affiliation(s)
- Yulseung Sung
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, South Korea
| | - Ya Chun Yu
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, South Korea
| | - Jung Min Han
- Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon, 21983, South Korea.
- Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul, 03722, South Korea.
- POSTECH Biotech Center, Pohang University of Science and Technology, Pohang, 37673, South Korea.
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Yoshioka S, Ikeda T, Fukuchi S, Kawai Y, Ohta K, Murakami H, Ogo N, Muraoka D, Takikawa O, Asai A. Identification and Characterization of a Novel Dual Inhibitor of
Indoleamine 2,3-dioxygenase 1 and Tryptophan 2,3-dioxygenase. Int J Tryptophan Res 2022; 15:11786469221138456. [PMCID: PMC9716449 DOI: 10.1177/11786469221138456] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 10/21/2022] [Indexed: 12/05/2022] Open
Abstract
Kynurenine (Kyn), a metabolite of tryptophan (Trp), is a key regulator of mammal
immune responses such as cancer immune tolerance. Indoleamine-2,3-dioxygenase
(IDO) and tryptophan-2,3-dioxygenase (TDO) are main enzymes regulating the first
and rate-limiting step of the Kyn pathway. To identify new small molecule
inhibitors of TDO, we selected A172 glioblastoma cell line constitutively
expressed TDO. Characterization of this cell line using kinase inhibitor library
resulted in identification of MEK/ERK pathway-dependent TDO expression. After
knowing the properties for TDO expression, we further proceeded to screen
chemical library for TDO inhibitors. We previously determined that
S-benzylisothiourea derivatives are enzymatic inhibitors of indoleamine
2,3-dioxygenase 1 (IDO1) and suggested that the isothiourea moiety could be an
important pharmacophore for binding to heme. Based on this premise, we screened
an in-house library composed of various isothiourea derivatives and identified a
bisisothiourea derivative, PVZB3001, as an inhibitor of TDO. Interestingly,
PVZB3001 also inhibited the enzymatic activity of IDO1 in both cell-based and
cell-free assays but did not inhibit other heme enzymes. Molecular docking
studies suggested the importance of isothiourea moieties at the ortho position
of the phenyl ring for the inhibition of catalytic activity. PVZB3001 showed
competitive inhibition against TDO, and this was supported by the docking
simulation. PVZB3001 recovered natural killer (NK) cell viability and functions
by inhibiting Kyn accumulation in conditioned medium of both IDO1- and
TDO-expressing cells. Furthermore, oral administration of IDO1-overexpressing
tumor-bearing mice with PVZB3001 significantly inhibited tumor growth. Thus, we
identified a novel selective dual inhibitor of IDO1 and TDO using the Kyn
production assay with a glioblastoma cell line. This inhibitor could be a useful
pharmacological tool for modulating the Kyn pathway in a variety of experimental
systems.
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Affiliation(s)
- Saeko Yoshioka
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Tomonori Ikeda
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Sogo Fukuchi
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Yurika Kawai
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Katsumi Ohta
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Hisashi Murakami
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Naohisa Ogo
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Daisuke Muraoka
- Department of Oncology, Nagasaki
University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Osamu Takikawa
- National Institute for Longevity
Sciences, National Center for Geriatrics and Gerontology, Aichi, Japan
| | - Akira Asai
- Center for Drug Discovery, Graduate
School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan,Akira Asai, Graduate School of
Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka
422-8526, Japan.
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Interactions between Tryptophan Metabolism, the Gut Microbiome and the Immune System as Potential Drivers of Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Diseases. Metabolites 2022; 12:metabo12060514. [PMID: 35736447 PMCID: PMC9227929 DOI: 10.3390/metabo12060514] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 02/01/2023] Open
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing and therefore is its burden of disease as NALFD is a risk factor for cirrhosis and is associated with other metabolic conditions such as type II diabetes, obesity, dyslipidaemia and atherosclerosis. Linking these cardiometabolic diseases is a state of low-grade inflammation, with higher cytokines and c-reactive protein levels found in individuals with NAFLD, obesity and type II diabetes. A possible therapeutic target to decrease this state of low-grade inflammation is the metabolism of the essential amino-acid tryptophan. Its three main metabolic pathways (kynurenine pathway, indole pathway and serotonin/melatonin pathway) result in metabolites such as kynurenic acid, xanturenic acid, indole-3-propionic acid and serotonin/melatonin. The kynurenine pathway is regulated by indoleamine 2,3-dioxygenase (IDO), an enzyme that is upregulated by pro-inflammatory molecules such as INF, IL-6 and LPS. Higher activity of IDO is associated with increased inflammation and fibrosis in NAFLD, as well with increased glucose levels, obesity and atherosclerosis. On the other hand, increased concentrations of the indole pathway metabolites, regulated by the gut microbiome, seem to result in more favorable outcomes. This narrative review summarizes the interactions between tryptophan metabolism, the gut microbiome and the immune system as potential drivers of cardiometabolic diseases in NAFLD.
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Kodama T, Kodama M, Jenkins NA, Copeland NG, Chen HJ, Wei Z. Ring Finger Protein 125 Is an Anti-Proliferative Tumor Suppressor in Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14112589. [PMID: 35681566 PMCID: PMC9179258 DOI: 10.3390/cancers14112589] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 02/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide and the only cancer with an increasing incidence in the United States. Recent advances in sequencing technology have enabled detailed profiling of liver cancer genomes and revealed extensive inter- and intra-tumor heterogeneity, making it difficult to identify driver genes for HCC. To identify HCC driver genes, we performed transposon mutagenesis screens in a mouse HBV model of HCC and discovered many candidate cancer genes (SB/HBV-CCGs). Here, we show that one of these genes, RNF125 is a potent anti-proliferative tumor suppressor gene in HCC. RNF125 is one of nine CCGs whose expression was >3-fold downregulated in human HCC. Depletion of RNF125 in immortalized mouse liver cells led to tumor formation in transplanted mice and accelerated growth of human liver cancer cell lines, while its overexpression inhibited their growth, demonstrating the tumor-suppressive function of RNF125 in mouse and human liver. Whole-transcriptome analysis revealed that RNF125 transcriptionally suppresses multiple genes involved in cell proliferation and/or liver regeneration, including Egfr, Met, and Il6r. Blocking Egfr or Met pathway expression inhibited the increased cell proliferation observed in RNF125 knockdown cells. In HCC patients, low expression levels of RNF125 were correlated with poor prognosis demonstrating an important role for RNF125 in HCC. Collectively, our results identify RNF125 as a novel anti-proliferative tumor suppressor in HCC.
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Affiliation(s)
- Takahiro Kodama
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan
- Correspondence: (T.K.); (Z.W.)
| | - Michiko Kodama
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka 5650871, Japan
| | - Nancy A. Jenkins
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Neal G. Copeland
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Huanhuan Joyce Chen
- The Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA;
- The Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA
| | - Zhubo Wei
- Houston Methodist Research Institute, Houston Methodist Hospital, Houston, TX 77030, USA; (M.K.); (N.A.J.); (N.G.C.)
- Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA
- Correspondence: (T.K.); (Z.W.)
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11
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Zhang R, Wang Y, Liu D, Luo Q, Du P, Zhang H, Wu W. Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice. Front Pharmacol 2022; 13:870848. [PMID: 35571116 PMCID: PMC9091350 DOI: 10.3389/fphar.2022.870848] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/28/2022] [Indexed: 02/05/2023] Open
Abstract
Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.
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Affiliation(s)
- Rongjie Zhang
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Yuanfeiyi Wang
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Dan Liu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Qing Luo
- School of Pharmacy, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, China
| | - Peixin Du
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Haiyan Zhang
- Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu, China.,The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, China
| | - Wenshuang Wu
- Department of Thyroid Surgery, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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12
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Song T, Zhang X, Ding M, Rodriguez-Paton A, Wang S, Wang G. DeepFusion: A Deep Learning Based Multi-Scale Feature Fusion Method for Predicting Drug-Target Interactions. Methods 2022; 204:269-277. [DOI: 10.1016/j.ymeth.2022.02.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/28/2022] [Accepted: 02/20/2022] [Indexed: 12/15/2022] Open
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13
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Williams MM, Hafeez SA, Christenson JL, O’Neill KI, Hammond NG, Richer JK. Reversing an Oncogenic Epithelial-to-Mesenchymal Transition Program in Breast Cancer Reveals Actionable Immune Suppressive Pathways. Pharmaceuticals (Basel) 2021; 14:ph14111122. [PMID: 34832904 PMCID: PMC8622696 DOI: 10.3390/ph14111122] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/16/2022] Open
Abstract
Approval of checkpoint inhibitors for treatment of metastatic triple negative breast cancer (mTNBC) has opened the door for the use of immunotherapies against this disease. However, not all patients with mTNBC respond to current immunotherapy approaches such as checkpoint inhibitors. Recent evidence demonstrates that TNBC metastases are more immune suppressed than primary tumors, suggesting that combination or additional immunotherapy strategies may be required to activate an anti-tumor immune attack at metastatic sites. To identify other immune suppressive mechanisms utilized by mTNBC, our group and others manipulated oncogenic epithelial-to-mesenchymal transition (EMT) programs in TNBC models to reveal differences between this breast cancer subtype and its more epithelial counterpart. This review will discuss how EMT modulation revealed several mechanisms, including tumor cell metabolism, cytokine milieu and secretion of additional immune modulators, by which mTNBC cells may suppress both the innate and adaptive anti-tumor immune responses. Many of these pathways/proteins are under preclinical or clinical investigation as therapeutic targets in mTNBC and other advanced cancers to enhance their response to chemotherapy and/or checkpoint inhibitors.
