DOCSLIB.ORG

Inhibition of Interferon-Mediated Induction of Indoleamine 2,3

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Inhibition of Interferon-Mediated Induction of Indoleamine 2,3 Proc. Natt Acad. Sci. USA Vol. 78, No. 12, pp. 7327-7330, December 1981 Biochemistry Inhibition of interferon-mediated induction of indoleamine 2,3-dioxygenase in mouse lung by inhibitors of prostaglandin biosynthesis (lung slices/cyclooxygenase/phospholipase AO) SHIGETOSHI SAYAMA*, RYOTARO YOSHIDA*, TOHRU OKUt, JIRO IMANISHIt, TSUNATARO KISHIDAt, AND OSAMU HAYAISHI* *Department of Medical Chemistry, Kyoto University Faculty of Medicine, Kyoto 606, Japan; and tDepartment of Microbiology, Kyoto Prefectural University of Medicine, Kyoto 602, Japan Contributed by Osamu Hayaishi, August 10, 1981 ABSTRACT Inhibitors of fatty acid cyclooxygenase such as I'lnergie Atomique, France, and purified by column chro- indomethacin (0.1 mM), phenylbutazone (0.3 mM), and aspirin (1 matography on Dowex 50W-X2 (H' form; 0.5 x 1.0 cm) as de- mM) were found to suppress almost completely the interferon- scribed (2). Catalase was a product of Boehringer Mannheim mediated induction ofindoleamine 2,3-dioxygenase in mouse lung and was dialyzed to remove a thymol preservative. Methylene slices. However, phenacetin, an anti-inflammatory agent devoid blue and ascorbic acid were obtained from Wako Pure Chem- ofcyclooxygenase inhibitory activity, and sodium salicylate, a weak icals (Osaka, Japan). Aspirin, phenylbutazone, indomethacin, inhibitor ofcyclooxygenase, were much less active under identical dexamethasone, betamethasone, and 17(3estradiol were pur- conditions. Glucocorticoids including dexamethasone, betametha- chased from Sigma. Sodium salicylate, testosterone, and phen- sone, and cortisone, all of which are inhibitors of phospholipase acetin were from Nakarai Chemicals (Kyoto, A2, blocked induction of the dioxygenase by interferon in the na- Japan), and aldos- nomolar range, whereas other steroid hormones, such as aldos- terone was from Merck (Darmstadt, Federal Republic of terone, testosterone, and 171-estradiol, were all but ineffective. Germany). Cortisone acetate was a product of Banyu Pharma- These results suggest that the enzymes phospholipase A2 and fatty ceutical (Tokyo). Collagenase (type III) was purchased from acid cyclooxygenase, both of which are essential for the biosyn- Worthington and trypsin was from Difco. Mouse L-cell inter- thesis of prostaglandins, play an important role in the induction feron (specific activity, 2.96 X 10r' units/mg of protein) was of indoleamine 2,3-dioxygenase by interferon. purified as described (3). All other chemicals were of reagent grade. Indoleamine 2,3-dioxygenase [IDOase; indoleamine:oxygen Animals. Specific-pathogen-free male slc:ICR mice weighing 2,3-oxidoreductase (decyclizing)], a heme-containing enzyme, 31 ± 2 g were purchased from the Shizuoka Agricultural Co- catalyzes oxidative cleavage ofthe indole ring ofvarious indole- operative Association for Laboratory Animals (Shizuoka, Japan), amine derivatives such as tryptophan, 5-hydroxytryptophan, and raised under specific-pathogen-free conditions at 25 ± 20C tryptamine, and serotonin, with the incorporation oftwo atoms and -50% humidity in the Institute of Laboratory Animals, of oxygen into the pyrrole moiety (1). The enzyme is ubiqui- Kyoto University. tously distributed in various organs ofmammals except for the Incubation of Tissues, Enzyme Assay, and Viability of Dis- liver (2). We previously reported that IDOase is markedly in- persed Lung Cells. The preparation of lung slices, incubation duced by mouse interferon in mouse lung slices (3). conditions, and enzyme assays were carried out as described Recently, considerable attention has been directed to the in- (3) except that the medium did not contain fetal calfserum. After terferon-associated