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14
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Mammoli A, Riccio A, Bianconi E, Coletti A, Camaioni E, Macchiarulo A. One Key and Multiple Locks: Substrate Binding in Structures of Tryptophan Dioxygenases and Hydroxylases. ChemMedChem 2021; 16:2732-2743. [PMID: 34137184 PMCID: PMC8518741 DOI: 10.1002/cmdc.202100312] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 06/14/2021] [Indexed: 12/18/2022]
Abstract
Since its discovery at the beginning of the past century, the essential nutrient l-Tryptophan (l-Trp) and its catabolic pathways have acquired an increasing interest in an ever wider scientific community for their pivotal roles in underlying many important physiological functions and associated pathological conditions. As a consequence, enzymes catalyzing rate limiting steps along l-Trp catabolic pathways - including IDO1, TDO, TPH1 and TPH2 - have turned to be interesting drug targets for the design and development of novel therapeutic agents for different disorders such as carcinoid syndrome, cancer and autoimmune diseases. This article provides a fresh comparative overview on the most recent advancements that crystallographic studies, biophysical and computational works have brought on structural aspects and molecular recognition patterns of these enzymes toward l-Trp. Finally, a conformational analysis of l-Trp is also discussed as part of the molecular recognition process governing the binding of a substrate to its cognate enzymes.
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Affiliation(s)
- Andrea Mammoli
- Department of Pharmaceutical SciencesUniversity of PerugiaVia del Liceo N. 106123PerugiaItaly
| | - Alessandra Riccio
- Department of Pharmaceutical SciencesUniversity of PerugiaVia del Liceo N. 106123PerugiaItaly
| | - Elisa Bianconi
- Department of Pharmaceutical SciencesUniversity of PerugiaVia del Liceo N. 106123PerugiaItaly
| | - Alice Coletti
- Department of Medicine and SurgeryUniversity of PerugiaP. le Gambuli06132PerugiaItaly
| | - Emidio Camaioni
- Department of Pharmaceutical SciencesUniversity of PerugiaVia del Liceo N. 106123PerugiaItaly
| | - Antonio Macchiarulo
- Department of Pharmaceutical SciencesUniversity of PerugiaVia del Liceo N. 106123PerugiaItaly
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15
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Asghar K, Farooq A, Zulfiqar B, Loya A. Review of 10 years of research on breast cancer patients: Focus on indoleamine 2,3-dioxygenase. World J Clin Oncol 2021; 12:429-436. [PMID: 34189067 PMCID: PMC8223715 DOI: 10.5306/wjco.v12.i6.429] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 12/30/2020] [Accepted: 04/08/2021] [Indexed: 02/06/2023] Open
Abstract
Therapeutic manipulation of the immune system in cancer has been an extensive area of research in the field of oncoimmunology. Immunosuppression regulates antitumour immune responses. An immunosuppressive enzyme, indoleamine 2,3-dioxygenase (IDO) mediates tumour immune escape in various malignancies including breast cancer. IDO upregulation in breast cancer cells may lead to the recruitment of regulatory T (T-regs) cells into the tumour microenvironment, thus inhibiting local immune responses and promoting metastasis. Immunosuppression induced by myeloid derived suppressor cells activated in an IDO-dependent manner may enhance the possibility of immune evasion in breast cancer. IDO overexpression has independent prognostic significance in a subtype of breast cancer of emerging interest, basal-like breast carcinoma. IDO inhibitors as adjuvant therapeutic agents may have clinical implications in breast cancer. This review proposes future prospects of IDO not only as a therapeutic target but also as a valuable prognostic marker for breast cancer.
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Affiliation(s)
- Kashif Asghar
- Department of Basic Sciences Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore 54000, Pakistan
| | - Asim Farooq
- Department of Clinical Research, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore 54000, Pakistan
| | - Bilal Zulfiqar
- Griffith Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia
| | - Asif Loya
- Department of Pathology, Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore 54000, Pakistan
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16
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Behl T, Kaur I, Sehgal A, Singh S, Bhatia S, Al-Harrasi A, Zengin G, Bumbu AG, Andronie-Cioara FL, Nechifor AC, Gitea D, Bungau AF, Toma MM, Bungau SG. The Footprint of Kynurenine Pathway in Neurodegeneration: Janus-Faced Role in Parkinson's Disorder and Therapeutic Implications. Int J Mol Sci 2021; 22:6737. [PMID: 34201647 PMCID: PMC8268239 DOI: 10.3390/ijms22136737] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/17/2021] [Accepted: 06/21/2021] [Indexed: 02/06/2023] Open
Abstract
Progressive degeneration of neurons and aggravation of dopaminergic neurons in the substantia nigra pars compacta results in the loss of dopamine in the brain of Parkinson's disease (PD) patients. Numerous therapies, exhibiting transient efficacy have been developed; however, they are mostly accompanied by side effects and limited reliability, therefore instigating the need to develop novel optimistic treatment targets. Significant therapeutic targets have been identified, namely: chaperones, protein Abelson, glucocerebrosidase-1, calcium, neuromelanin, ubiquitin-proteasome system, neuroinflammation, mitochondrial dysfunction, and the kynurenine pathway (KP). The role of KP and its metabolites and enzymes in PD, namely quinolinic acid (QUIN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), 3-hydroxyanthranillic acid (3-HAA), kunurenine-3-monooxygenase (KMO), etc. has been reported. The neurotoxic QUIN, N-methyl-D-aspartate (NMDA) receptor agonist, and neuroprotective KYNA-which antagonizes QUIN actions-primarily justify the Janus-faced role of KP in PD. Moreover, KP has been reported to play a biomarker role in PD detection. Therefore, the authors detail the neurotoxic, neuroprotective, and immunomodulatory neuroactive components, alongside the upstream and downstream metabolic pathways of KP, forming a basis for a therapeutic paradigm of the disease while recognizing KP as a potential biomarker in PD, thus facilitating the development of a suitable target in PD management.
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Affiliation(s)
- Tapan Behl
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (I.K.); (A.S.); (S.S.)
| | - Ishnoor Kaur
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (I.K.); (A.S.); (S.S.)
| | - Aayush Sehgal
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (I.K.); (A.S.); (S.S.)
| | - Sukhbir Singh
- Department of Pharmacology, Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India; (I.K.); (A.S.); (S.S.)
| | - Saurabh Bhatia
- Amity Institute of Pharmacy, Amity University, Gurugram, Haryana 122412, India;
- Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, PC 616 Birkat Al Mouz, Nizwa 611, Oman;
| | - Ahmed Al-Harrasi
- Natural and Medical Sciences Research Centre, University of Nizwa, P.O. Box 33, PC 616 Birkat Al Mouz, Nizwa 611, Oman;
| | - Gokhan Zengin
- Department of Biology, Faculty of Science, Selcuk University Campus, Konya 42130, Turkey;
| | - Adrian Gheorghe Bumbu
- Department of Surgical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Felicia Liana Andronie-Cioara
- Department of Psycho-Neuroscience and Recovery, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Aurelia Cristina Nechifor
- Analytical Chemistry and Environmental Engineering Department, Polytechnic University of Bucharest, 011061 Bucharest, Romania;
| | - Daniela Gitea
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania; (D.G.); (M.M.T.)
| | | | - Mirela Marioara Toma
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania; (D.G.); (M.M.T.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania; (D.G.); (M.M.T.)
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
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17
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Tryptophanemia is controlled by a tryptophan-sensing mechanism ubiquitinating tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A 2021; 118:2022447118. [PMID: 34074763 DOI: 10.1073/pnas.2022447118] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Maintaining stable tryptophan levels is required to control neuronal and immune activity. We report that tryptophan homeostasis is largely controlled by the stability of tryptophan 2,3-dioxygenase (TDO), the hepatic enzyme responsible for tryptophan catabolism. High tryptophan levels stabilize the active tetrameric conformation of TDO through binding noncatalytic exosites, resulting in rapid catabolism of tryptophan. In low tryptophan, the lack of tryptophan binding in the exosites destabilizes the tetramer into inactive monomers and dimers and unmasks a four-amino acid degron that triggers TDO polyubiquitination by SKP1-CUL1-F-box complexes, resulting in proteasome-mediated degradation of TDO and rapid interruption of tryptophan catabolism. The nonmetabolizable analog alpha-methyl-tryptophan stabilizes tetrameric TDO and thereby stably reduces tryptophanemia. Our results uncover a mechanism allowing a rapid adaptation of tryptophan catabolism to ensure quick degradation of excess tryptophan while preventing further catabolism below physiological levels. This ensures a tight control of tryptophanemia as required for both neurological and immune homeostasis.
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Dolšak A, Gobec S, Sova M. Indoleamine and tryptophan 2,3-dioxygenases as important future therapeutic targets. Pharmacol Ther 2020; 221:107746. [PMID: 33212094 DOI: 10.1016/j.pharmthera.2020.107746] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 02/07/2023]
Abstract
Conversion of tryptophan to N-formylkynurenine is the first and rate-limiting step of the tryptophan metabolic pathway (i.e., the kynurenine pathway). This conversion is catalyzed by three enzyme isoforms: indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and tryptophan 2,3-dioxygenase (TDO). As this pathway generates numerous metabolites that are involved in various pathological conditions, IDOs and TDO represent important targets for therapeutic intervention. This pathway has especially drawn attention due to its importance in tumor resistance. Over the last decade, a large number of IDO and TDO inhibitors have been developed, many of which have entered clinical trials. Here, detailed structural comparisons of these three enzymes (with emphasis on their active sites), their involvement in cellular signaling, and their role(s) in pathological conditions are discussed. Furthermore, the most important recent inhibitors described in papers and patents and involved in clinical trials are reviewed, with a focus on both selective and multiple inhibitors. A short overview of the biochemical and cellular assays used for inhibitory potency evaluation is also presented. This review summarizes recent advances on IDO and TDO as potential drug targets, and provides the key features and perspectives for further research and development of potent inhibitors of the kynurenine pathway.
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Affiliation(s)
- Ana Dolšak
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Stanislav Gobec
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia
| | - Matej Sova
- University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
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Zlatopolskiy BD, Endepols H, Krasikova RN, Fedorova OS, Ermert J, Neumaier B. 11C- and 18F-labelled tryptophans as PET-tracers for imaging of altered tryptophan metabolism in age-associated disorders. RUSSIAN CHEMICAL REVIEWS 2020. [DOI: 10.1070/rcr4954] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The ageing of the world’s population is the result of increased life expectancy observed in almost all countries throughout the world. Consequently, a rising tide of ageing-associated disorders, like cancer and neurodegenerative diseases, represents one of the main global challenges of the 21st century. The ability of mankind to overcome these challenges is directly dependent on the capability to develop novel methods for therapy and diagnosis of age-associated diseases. One hallmark of age-related pathologies is an altered tryptophan metabolism. Numerous pathological processes including neurodegenerative and neurological diseases like epilepsy, Parkinson’s and Alzheimer’s diseases, cancer and diabetes exhibit marked changes in tryptophan metabolism. Visualization of key processes of tryptophan metabolic pathways, especially using positron emission tomography (PET) and related hybrid methods like PET/CT and PET/MRI, can be exploited to early detect the aforementioned disorders with considerable accuracy, allowing appropriate and timely treatment of patients. Here we review the published 11C- and 18F-labelled tryptophans with respect to the production and also preclinical and clinical evaluation as PET-tracers for visualization of different branches of tryptophan metabolism.
The bibliography includes 159 references.
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20
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Indoximod opposes the immunosuppressive effects mediated by IDO and TDO via modulation of AhR function and activation of mTORC1. Oncotarget 2020; 11:2438-2461. [PMID: 32637034 PMCID: PMC7321702 DOI: 10.18632/oncotarget.27646] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 06/01/2020] [Indexed: 12/11/2022] Open
Abstract
Indoximod has shaped our understanding of the biology of IDO1 in the control of immune responses, though its mechanism of action has been poorly understood. Previous studies demonstrated that indoximod creates a tryptophan (Trp) sufficiency signal that reactivates mTOR in the context of low Trp concentrations, thus opposing the effects caused by IDO1. Here we extend the understanding of indoximod’s mechanism of action by showing that it has pleiotropic effects on immune regulation. Indoximod can have a direct effect on T cells, increasing their proliferation as a result of mTOR reactivation. Further, indoximod modulates the differentiation of CD4+ T cells via the aryl hydrocarbon receptor (AhR), which controls transcription of several genes in response to different ligands including kynurenine (Kyn). Indoximod increases the transcription of RORC while inhibiting transcription of FOXP3, thus favoring differentiation to IL-17-producing helper T cells and inhibiting the differentiation of regulatory T cells. These indoximod-driven effects on CD8+ and CD4+ T cells were independent from the activity of IDO/TDO and from the presence of exogenous Kyn, though they do oppose the effects of Kyn produced by these Trp catabolizing enzymes. Indoximod can also downregulate expression of IDO protein in vivo in murine lymph node dendritic cells and in vitro in human monocyte-derived dendritic cells via a mechanism that involves signaling through the AhR. Together, these data improve the understanding of how indoximod influences the effects of IDO, beyond and distinct from direct enzymatic inhibition of the enzyme.
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21
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Qiao Z, Mardon K, Stimson DHR, Migotto MA, Reutens DC, Bhalla R. Synthesis and evaluation of 6-[18F]fluoro-3-(pyridin-3-yl)-1H-indole as potential PET tracer for targeting tryptophane 2, 3-dioxygenase (TDO). Nucl Med Biol 2020; 84-85:1-10. [PMID: 31927462 DOI: 10.1016/j.nucmedbio.2019.12.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/17/2019] [Accepted: 12/17/2019] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The increase in expression of tryptophan 2, 3-dioxygenases (TDO) and indoleamine 2,3-dioxygenase (IDO) have been reported as potential tumor biomarkers. TDO and IDO are enzymes that catalyze the first and rate-limiting step of the kynurenine pathway. Positron emitting tomography (PET) tracers investigating the kynurenine pathway may allow for the detection of different disease pathologies in vivo including cancer. However, current PET tracers being developed for TDO and IDO have suffered from either multi-step low yielding syntheses or de-fluorination of the tracer in vivo. RESULTS TDO inhibitors based on 6-fluoroindole with C3 substituents are a class of small molecules that have been shown to bind to TDO effectively, restore tryptophan concentration and decrease the production of immunosuppressive metabolites. The compound 6-fluoro-3-(pyridine-3-yl)-1H-indole has been reported to have high in vitro affinity for TDO. Herein we report the fully automated radiosynthesis of 6-[18F]fluoro-3-(pyridine-3-yl)-1H-indole [18F]4 using a copper-mediated nucleophilic 18F-fluorination resulting in a non-corrected yield of 5 to 6% of the tracer with a radiochemical purity of >99% after 4 h. Small animal dynamic PET/CT imaging of [18F]4 intravenously injected into normal C57BL/6 mice revealed rapid accumulation in heart and brain, reaching maximum occupancy in heart (10.9% ID/g) and brain (8.1% ID/g) at 1.75 min and 2.25 min, respectively. Furthermore, these in vivo studies revealed no de-fluorination of the tracer, as evidence by the absence of [18F]fluoride accumulation in bone. CONCLUSION In vitro studies demonstrate that 4 has good affinity for hTDO and the radiolabeled analogue [18F]4 can be synthesized with suitable radiochemical yields. [18F]4 demonstrates good uptake in the brain and the radiolabeled compound shows no de-fluorination in vivo in C57BL/6 mice.
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Affiliation(s)
- Zheng Qiao
- Centre for Advanced Imaging, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - Karine Mardon
- Centre for Advanced Imaging, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia; National Imaging Facility, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - Damion H R Stimson
- Centre for Advanced Imaging, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - Mary-Anne Migotto
- Centre for Advanced Imaging, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - David C Reutens
- Centre for Advanced Imaging, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia
| | - Rajiv Bhalla
- Centre for Advanced Imaging, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
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Hoffmann D, Dvorakova T, Stroobant V, Bouzin C, Daumerie A, Solvay M, Klaessens S, Letellier MC, Renauld JC, van Baren N, Lelotte J, Marbaix E, Van den Eynde BJ. Tryptophan 2,3-Dioxygenase Expression Identified in Human Hepatocellular Carcinoma Cells and in Intratumoral Pericytes of Most Cancers. Cancer Immunol Res 2019; 8:19-31. [DOI: 10.1158/2326-6066.cir-19-0040] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 06/27/2019] [Accepted: 11/15/2019] [Indexed: 11/16/2022]
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23
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Wang XX, Sun SY, Dong QQ, Wu XX, Tang W, Xing YQ. Recent advances in the discovery of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors. MEDCHEMCOMM 2019; 10:1740-1754. [PMID: 32055299 DOI: 10.1039/c9md00208a] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 08/14/2019] [Indexed: 12/13/2022]
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1), an important immunoregulatory enzyme ubiquitously expressed in various tissues and cells, plays a key role in tryptophan metabolism via the kynurenine pathway and has emerged as an attractive therapeutic target for the treatment of cancer and other diseases, such as Alzheimer's disease and arthritis. IDO1 has diverse biological roles in immune suppression and tumor progression by tryptophan catabolism. In addition, IDO1-mediated immune tolerance assists tumor cells in escaping the immune surveillance. Recently, extensive and enormous investigations have been made in the discovery of IDO1 inhibitors in both academia and pharmaceutical companies. In this review, IDO1 inhibitors are grouped as tryptophan derivatives, inhibitors with an imidazole, 1,2,3-triazole or tetrazole scaffold, inhibitors with quinone or iminoquinone, N-hydroxyamidines and other derivatives, and their enzymatic inhibitory activity, selectivity and other biological activities are also introduced and summarized.
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Affiliation(s)
- Xiu-Xiu Wang
- Department of Pharmacy , The Second Affliated Hospital of Bengbu Medical College , Bengbu , Anhuir 233040 , P.R. China .
| | - Si-Yu Sun
- Department of Pharmacy , The Second Affliated Hospital of Bengbu Medical College , Bengbu , Anhuir 233040 , P.R. China .
| | - Qing-Qing Dong
- Department of Pharmacy , The Second Affliated Hospital of Bengbu Medical College , Bengbu , Anhuir 233040 , P.R. China .
| | - Xiao-Xiang Wu
- Department of Pharmacy , The Second Affliated Hospital of Bengbu Medical College , Bengbu , Anhuir 233040 , P.R. China .
| | - Wei Tang
- Department of Pharmacy , The Second Affliated Hospital of Bengbu Medical College , Bengbu , Anhuir 233040 , P.R. China .
| | - Ya-Qun Xing
- Department of Pharmacy , The Second Affliated Hospital of Bengbu Medical College , Bengbu , Anhuir 233040 , P.R. China .