changes in the level ofprostaglandins (4, 5). incubation, lung slices were totally digested with 0.1% trypsin/ Pottathil et aL (6) have shown that establishment of the inter- 0.2% collagenase and viability of the dispersed lung cells was feron-mediated antiviral state is suppressed by nonsteroidal estimated by the trypan blue exclusion technique (8). Detailed anti-inflammatory agents that inhibit fatty acid cyclooxygenase. methods for the tissue digestion will be described elsewhere. In addition, Chandrabose et aL (7) showed that cells of the in- Protein Determination. Protein concentration was deter- terferon-resistant R3 clone of L 1210 mouse leukemia cells lack mined by the method of Lowry et aL (9) using bovine serum fatty acid cyclooxygenase activity. To elucidate the precise albumin as standard. mechanism of the IDOase induction in the mouse lung by in- terferon, effects of various anti-inflammatory agents on the RESULTS IDOase induction were examined. The present study shows When mouse lung slices were incubated with interferon (104 that nonsteroidal anti-inflammatory agents that possess fatty units/ml), the specific activity of IDOase6in the supernatant acid cyclooxygenase inhibitory activity and steroid hormones fraction of the slices increased almost linearly for 50 hr. then that inhibit phospholipase A2 suppress the induction ofIDOase started to decrease, and reached a normal value after --7 days by mouse interferon. as reported previously (3) (Fig. 1). When indomethacin (10 or 30 AiM) was added simultaneously with interferon (104 units/ ml) to the mouse lung slices, the time course of the IDOase MATERIALS AND METHODS induction was essentially identical but the initial rate, as well Chemicals. L-[ring-2-'4C]Tryptophan (30-35 Ci/mol; 1 Ci as the extent ofinduction, decreased in a dose dependent man- = 3.7 X 10'° becquerels) was purchased from Commisariat a ner. In the absence of interferon, slight but reproducible en- The publication costs ofthis article were defrayed in part by page charge Abbreviations: IDOase, indoleamine 2,3-dioxygenase [indole- payment. This article must therefore be hereby marked "advertise- amine:oxygen 2,3-oxidoreductase(decyclizing)]; IC50, concentration re- ment" in accordance with 18 U. S. C. §1734 solely to indicate this fact. quired for 50% inhibition. 7327 Downloaded by guest on September 25, 2021 7328 Biochemistry: Sayama et aL Proc. Nad Acad. Sci. USA 78 (1981) 100 *d 04 c0~ U bo < 50 U~~~~~ 2 4 6 Time, days FIG. 1. Time course of induction of IDOase by interferon with or without indomethacin. Indomethacin was added simultaneously with lo1-6 10-5 10-4 10-3 interferon (104 units/ml) at zero time and mouse lung slices were in- cubated. Samples were harvested at the indicated times and the spe- Inhibitor, M cific activity of IDOase was determined. Results represent means of duplicate experiments. o, Untreated; 9, interferon alone; A, interferon/ FIG. 2. Effects of nonsteroidal anti-inflammatory agents on in- 10 indomethacin; A, interferon/30 indomethacin. duction of IDOase by interferon. Anti-inflammatory agents were ttM /iM added simultaneously with interferon (104 units/ml) to the culture medium at zero time, and incubation was carried out for 30 hr. Enzyme activity is expressed as nmol of product per hr/mg of protein. Results zyme induction was observed as reported previously (3). The represent mean ± SEM of quadruplicate experiments. Enzyme activ- induction in the absence of interferon was inhibited by indo- ity of interferon-treated samples minus enzyme activity of untreated methacin to the same extent. The IDOase activity was deter- samples in the absence of inhibitors represents 100% activity. o, As- mined at 30 hr of incubation in the following experiments be- pirin; *, sodium salicylate; A, indomethacin; A, phenylbutazone; a, cause this incubation time seemed most suitable to show clearly phenacetin. the effects of various agents on the induction of IDOase by interferon. pholipase A2 reported by other investigators (14), although the When inhibitors offatty acid cyclooxygenase such as aspirin, effective concentrations were three orders ofmagnitude higher indomethacin, and phenylbutazone were added simultaneously in the latter case. with interferon (10 units/ml), these agents blocked the induc- tion ofIDOase by interferon in a dose-dependent manner (Fig. 2). In contrast, sodium salicylate, a weak inhibitor offatty acid DISCUSSION cyclooxygenase, and phenacetin, an anti-inflammatory agent Interferon has been reported to be involved in various biological devoid of cyclooxygenase inhibitory activity, were much less events including establishment ofthe antiviral state (15), phago- effective at 1 mM. The total number of cells in the dispersed cytosis (16), cell-mediated immunity (17), and tumorigenesis cell suspensions from lung slices was almost the same in the (18). Numerous studies have been carried out concerning the presence and absence of inhibitors during the incubation pe- mechanisms of these interferon actions. Four enzymes (2'- riod, and the viability ofcells after 30 hrofincubation was >90% 5')oligoadenylate synthetase (19), protein kinase (20), phospho- in all cases (data not shown). The concentrations of inhibitors diesterase (21), and IDOase (3), have been reported to date to required for 50% inhibition (IC50) ofIDOase induction showed be induced by interferon. The first two have been suggested fairly good correlation with those of fatty acid cyclooxygenase as mediators in the establishment of the antiviral state by in- reported by other investigators (10-12) (Table 1). terferon (22). However, Wood and Hovanessian reported re- To ascertain that this inhibition ofenzyme induction by non- cently that (2'-5')oligoadenylate increased in embryonal carci- steroidal anti-inflammatory agents is due to inhibition of the noma cells without consequent
Load more

Recommended publications
  • Bioinorganic Chemistry of Nickel
    inorganics Editorial Bioinorganic Chemistry of Nickel Michael J. Maroney 1,* and Stefano Ciurli 2,* 1 Department of Chemistry and Program in Molecular and Cellular Biology, University of Massachusetts Amherst, 240 Thatcher Rd. Life Sciences, Laboratory Rm N373, Amherst, MA 01003, USA 2 Laboratory of Bioinorganic Chemistry, Department of Pharmacy and Biotechnology, University of Bologna, Viale G. Fanin 40, I-40127 Bologna, Italy * Correspondence: [email protected] (M.J.M.); [email protected] (S.C.) Received: 11 October 2019; Accepted: 11 October 2019; Published: 30 October 2019 Following the discovery of the first specific and essential role of nickel in biology in 1975 (the dinuclear active site of the enzyme urease) [1], nickel has become a major player in bioinorganic chemistry,particularly in microorganisms, having impacts on both environmental settings and human pathologies. At least nine classes of enzymes are now known to require nickel in their active sites, including catalysis of redox [(Ni,Fe) hydrogenases, carbon monoxide dehydrogenase, methyl coenzyme M reductase, acetyl coenzyme A synthase, superoxide dismutase] and nonredox (glyoxalase I, acireductone dioxygenase, lactate isomerase, urease) chemistries. In addition, the dark side of nickel has been illuminated in regard to its participation in microbial pathogenesis, cancer, and immune responses. Knowledge gleaned from the investigations of inorganic chemists into the coordination and redox chemistry of this element have boosted the understanding of these biological roles of nickel in each context. In this issue, eleven contributions, including four original research articles and seven critical reviews, will update the reader on the broad spectrum of the role of nickel in biology.