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24
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Ye Z, Yue L, Shi J, Shao M, Wu T. Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications. J Cancer 2019; 10:2771-2782. [PMID: 31258785 PMCID: PMC6584917 DOI: 10.7150/jca.31727] [Citation(s) in RCA: 125] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 04/10/2019] [Indexed: 02/06/2023] Open
Abstract
Kynurenine (Kyn) pathway is a significant metabolic pathway of tryptophan (Trp). The metabolites of the Kyn pathway are closely correlated with numerous diseases. Two main enzymes, indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO or TDO2), regulate the first and rate-limiting step of the Kyn pathway. These enzymes are directly or indirectly involved in various diseases, including inflammatory diseases, cancer, diabetes, and mental disorders. Presently, an increasing number of potential mechanisms have been revealed. In the present review, we depict the structure of IDO and TDO and explicate their functions in various diseases to facilitate a better understanding of them and to indicate new therapeutic plans to target them. Moreover, we summarize the inhibitors of IDO/TDO that are currently under development and their efficacy in the treatment of cancer and other diseases.
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Affiliation(s)
- Zixiang Ye
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Linxiu Yue
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jiachen Shi
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Mingmei Shao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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25
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Keaton SA, Heilman P, Bryleva EY, Madaj Z, Krzyzanowski S, Grit J, Miller ES, Jälmby M, Kalapotharakos G, Racicot K, Fazleabas A, Hansson SR, Brundin L. Altered Tryptophan Catabolism in Placentas From Women With Pre-eclampsia. Int J Tryptophan Res 2019; 12:1178646919840321. [PMID: 31007529 PMCID: PMC6457019 DOI: 10.1177/1178646919840321] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 02/10/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The kynurenine pathway enzymes, breaking down tryptophan, are abundant in placental tissue. These metabolites are involved in immunoregulatory mechanisms, although the role of this pathway in pre-eclampsia (PE) has only begun to be characterized. Here, we determined tryptophan and metabolite levels together with the expression of kynurenine pathway enzymes and inflammatory factors in placental tissue from women with and without PE. METHODS Thirty-six placentas (18 PE and 18 controls) were analyzed for expression of kynurenine pathway enzymes indoleamine-2,3-dioxygenase (IDO1 and 2), tryptophan-2,3-dioxygenase (TDO), kynurenine-3-mono-oxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) as well as interleukin (IL)-1β, IL-6, and serum amyloid A (SAA). Tryptophan and kynurenine content were measured using high-pressure liquid chromatography and quinolinic acid was measured using gas chromatography-mass spectrometry. CONCLUSIONS Tryptophan content was reduced in placentas from women with PE. There was an increased kynurenine/tryptophan ratio in placentas from women with PE but no significant change in downstream metabolites. We confirmed a reduction in IDO1 expression and found a compensatory increase in TDO expression in placentas from women with PE. SAA was reduced in PE placentas compared with controls. Our data show that tryptophan content and the inflammatory mediator SAA are both compromised in placentas from women with PE. Further studies on the role of tryptophan catabolism and mediators of inflammation in sustaining healthy immunobiological pathways in the placenta are warranted.
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Affiliation(s)
- Sarah A Keaton
- Department of Physiology, Michigan State
University, East Lansing, MI, USA
- Center for Neurodegenerative Science,
Van Andel Research Institute, Grand Rapids, MI, USA
| | - Patrick Heilman
- Center for Neurodegenerative Science,
Van Andel Research Institute, Grand Rapids, MI, USA
| | - Elena Y Bryleva
- Center for Neurodegenerative Science,
Van Andel Research Institute, Grand Rapids, MI, USA
| | - Zachary Madaj
- Bioinformatics and Biostatistics Core,
Van Andel Research Institute, Grand Rapids, MI, USA
| | - Stanislaw Krzyzanowski
- Center for Neurodegenerative Science,
Van Andel Research Institute, Grand Rapids, MI, USA
| | - Jamie Grit
- Center for Cancer and Cell Biology, Van
Andel Research Institute, Grand Rapids, MI, USA
| | - Emily S Miller
- Feinberg School of Medicine,
Northwestern University, Chicago, IL, USA
| | - Maya Jälmby
- Department of Obstetrics and Gynecology,
Institute of Clinical Sciences, Lund University, Lund, Sweden
| | - Grigoros Kalapotharakos
- Department of Obstetrics and Gynecology,
Institute of Clinical Sciences, Lund University, Lund, Sweden
| | - Karen Racicot
- Department of Obstetrics, Gynecology and
Reproductive Biology, Michigan State University, Grand Rapids, MI, USA
| | - Asgerally Fazleabas
- Department of Obstetrics, Gynecology and
Reproductive Biology, Michigan State University, Grand Rapids, MI, USA
| | - Stefan R Hansson
- Department of Obstetrics and Gynecology,
Institute of Clinical Sciences, Lund University, Lund, Sweden
| | - Lena Brundin
- Center for Neurodegenerative Science,
Van Andel Research Institute, Grand Rapids, MI, USA
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26
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Liu XJ, Zhang CE, Yu XH, Liu RX, Qin XM, Jia JD, Ma ZJ. Serum metabonomics characterization of liver fibrosis induced by bile duct-ligated in rats and the intervention effects of herb compound 861. J LIQ CHROMATOGR R T 2019. [DOI: 10.1080/10826076.2019.1574815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Xiao-Jie Liu
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, P. R. China
| | - Cong-En Zhang
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Xiao-Hong Yu
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Rui-Xia Liu
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Xue-Mei Qin
- Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan, P. R. China
| | - Ji-Dong Jia
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis
| | - Zhi-Jie Ma
- Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis
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27
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Söderlund J, Lindskog M. Relevance of Rodent Models of Depression in Clinical Practice: Can We Overcome the Obstacles in Translational Neuropsychiatry? Int J Neuropsychopharmacol 2018; 21:668-676. [PMID: 29688411 PMCID: PMC6030948 DOI: 10.1093/ijnp/pyy037] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 02/22/2018] [Accepted: 04/13/2018] [Indexed: 12/26/2022] Open
Abstract
The diagnosis of a mental disorder generally depends on clinical observations and phenomenological symptoms reported by the patient. The definition of a given diagnosis is criteria based and relies on the ability to accurately interpret subjective symptoms and complex behavior. This type of diagnosis comprises a challenge to translate to reliable animal models, and these translational uncertainties hamper the development of new treatments. In this review, we will discuss how depressive-like behavior can be induced in rodents, and the relationship between these models and depression in humans. Specifically, we suggest similarities between triggers of depressive-like behavior in animal models and human conditions known to increase the risk of depression, for example exhaustion and bullying. Although we acknowledge the potential problems in comparing animal findings to human conditions, such comparisons are useful for understanding the complexity of depression, and we highlight the need to develop clinical diagnoses and animal models in parallel to overcome translational uncertainties.
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Affiliation(s)
- Johan Söderlund
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Maria Lindskog
- Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
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28
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Abstract
Iron-containing enzymes such as heme enzymes play crucial roles in biological systems. Three distinct heme-containing dioxygenase enzymes, tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase 1 (IDO1) and indoleamine 2,3-dioxygenase 2 (IDO2) catalyze the initial and rate-limiting step of l-tryptophan catabolism through the kynurenine pathway in mammals. Overexpression of these enzymes causes depletion of tryptophan and the accumulation of metabolic products, which contributes to tumor immune tolerance and immune dysregulation in a variety of disease pathologies. In the past few decades, IDO1 has garnered the most attention as a therapeutic target with great potential in cancer immunotherapy. Many potential inhibitors of IDO1 have been designed, synthesized and evaluated, among which indoximod (d-1-MT), INCB024360, GDC-0919 (formerly NLG-919), and an IDO1 peptide-based vaccine have advanced to the clinical trial stage. However, recently, the roles of TDO and IDO2 have been elucidated in immune suppression. In this review, the current drug discovery landscape for targeting TDO, IDO1 and IDO2 is highlighted, with particular attention to the recent use of drugs in clinical trials. Moreover, the crystal structures of these enzymes, in complex with inhibitors, and the mechanisms of Trp catabolism in the first step, are summarized to provide information for facilitating the discovery of new enzyme inhibitors.
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Affiliation(s)
- Daojing Yan
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai 200433, China.
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29
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Endothelial indoleamine 2,3-dioxygenase-1 regulates the placental vascular tone and is deficient in intrauterine growth restriction and pre-eclampsia. Sci Rep 2018; 8:5488. [PMID: 29615752 PMCID: PMC5883010 DOI: 10.1038/s41598-018-23896-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 03/21/2018] [Indexed: 11/16/2022] Open
Abstract
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). In the large arteries of the chorionic plate L-Trp induced relaxation only after upregulation of IDO1 using interferon gamma and tumor necrosis factor alpha. However, ex vivo placental perfusion of pre-constricted cotyledonic vasculature with L-Trp decreases the vessel back pressure without prior IDO1 induction. Further to this finding, IDO1 protein expression and activity is reduced in IUGR and PE when compared to gestational age–matched control tissue. These data suggest that L-Trp catabolism plays a role in the regulation of placental vascular tone, a finding which is potentially linked to placental and fetal growth. In this context our data suggest that IDO1 deficiency is related to the pathogenesis of IUGR and PE.