    [Show full text]
  • Cysteine Dioxygenase 1 Is a Metabolic Liability for Non-Small Cell Lung Cancer Authors: Yun Pyo Kang1, Laura Torrente1, Min Liu2, John M
    bioRxiv preprint doi: https://doi.org/10.1101/459602; this version posted November 1, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer Authors: Yun Pyo Kang1, Laura Torrente1, Min Liu2, John M. Asara3,4, Christian C. Dibble5,6 and Gina M. DeNicola1,* Affiliations: 1 Department of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA 2 Proteomics and Metabolomics Core Facility, Moffitt Cancer Center and Research Institute, Tampa, FL, USA 3 Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA 4 Department of Medicine, Harvard Medical School, Boston, MA, USA 5 Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, MA, USA 6 Department of Pathology, Harvard Medical School, Boston, MA, USA *Correspondence to: [email protected]. Keywords: KEAP1, NRF2, cysteine, CDO1, sulfite Summary NRF2 is emerging as a major regulator of cellular metabolism. However, most studies have been performed in cancer cells, where co-occurring mutations and tumor selective pressures complicate the influence of NRF2 on metabolism. Here we use genetically engineered, non-transformed primary cells to isolate the most immediate effects of NRF2 on cellular metabolism. We find that NRF2 promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1 (CDO1), which catalyzes the irreversible metabolism of cysteine to cysteine sulfinic acid (CSA). Notably, CDO1 is preferentially silenced by promoter methylation in non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2.
    [Show full text]
  • Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer George C
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Scholarship, Research, and Creative Work at Bryn Mawr College | Bryn Mawr College... Bryn Mawr College Scholarship, Research, and Creative Work at Bryn Mawr College Chemistry Faculty Research and Scholarship Chemistry 2018 Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer George C. Prendergast William Paul Malachowski Bryn Mawr College, [email protected] Arpita Mondal Peggy Scherle Alexander J. Muller Let us know how access to this document benefits ouy . Follow this and additional works at: https://repository.brynmawr.edu/chem_pubs Part of the Chemistry Commons Custom Citation George C. Prendergast, William J. Malachowski, Arpita Mondal, Peggy Scherle, and Alexander J. Muller. 2018. "Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer." International Review of Cell and Molecular Biology 336: 175-203. This paper is posted at Scholarship, Research, and Creative Work at Bryn Mawr College. https://repository.brynmawr.edu/chem_pubs/25 For more information, please contact [email protected]. Indoleamine 2,3-Dioxygenase and Its Therapeutic Inhibition in Cancer George C. Prendergast, William, Malachowski, Arpita Mondal, Peggy Scherle, and Alexander J. Muller International Review of Cell and Molecular Biology 336: 175-203. http://doi.org/10.1016/bs.ircmb.2017.07.004 ABSTRACT The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase-1 (IDO1) has attracted enormous attention in driving cancer immunosuppression, neovascularization, and metastasis. IDO1 suppresses local CD8+ T effector cells and natural killer cells and induces CD4+ T regulatory cells (iTreg) and myeloid-derived suppressor cells (MDSC). The structurally distinct enzyme tryptophan dioxygenase (TDO) also has been implicated recently in immune escape and metastatic progression.
    [Show full text]
  • Muscle Regeneration Controlled by a Designated DNA Dioxygenase
    Wang et al. Cell Death and Disease (2021) 12:535 https://doi.org/10.1038/s41419-021-03817-2 Cell Death & Disease ARTICLE Open Access Muscle regeneration controlled by a designated DNA dioxygenase Hongye Wang1, Yile Huang2,MingYu3,YangYu1, Sheng Li4, Huating Wang2,5,HaoSun2,5,BingLi 3, Guoliang Xu6,7 andPingHu4,8,9 Abstract Tet dioxygenases are responsible for the active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2, but not Tet1 and Tet3, is specifically required for muscle regeneration in vivo. Loss of Tet2 leads to severe muscle regeneration defects. Further analysis indicates that Tet2 regulates myoblast differentiation and fusion. Tet2 activates transcription of the key differentiation modulator Myogenin (MyoG) by actively demethylating its enhancer region. Re-expressing of MyoG in Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 enhances MyoD binding by demethylating the flanking CpG sites of E boxes to facilitate the recruitment of active histone modifications and increase chromatin accessibility and activate its transcription. These findings shed new lights on DNA methylation and pioneer transcription factor activity regulation. Introduction Ten-Eleven Translocation (Tet) family of DNA dioxy- 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Skeletal muscles can regenerate due to the existence of genases catalyze the active DNA demethylation and play muscle stem cells (MuSCs)1,2. The normally quiescent critical roles in embryonic development, neural regen- MuSCs are activated after muscle injury and further dif- eration, oncogenesis, aging, and many other important – ferentiate to support muscle regeneration3,4.