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30
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Carroll L, Pattison DI, Davies JB, Anderson RF, Lopez-Alarcon C, Davies MJ. Superoxide radicals react with peptide-derived tryptophan radicals with very high rate constants to give hydroperoxides as major products. Free Radic Biol Med 2018; 118:126-136. [PMID: 29496618 DOI: 10.1016/j.freeradbiomed.2018.02.033] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 02/22/2018] [Accepted: 02/23/2018] [Indexed: 11/23/2022]
Abstract
Oxidative damage is a common process in many biological systems and proteins are major targets for damage due to their high abundance and very high rate constants for reaction with many oxidants (both radicals and two-electron species). Tryptophan (Trp) residues on peptides and proteins are a major sink for a large range of biological oxidants as these side-chains have low radical reduction potentials. The resulting Trp-derived indolyl radicals (Trp•) have long lifetimes in some circumstances due to their delocalized structures, and undergo only slow reaction with molecular oxygen, unlike most other biological radicals. In contrast, we have shown previously that Trp• undergo rapid dimerization. In the current study, we show that Trp• also undergo very fast reaction with superoxide radicals, O2•-, with k 1-2 × 109 M-1 s-1. These values do not alter dramatically with peptide structure, but the values of k correlate with overall peptide positive charge, consistent with positive electrostatic interactions. These reactions compete favourably with Trp• dimerization and O2 addition, indicating that this may be a major fate in some circumstances. The Trp• + O2•- reactions occur primarily by addition, rather than electron transfer, with this resulting in high yields of Trp-derived hydroperoxides. Subsequent degradation of these species, both stimulated and native decay, gives rise to N-formylkynurenine, kynurenine, alcohols and diols. These data indicate that reaction of O2•- with Trp• should be considered as a major pathway to Trp degradation on peptides and proteins subjected to oxidative damage.
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Affiliation(s)
- Luke Carroll
- The Heart Research Institute, Sydney, Australia; Sydney Medical School, University of Sydney, Australia; Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Denmark
| | - David I Pattison
- The Heart Research Institute, Sydney, Australia; Sydney Medical School, University of Sydney, Australia
| | - Justin B Davies
- Australian Nuclear Science and Technology Organisation, Lucas Heights, Australia
| | - Robert F Anderson
- School of Chemical Sciences, University of Auckland, Auckland, New Zealand
| | - Camilo Lopez-Alarcon
- Departmento de Quimica Fisica, Facultad de Quimica, Pontificia Universidad Catolica de Chile, Chile
| | - Michael J Davies
- The Heart Research Institute, Sydney, Australia; Sydney Medical School, University of Sydney, Australia; Department of Biomedical Sciences, Panum Institute, University of Copenhagen, Denmark.
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31
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Alexandre JAC, Swan MK, Latchem MJ, Boyall D, Pollard JR, Hughes SW, Westcott J. New 4-Amino-1,2,3-Triazole Inhibitors of Indoleamine 2,3-Dioxygenase Form a Long-Lived Complex with the Enzyme and Display Exquisite Cellular Potency. Chembiochem 2018; 19:552-561. [PMID: 29240291 DOI: 10.1002/cbic.201700560] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Indexed: 11/09/2022]
Abstract
Indoleamine-2,3 dioxygenase 1 (IDO1) has emerged as a central regulator of immune responses in both normal and disease biology. Due to its established role in promoting tumour immune escape, IDO1 has become an attractive target for cancer treatment. A novel series of highly cell potent IDO1 inhibitors based on a 4-amino-1,2,3-triazole core have been identified. Comprehensive kinetic, biochemical and structural studies demonstrate that compounds from this series have a noncompetitive kinetic mechanism of action with respect to the tryptophan substrate. In co-complex crystal structures, the compounds bind in the tryptophan pocket and make a direct ligand interaction with the haem iron of the porphyrin cofactor. It is proposed that these data can be rationalised by an ordered-binding mechanism, in which the inhibitor binds an apo form of the enzyme that is not competent to bind tryptophan. These inhibitors also form a very tight, long-lived complex with the enzyme, which partially explains their exquisite cellular potency. This novel series represents an attractive starting point for the future development of potent IDO1-targeted drugs.
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Affiliation(s)
| | - Michael Kenneth Swan
- Vertex Pharmaceuticals (Europe) Limited, 86-88 Jubilee Avenue, Abingdon, Oxfordshire, OX14 4RW, UK
| | - Mike John Latchem
- Vertex Pharmaceuticals (Europe) Limited, 86-88 Jubilee Avenue, Abingdon, Oxfordshire, OX14 4RW, UK
| | - Dean Boyall
- Vertex Pharmaceuticals (Europe) Limited, 86-88 Jubilee Avenue, Abingdon, Oxfordshire, OX14 4RW, UK
| | - John Robert Pollard
- Vertex Pharmaceuticals (Europe) Limited, 86-88 Jubilee Avenue, Abingdon, Oxfordshire, OX14 4RW, UK
| | - Stuart Wynn Hughes
- Vertex Pharmaceuticals (Europe) Limited, 86-88 Jubilee Avenue, Abingdon, Oxfordshire, OX14 4RW, UK
| | - James Westcott
- Vertex Pharmaceuticals (Europe) Limited, 86-88 Jubilee Avenue, Abingdon, Oxfordshire, OX14 4RW, UK
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32
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Nienhaus K, Nienhaus GU. Different Mechanisms of Catalytic Complex Formation in Two L-Tryptophan Processing Dioxygenases. Front Mol Biosci 2018; 4:94. [PMID: 29354636 PMCID: PMC5758539 DOI: 10.3389/fmolb.2017.00094] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 12/18/2017] [Indexed: 01/25/2023] Open
Abstract
The human heme enzymes tryptophan 2,3-dioxygenase (hTDO) and indoleamine 2,3 dioxygenase (hIDO) catalyze the initial step in L-tryptophan (L-Trp) catabolism, the insertion of dioxygen into L-Trp. Overexpression of these enzymes causes depletion of L-Trp and accumulation of metabolic products, and thereby contributes to tumor immune tolerance and immune dysregulation in a variety of disease pathologies. Understanding the assembly of the catalytically active, ternary enzyme-substrate-ligand complexes is not yet fully resolved, but an essential prerequisite for designing efficient and selective de novo inhibitors. Evidence is mounting that the ternary complex forms by sequential binding of ligand and substrate in a specific order. In hTDO, the apolar L-Trp binds first, decreasing active-site solvation and, as a result, reducing non-productive oxidation of the heme iron by the dioxygen ligand, which may leave the substrate bound to a ferric heme iron. In hIDO, by contrast, dioxygen must first coordinate to the heme iron because a bound substrate would occlude ligand access to the heme iron, so the ternary complex can no longer form. Consequently, faster association of L-Trp at high concentrations results in substrate inhibition. Here, we summarize our present knowledge of ternary complex formation in hTDO and hIDO and relate these findings to structural peculiarities of their active sites.
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Affiliation(s)
- Karin Nienhaus
- Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany
| | - G Ulrich Nienhaus
- Institute of Applied Physics, Karlsruhe Institute of Technology, Karlsruhe, Germany.,Institute of Nanotechnology and Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.,Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL, United States
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33
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Nienhaus K, Hahn V, Hüpfel M, Nienhaus GU. Substrate Binding Primes Human Tryptophan 2,3-Dioxygenase for Ligand Binding. J Phys Chem B 2017; 121:7412-7420. [PMID: 28715185 DOI: 10.1021/acs.jpcb.7b03463] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The human heme enzyme tryptophan 2,3-dioxygenase (hTDO) catalyzes the insertion of dioxygen into its cognate substrate, l-tryptophan (l-Trp). Its active site structure is highly dynamic, and the mechanism of enzyme-substrate-ligand complex formation and the ensuing enzymatic reaction is not yet understood. Here we have studied complex formation in hTDO by using time-resolved optical and infrared spectroscopy with carbon monoxide (CO) as a ligand. We have observed that both substrate-free and substrate-bound hTDO coexist in two discrete conformations with greatly different ligand binding rates. In the fast rebinding hTDO conformation, there is facile ligand access to the heme iron, but it is greatly hindered in the slowly rebinding conformation. Spectroscopic evidence implicates active site solvation as playing a crucial role for the observed kinetic differences. Substrate binding shifts the conformational equilibrium markedly toward the fast species and thus primes the active site for subsequent ligand binding, ensuring that formation of the ternary complex occurs predominantly by first binding l-Trp and then the ligand. Consequently, the efficiency of catalysis is enhanced because O2 binding prior to substrate binding, resulting in nonproductive oxidation of the heme iron, is greatly suppressed.
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Affiliation(s)
- Karin Nienhaus
- Institute of Applied Physics, Karlsruhe Institute of Technology (KIT) , Wolfgang-Gaede-Straße 1, 76131 Karlsruhe, Germany
| | - Vincent Hahn
- Institute of Applied Physics, Karlsruhe Institute of Technology (KIT) , Wolfgang-Gaede-Straße 1, 76131 Karlsruhe, Germany
| | - Manuel Hüpfel
- Institute of Applied Physics, Karlsruhe Institute of Technology (KIT) , Wolfgang-Gaede-Straße 1, 76131 Karlsruhe, Germany
| | - G Ulrich Nienhaus
- Institute of Applied Physics, Karlsruhe Institute of Technology (KIT) , Wolfgang-Gaede-Straße 1, 76131 Karlsruhe, Germany.,Institute of Nanotechnology (INT) and Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT) , 76344 Eggenstein-Leopoldshafen, Germany.,Department of Physics, University of Illinois at Urbana-Champaign , 1110 W. Green Street, Urbana, Illinois 61801, United States
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34
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Coletti A, Greco FA, Dolciami D, Camaioni E, Sardella R, Pallotta MT, Volpi C, Orabona C, Grohmann U, Macchiarulo A. Advances in indoleamine 2,3-dioxygenase 1 medicinal chemistry. MEDCHEMCOMM 2017; 8:1378-1392. [PMID: 30108849 PMCID: PMC6072487 DOI: 10.1039/c7md00109f] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 05/11/2017] [Indexed: 12/11/2022]
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) mediates multiple immunoregulatory processes including the induction of regulatory T cell differentiation and activation, suppression of T cell immune responses and inhibition of dendritic cell function, which impair immune recognition of cancer cells and promote tumor growth. On this basis, this enzyme is widely recognized as a valuable drug target for the development of immunotherapeutic small molecules in oncology. Although medicinal chemistry has made a substantial contribution to the discovery of numerous chemical classes of potent IDO1 inhibitors in the past 20 years, only very few compounds have progressed in clinical trials. In this review, we provide an overview of the current understanding of structure-function relationships of the enzyme, and discuss structure-activity relationships of selected classes of inhibitors that have shaped the hitherto few successes of IDO1 medicinal chemistry. An outlook opinion is also given on trends in the design of next generation inhibitors of the enzyme.
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Affiliation(s)
- Alice Coletti
- Department of Pharmaceutical Sciences , University of Perugia , via del Liceo 1 , 06123 Perugia , Italy . ; ; Tel: +39 075 585 5160
| | - Francesco Antonio Greco
- Department of Pharmaceutical Sciences , University of Perugia , via del Liceo 1 , 06123 Perugia , Italy . ; ; Tel: +39 075 585 5160
| | - Daniela Dolciami
- Department of Pharmaceutical Sciences , University of Perugia , via del Liceo 1 , 06123 Perugia , Italy . ; ; Tel: +39 075 585 5160
| | - Emidio Camaioni
- Department of Pharmaceutical Sciences , University of Perugia , via del Liceo 1 , 06123 Perugia , Italy . ; ; Tel: +39 075 585 5160
| | - Roccaldo Sardella
- Department of Pharmaceutical Sciences , University of Perugia , via del Liceo 1 , 06123 Perugia , Italy . ; ; Tel: +39 075 585 5160
| | - Maria Teresa Pallotta
- Department of Experimental Medicine , University of Perugia , P.le Gambuli , 06132 Perugia , Italy
| | - Claudia Volpi
- Department of Experimental Medicine , University of Perugia , P.le Gambuli , 06132 Perugia , Italy
| | - Ciriana Orabona
- Department of Experimental Medicine , University of Perugia , P.le Gambuli , 06132 Perugia , Italy
| | - Ursula Grohmann
- Department of Experimental Medicine , University of Perugia , P.le Gambuli , 06132 Perugia , Italy
| | - Antonio Macchiarulo
- Department of Pharmaceutical Sciences , University of Perugia , via del Liceo 1 , 06123 Perugia , Italy . ; ; Tel: +39 075 585 5160
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35
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Asghar K, Farooq A, Zulfiqar B, Rashid MU. Indoleamine 2,3-dioxygenase: As a potential prognostic marker and immunotherapeutic target for hepatocellular carcinoma. World J Gastroenterol 2017; 23:2286-2293. [PMID: 28428708 PMCID: PMC5385395 DOI: 10.3748/wjg.v23.i13.2286] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 02/23/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
Tumor cells induce an immunosuppressive microenvironment which leads towards tumor immune escape. Understanding the intricacy of immunomodulation by tumor cells is essential for immunotherapy. Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive enzyme which mediates tumor immune escape in various cancers including hepatocellular carcinoma (HCC). IDO up-regulation in HCC may lead to recruitment of regulatory T-cells into tumor microenvironment and therefore inhibit local immune responses and promote metastasis. HCC associated fibroblasts stimulate natural killer cells dysfunction through prostaglandin E2 and subsequently IDO promotes favorable condition for tumor metastasis. IDO up-regulation induces immunosuppression and may enhance the risk of hepatitis C virus and hepatitis B virus induced HCC. Therefore, IDO inhibitors as adjuvant therapeutic agents may have clinical implications in HCC. This review proposes future prospects of IDO not only as a therapeutic target but also as a prognostic marker for HCC.
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36
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Nienhaus K, Nickel E, Nienhaus GU. Substrate binding in human indoleamine 2,3-dioxygenase 1: A spectroscopic analysis. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2017; 1865:453-463. [DOI: 10.1016/j.bbapap.2017.02.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 01/22/2017] [Accepted: 02/07/2017] [Indexed: 11/27/2022]
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37
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Fang K, Wu S, Dong G, Wu Y, Chen S, Liu J, Wang W, Sheng C. Discovery of IDO1 and DNA dual targeting antitumor agents. Org Biomol Chem 2017; 15:9992-9995. [DOI: 10.1039/c7ob02529g] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The development of small molecules for cancer immunotherapy is highly challenging and indoleamine 2,3-dioxygenase 1 (IDO1) represents a promising target.
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Affiliation(s)
- Kun Fang
- School of Pharmacy
- East China University of Science and Technology
- Shanghai 200237
- P. R. China
- Department of Medicinal Chemistry
| | - Shanchao Wu
- Department of Medicinal Chemistry
- School of Pharmacy
- Second Military Medical University
- Shanghai 200433
- P. R. China
| | - Guoqiang Dong
- Department of Medicinal Chemistry
- School of Pharmacy
- Second Military Medical University
- Shanghai 200433
- P. R. China
| | - Ying Wu
- Department of Medicinal Chemistry
- School of Pharmacy
- Second Military Medical University
- Shanghai 200433
- P. R. China
| | - Shuqiang Chen
- Department of Medicinal Chemistry
- School of Pharmacy
- Second Military Medical University
- Shanghai 200433
- P. R. China
| | - Jianhe Liu
- Department of Urology
- Xinhua Hospital
- Shanghai Jiao Tong University
- School of Medicine
- Shanghai
| | - Wei Wang
- School of Pharmacy
- East China University of Science and Technology
- Shanghai 200237
- P. R. China
- Department of Chemistry and Chemical Biology
| | - Chunquan Sheng
- Department of Medicinal Chemistry
- School of Pharmacy
- Second Military Medical University
- Shanghai 200433
- P. R. China
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38
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Strasser B, Becker K, Fuchs D, Gostner JM. Kynurenine pathway metabolism and immune activation: Peripheral measurements in psychiatric and co-morbid conditions. Neuropharmacology 2017; 112:286-296. [DOI: 10.1016/j.neuropharm.2016.02.030] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Revised: 02/17/2016] [Accepted: 02/23/2016] [Indexed: 12/14/2022]
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González Esquivel D, Ramírez-Ortega D, Pineda B, Castro N, Ríos C, Pérez de la Cruz V. Kynurenine pathway metabolites and enzymes involved in redox reactions. Neuropharmacology 2017; 112:331-345. [DOI: 10.1016/j.neuropharm.2016.03.013] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 02/28/2016] [Accepted: 03/06/2016] [Indexed: 11/27/2022]
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40
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Larkin PB, Sathyasaikumar KV, Notarangelo FM, Funakoshi H, Nakamura T, Schwarcz R, Muchowski PJ. Tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase 1 make separate, tissue-specific contributions to basal and inflammation-induced kynurenine pathway metabolism in mice. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1860:2345-2354. [PMID: 27392942 PMCID: PMC5808460 DOI: 10.1016/j.bbagen.2016.07.002] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 06/25/2016] [Accepted: 07/04/2016] [Indexed: 01/06/2023]
Abstract
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. METHODS Here, we conducted a comprehensive biochemical characterization of mice with a targeted deletion of either tryptophan 2,3-dioxygenase (TDO) or indoleamine 2,3-dioxygenase (IDO), the two initial rate-limiting enzymes of the KP. These enzymes catalyze the same reaction, but differ in biochemical characteristics and expression patterns. We measured KP metabolite levels and enzyme activities and expression in several tissues in basal and immune-stimulated conditions. RESULTS AND CONCLUSIONS Although our study revealed several unexpected downstream effects on KP metabolism in both knockout mice, the results were essentially consistent with TDO-mediated control of basal KP metabolism and a role of IDO in phenomena involving stimulation of the immune system.
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Affiliation(s)
- Paul B Larkin
- Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, CA, USA
| | - Korrapati V Sathyasaikumar
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Francesca M Notarangelo
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Hiroshi Funakoshi
- Center for Advanced Research and Education (CARE), Asahikawa Medical University, 1-1-1- Higashinijo Midorigaoka, Asahikawa 078-8510, Japan
| | | | - Robert Schwarcz
- Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Paul J Muchowski
- Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, CA, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA; Department of Neurology, University of California, San Francisco, CA, USA; The Taube-Koret Center for Huntington's Disease Research, San Francisco, CA, USA.
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41
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Álvarez L, Lewis-Ballester A, Roitberg A, Estrin DA, Yeh SR, Marti MA, Capece L. Structural Study of a Flexible Active Site Loop in Human Indoleamine 2,3-Dioxygenase and Its Functional Implications. Biochemistry 2016; 55:2785-93. [PMID: 27112409 DOI: 10.1021/acs.biochem.6b00077] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Human indoleamine 2,3-dioxygenase catalyzes the oxidative cleavage of tryptophan to N-formyl kynurenine, the initial and rate-limiting step in the kynurenine pathway. Additionally, this enzyme has been identified as a possible target for cancer therapy. A 20-amino acid protein segment (the JK loop), which connects the J and K helices, was not resolved in the reported hIDO crystal structure. Previous studies have shown that this loop undergoes structural rearrangement upon substrate binding. In this work, we apply a combination of replica exchange molecular dynamics simulations and site-directed mutagenesis experiments to characterize the structure and dynamics of this protein region. Our simulations show that the JK loop can be divided into two regions: the first region (JK loop(C)) displays specific and well-defined conformations and is within hydrogen bonding distance of the substrate, while the second region (JK loop(N)) is highly disordered and exposed to the solvent. The peculiar flexible nature of JK loop(N) suggests that it may function as a target for post-translational modifications and/or a mediator for protein-protein interactions. In contrast, hydrogen bonding interactions are observed between the substrate and Thr379 in the highly conserved "GTGG" motif of JK loop(C), thereby anchoring JK loop(C) in a closed conformation, which secures the appropriate substrate binding mode for catalysis. Site-directed mutagenesis experiments confirm the key role of this residue, highlighting the importance of the JK loop(C) conformation in regulating the enzymatic activity. Furthermore, the existence of the partially and totally open conformations in the substrate-free form suggests a role of JK loop(C) in controlling substrate and product dynamics.
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Affiliation(s)
- Lucía Álvarez
- Dto. de Química Inorgánica, Analítica y Química Física, Fac. de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Buenos Aires C1428EGA, Argentina.,INQUIMAE-CONICET , Buenos Aires C1428EGA, Argentina
| | - Ariel Lewis-Ballester
- Department of Physiology and Biophysics, Albert Einstein College of Medicine , 1300 Morris Park Avenue, New York, New York 10461, United States
| | - Adrián Roitberg
- Department of Chemistry, University of Florida , 440 Leigh Hall, Gainesville, Florida 32611-7200, United States
| | - Darío A Estrin
- Dto. de Química Inorgánica, Analítica y Química Física, Fac. de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Buenos Aires C1428EGA, Argentina.,INQUIMAE-CONICET , Buenos Aires C1428EGA, Argentina
| | - Syun-Ru Yeh
- Department of Physiology and Biophysics, Albert Einstein College of Medicine , 1300 Morris Park Avenue, New York, New York 10461, United States
| | - Marcelo A Marti
- Dto. de Química Biologica Fac. de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Buenos Aires C1428EGA, Argentina.,IQUIBICEN-CONICET , Buenos Aires C1428EGA, Argentina
| | - Luciana Capece
- Dto. de Química Inorgánica, Analítica y Química Física, Fac. de Ciencias Exactas y Naturales, Universidad de Buenos Aires , Buenos Aires C1428EGA, Argentina.,INQUIMAE-CONICET , Buenos Aires C1428EGA, Argentina
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42
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Takahashi S, Iizuka H, Kuwabara R, Naito Y, Sakamoto T, Miyagi A, Onozato M, Ichiba H, Fukushima T. Determination ofl-tryptophan andl-kynurenine derivatized with (R)-4-(3-isothiocyanatopyrrolidin-1-yl)-7-(N,N-dimethylaminosulfonyl)-2,1,3-benzoxadiazole by LC-MS/MS on a triazole-bonded column and their quantification in human serum. Biomed Chromatogr 2016; 30:1481-6. [DOI: 10.1002/bmc.3709] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Revised: 02/05/2016] [Accepted: 02/11/2016] [Indexed: 11/08/2022]
Affiliation(s)
- Shuuhei Takahashi
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences; Toho University; 2-2-1 Miyama, Funabashi-shi Chiba 274-8510 Japan
| | - Hideaki Iizuka
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences; Toho University; 2-2-1 Miyama, Funabashi-shi Chiba 274-8510 Japan
| | - Ryousuke Kuwabara
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences; Toho University; 2-2-1 Miyama, Funabashi-shi Chiba 274-8510 Japan
| | - Yoko Naito
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences; Toho University; 2-2-1 Miyama, Funabashi-shi Chiba 274-8510 Japan
| | - Tatsuya Sakamoto
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences; Toho University; 2-2-1 Miyama, Funabashi-shi Chiba 274-8510 Japan
| | - Aya Miyagi
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences; Toho University; 2-2-1 Miyama, Funabashi-shi Chiba 274-8510 Japan
| | - Mayu Onozato
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences; Toho University; 2-2-1 Miyama, Funabashi-shi Chiba 274-8510 Japan
| | - Hideaki Ichiba
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences; Toho University; 2-2-1 Miyama, Funabashi-shi Chiba 274-8510 Japan
| | - Takeshi Fukushima
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences; Toho University; 2-2-1 Miyama, Funabashi-shi Chiba 274-8510 Japan
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43
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Slyepchenko A, Maes M, Köhler CA, Anderson G, Quevedo J, Alves GS, Berk M, Fernandes BS, Carvalho AF. T helper 17 cells may drive neuroprogression in major depressive disorder: Proposal of an integrative model. Neurosci Biobehav Rev 2016; 64:83-100. [PMID: 26898639 DOI: 10.1016/j.neubiorev.2016.02.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2015] [Revised: 01/04/2016] [Accepted: 02/02/2016] [Indexed: 02/07/2023]
Abstract
The exact pathophysiology of major depressive disorder (MDD) remains elusive. The monoamine theory, which hypothesizes that MDD emerges as a result of dysfunctional serotonergic, dopaminergic and noradrenergic pathways, has guided the therapy of this illness for several decades. More recently, the involvement of activated immune, oxidative and nitrosative stress pathways and of decreased levels of neurotrophic factors has provided emerging insights regarding the pathophysiology of MDD, leading to integrated theories emphasizing the complex interplay of these mechanisms that could lead to neuroprogression. In this review, we propose an integrative model suggesting that T helper 17 (Th17) cells play a pivotal role in the pathophysiology of MDD through (i) microglial activation, (ii) interactions with oxidative and nitrosative stress, (iii) increases of autoantibody production and the propensity for autoimmunity, (iv) disruption of the blood-brain barrier, and (v) dysregulation of the gut mucosa and microbiota. The clinical and research implications of this model are discussed.
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Affiliation(s)
- Anastasiya Slyepchenko
- Womens Health Concerns Clinic, St. Joseph's Healthcare Hamilton, MiNDS Program, McMaster University; Hamilton, Ontario, Canada
| | - Michael Maes
- IMPACT Strategic Research Centre, Deakin University, School of Medicine and Barwon Health, Geelong, VIC, Australia
| | - Cristiano A Köhler
- Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | | | - João Quevedo
- Center for Translational Psychiatry, Department of Psychiatry and Behavioral Sciences, The University of Texas Medical School at Houston, Houston, TX, USA; Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil
| | - Gilberto S Alves
- Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
| | - Michael Berk
- IMPACT Strategic Research Centre, Deakin University, School of Medicine and Barwon Health, Geelong, VIC, Australia; Department of Psychiatry, Florey Institute of Neuroscience and Mental Health, Orygen, The National Centre of Excellence in Youth Mental Health and Orygen Youth Health Research Centre, University of Melbourne, Parkville, VIC, Australia
| | - Brisa S Fernandes
- IMPACT Strategic Research Centre, Deakin University, School of Medicine and Barwon Health, Geelong, VIC, Australia; Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - André F Carvalho
- Department of Clinical Medicine and Translational Psychiatry Research Group, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil.
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44
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Astrocytes as Pharmacological Targets in the Treatment of Schizophrenia. HANDBOOK OF BEHAVIORAL NEUROSCIENCE 2016. [DOI: 10.1016/b978-0-12-800981-9.00025-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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45
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Jortzik E, Zocher K, Isernhagen A, Mailu BM, Rahlfs S, Viola G, Wittlin S, Hunt NH, Ihmels H, Becker K. Benzo[b]quinolizinium Derivatives Have a Strong Antimalarial Activity and Inhibit Indoleamine Dioxygenase. Antimicrob Agents Chemother 2016; 60:115-25. [PMID: 26459907 PMCID: PMC4704160 DOI: 10.1128/aac.01066-15] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 10/06/2015] [Indexed: 12/16/2022] Open
Abstract
The heme-containing enzymes indoleamine 2,3-dioxygenase-1 (IDO-1) and IDO-2 catalyze the conversion of the essential amino acid tryptophan into kynurenine. Metabolites of the kynurenine pathway and IDO itself are involved in immunity and the pathology of several diseases, having either immunoregulatory or antimicrobial effects. IDO-1 plays a central role in the pathogenesis of cerebral malaria, which is the most severe and often fatal neurological complication of infection with Plasmodium falciparum. Mouse models are usually used to study the underlying pathophysiology. In this study, we screened a natural compound library against mouse IDO-1 and identified 8-aminobenzo[b]quinolizinium (compound 2c) to be an inhibitor of IDO-1 with potency at nanomolar concentrations (50% inhibitory concentration, 164 nM). Twenty-one structurally modified derivatives of compound 2c were synthesized for structure-activity relationship analyses. The compounds were found to be selective for IDO-1 over IDO-2. We therefore compared the roles of prominent amino acids in the catalytic mechanisms of the two isoenzymes via homology modeling, site-directed mutagenesis, and kinetic analyses. Notably, methionine 385 of IDO-2 was identified to interfere with the entrance of l-tryptophan to the active site of the enzyme, which explains the selectivity of the inhibitors. Most interestingly, several benzo[b]quinolizinium derivatives (6 compounds with 50% effective concentration values between 2.1 and 6.7 nM) were found to be highly effective against P. falciparum 3D7 blood stages in cell culture with a mechanism independent of IDO-1 inhibition. We believe that the class of compounds presented here has unique characteristics; it combines the inhibition of mammalian IDO-1 with strong antiparasitic activity, two features that offer potential for drug development.
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MESH Headings
- Animals
- Antimalarials/chemical synthesis
- Antimalarials/chemistry
- Antimalarials/pharmacology
- Cell Line, Tumor
- Cell Survival/drug effects
- Cloning, Molecular
- Crystallography, X-Ray
- Erythrocytes/drug effects
- Erythrocytes/parasitology
- Escherichia coli/genetics
- Escherichia coli/metabolism
- Gene Expression
- Humans
- Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors
- Indoleamine-Pyrrole 2,3,-Dioxygenase/chemistry
- Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics
- Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
- Kynurenine/metabolism
- Malaria/drug therapy
- Malaria/parasitology
- Mice
- Mutagenesis, Site-Directed
- Plasmodium berghei/drug effects
- Plasmodium berghei/enzymology
- Plasmodium berghei/genetics
- Plasmodium falciparum/drug effects
- Plasmodium falciparum/enzymology
- Plasmodium falciparum/genetics
- Quinolizines/chemical synthesis
- Quinolizines/chemistry
- Quinolizines/pharmacology
- Recombinant Proteins/chemistry
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Structure-Activity Relationship
- Tryptophan/antagonists & inhibitors
- Tryptophan/metabolism
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Affiliation(s)
- Esther Jortzik
- Biochemistry and Molecular Biology, Justus Liebig University, Giessen, Germany
| | - Kathleen Zocher
- Biochemistry and Molecular Biology, Justus Liebig University, Giessen, Germany
| | - Antje Isernhagen
- Biochemistry and Molecular Biology, Justus Liebig University, Giessen, Germany
| | - Boniface M Mailu
- Biochemistry and Molecular Biology, Justus Liebig University, Giessen, Germany
| | - Stefan Rahlfs
- Biochemistry and Molecular Biology, Justus Liebig University, Giessen, Germany
| | - Giampietro Viola
- Department of Woman's and Child's Health, University of Padova, Padua, Italy
| | - Sergio Wittlin
- Swiss Tropical and Public Health Institute and University of Basel, Basel, Switzerland
| | - Nicholas H Hunt
- Molecular Immunopathology Unit, University of Sydney, Sydney, NSW, Australia
| | - Heiko Ihmels
- Department of Chemistry and Biology, University of Siegen, Siegen, Germany
| | - Katja Becker
- Biochemistry and Molecular Biology, Justus Liebig University, Giessen, Germany
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46
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Abstract
Indoleamine 2,3-dioxygenase (IDO, subsequently named IDO1) can degrade the level of essential amino acid tryptophan in mammals, and catalyze the initial and rate-limiting step through the kynurenine pathway. Broad evidence implies that IDO is overexpressed in both tumor cells and antigen-presenting cells, facilitating the escape of malignant tumors from immune surveillance. In the past decades, the inhibition of IDO has been one of the most promising areas in cancer immunotherapy and many potential inhibitors of IDO have been designed, synthesized and evaluated, among which d-1-methyl-tryptophan and INCB24360 have advanced to clinical trial stage. This review aims to give an overview of the rationale for IDO as a therapeutic target as well as the research progress of IDO inhibitors.
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47
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Wang Y, Zhu W, Qiu J, Wang X, Zhang P, Yan J, Zhou Z. Monitoring tryptophan metabolism after exposure to hexaconazole and the enantioselective metabolism of hexaconazole in rat hepatocytes in vitro. JOURNAL OF HAZARDOUS MATERIALS 2015; 295:9-16. [PMID: 25863579 DOI: 10.1016/j.jhazmat.2015.04.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 03/24/2015] [Accepted: 04/02/2015] [Indexed: 06/04/2023]
Abstract
In the present study, the enantioselective metabolism, cytotoxicity of hexaconazole and its influence on tryptophan metabolism in rat hepatocytes in vitro were investigated. Following the exposure of primary rat hepatocytes to rac-hexaconazole, the concentrations of its enantiomers in the media were determined by chiral high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The half-lives (t1/2) of (+)-hexaconazole and (-)-hexaconazole were 5.17 h and 19.80 h, respectively, indicating that the metabolic process was enantioselective with (-)-hexaconazole enrichment. Using the MTT method, the EC50 values of rac-hexaconazole, (+)-hexaconazole and (-)-hexaconazole after 12h of exposure were determined to be 71.62, 62.71 and 67.94 μM, respectively. Tryptophan metabolism was monitored using metabolomics profiling techniques. Hexaconazole and its enantiomers caused the down-regulation of tryptophan levels and the up-regulation of kynurenine (KYN) levels, suggesting a role for hexaconazole in the activation of the KYN pathway and providing information for the mechanism of its toxicity.
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Affiliation(s)
- Yao Wang
- Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
| | - Wentao Zhu
- Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
| | - Jing Qiu
- Institute of Quality Standards and Testing Technology for Agro-Products, Key Laboratory of Agro-Product Quality and Safety, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Xinru Wang
- Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
| | - Ping Zhang
- Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
| | - Jin Yan
- Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
| | - Zhiqiang Zhou
- Department of Applied Chemistry, China Agricultural University, Beijing 100193, China.
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48
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Abstract
IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1’s catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.
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49
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Chung LW, Sameera WMC, Ramozzi R, Page AJ, Hatanaka M, Petrova GP, Harris TV, Li X, Ke Z, Liu F, Li HB, Ding L, Morokuma K. The ONIOM Method and Its Applications. Chem Rev 2015; 115:5678-796. [PMID: 25853797 DOI: 10.1021/cr5004419] [Citation(s) in RCA: 811] [Impact Index Per Article: 81.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Lung Wa Chung
- †Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China
| | - W M C Sameera
- ‡Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho, Sakyo, Kyoto 606-8103, Japan
| | - Romain Ramozzi
- ‡Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho, Sakyo, Kyoto 606-8103, Japan
| | - Alister J Page
- §Newcastle Institute for Energy and Resources, The University of Newcastle, Callaghan 2308, Australia
| | - Miho Hatanaka
- ‡Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho, Sakyo, Kyoto 606-8103, Japan
| | - Galina P Petrova
- ∥Faculty of Chemistry and Pharmacy, University of Sofia, Bulgaria Boulevard James Bourchier 1, 1164 Sofia, Bulgaria
| | - Travis V Harris
- ‡Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho, Sakyo, Kyoto 606-8103, Japan.,⊥Department of Chemistry, State University of New York at Oswego, Oswego, New York 13126, United States
| | - Xin Li
- #State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Zhuofeng Ke
- ∇School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China
| | - Fengyi Liu
- ○Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, Shaanxi 710119, China
| | - Hai-Bei Li
- ■School of Ocean, Shandong University, Weihai 264209, China
| | - Lina Ding
- ▲School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Keiji Morokuma
- ‡Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho, Sakyo, Kyoto 606-8103, Japan
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50
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Maddison DC, Giorgini F. The kynurenine pathway and neurodegenerative disease. Semin Cell Dev Biol 2015; 40:134-41. [PMID: 25773161 DOI: 10.1016/j.semcdb.2015.03.002] [Citation(s) in RCA: 203] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 03/04/2015] [Indexed: 11/30/2022]
Abstract
Neuroactive metabolites of the kynurenine pathway (KP) of tryptophan degradation have been closely linked to the pathogenesis of several neurodegenerative diseases. Tryptophan is an essential amino acid required for protein synthesis, and in higher eukaryotes is also converted into the key neurotransmitters serotonin and tryptamine. However, in mammals >95% of tryptophan is metabolized through the KP, ultimately leading to the production of nicotinamide adenosine dinucleotide (NAD(+)). A number of the pathway metabolites are neuroactive; e.g. can modulate activity of several glutamate receptors and generate/scavenge free radicals. Imbalances in absolute and relative levels of KP metabolites have been strongly associated with neurodegenerative disorders including Huntington's, Alzheimer's, and Parkinson's diseases. The KP has also been implicated in the pathogenesis of other brain disorders (e.g. schizophrenia, bipolar disorder), as well as several cancers and autoimmune disorders such as HIV. Pharmacological and genetic manipulation of the KP has been shown to ameliorate neurodegenerative phenotypes in a number of model organisms, suggesting that it could prove to be a viable target for the treatment of such diseases. Here, we provide an overview of the KP, its role in neurodegeneration and the current strategies for therapeutic targeting of the pathway.
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Affiliation(s)
- Daniel C Maddison
- Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK
| | - Flaviano Giorgini
- Department of Genetics, University of Leicester, University Road, Leicester LE1 7RH, UK.
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