    [Show full text]
  • Relating Metatranscriptomic Profiles to the Micropollutant
    1 Relating Metatranscriptomic Profiles to the 2 Micropollutant Biotransformation Potential of 3 Complex Microbial Communities 4 5 Supporting Information 6 7 Stefan Achermann,1,2 Cresten B. Mansfeldt,1 Marcel Müller,1,3 David R. Johnson,1 Kathrin 8 Fenner*,1,2,4 9 1Eawag, Swiss Federal Institute of Aquatic Science and Technology, 8600 Dübendorf, 10 Switzerland. 2Institute of Biogeochemistry and Pollutant Dynamics, ETH Zürich, 8092 11 Zürich, Switzerland. 3Institute of Atmospheric and Climate Science, ETH Zürich, 8092 12 Zürich, Switzerland. 4Department of Chemistry, University of Zürich, 8057 Zürich, 13 Switzerland. 14 *Corresponding author (email: [email protected] ) 15 S.A and C.B.M contributed equally to this work. 16 17 18 19 20 21 This supporting information (SI) is organized in 4 sections (S1-S4) with a total of 10 pages and 22 comprises 7 figures (Figure S1-S7) and 4 tables (Table S1-S4). 23 24 25 S1 26 S1 Data normalization 27 28 29 30 Figure S1. Relative fractions of gene transcripts originating from eukaryotes and bacteria. 31 32 33 Table S1. Relative standard deviation (RSD) for commonly used reference genes across all 34 samples (n=12). EC number mean fraction bacteria (%) RSD (%) RSD bacteria (%) RSD eukaryotes (%) 2.7.7.6 (RNAP) 80 16 6 nda 5.99.1.2 (DNA topoisomerase) 90 11 9 nda 5.99.1.3 (DNA gyrase) 92 16 10 nda 1.2.1.12 (GAPDH) 37 39 6 32 35 and indicates not determined. 36 37 38 39 S2 40 S2 Nitrile hydration 41 42 43 44 Figure S2: Pearson correlation coefficients r for rate constants of bromoxynil and acetamiprid with 45 gene transcripts of ECs describing nucleophilic reactions of water with nitriles.
    [Show full text]
  • ALOX12 Antibody
    Efficient Professional Protein and Antibody Platforms ALOX12 Antibody Basic information: Catalog No.: UPA60470 Source: Rabbit Size: 50ul/100ul Clonality: polyclonal Concentration: 1mg/ml Isotype: Rabbit IgG Purification: affinity purified by Protein A Useful Information: Applications: WB:1:500-2000 Reactivity: Human, Mouse, Rat, Cow Specificity: This antibody recognizes ALOX12 protein. KLH conjugated synthetic peptide derived from human 12 Lipoxygenase Immunogen: 101-200/663 Non-heme iron-containing dioxygenase that catalyzes the stereo-specific peroxidation of free and esterified polyunsaturated fatty acids generating a spectrum of bioactive lipid mediators. Mainly converts arachidonic acid to (12S)-hydroperoxyeicosatetraenoic acid/(12S)-HPETE but can also metabo- lize linoleic acid. Has a dual activity since it also converts leukotriene A4/LTA4 into both the bioactive lipoxin A4/LXA4 and lipoxin B4/LXB4. Description: Through the production of specific bioactive lipids like (12S)-HPETE it regu- lates different biological processes including platelet activation. It also probably positively regulates angiogenesis through regulation of the expres- sion of the vascular endothelial growth factor. Plays a role in apoptotic pro- cess, promoting the survival of vascular smooth muscle cells for instance. May also play a role in the control of cell migration and proliferation. {ECO:0000269|PubMed:16638750, Uniprot: P18054 Human BiowMW: 76 KDa Buffer: 0.01M TBS(pH7.4) with 1% BSA, 0.03% Proclin300 and 50% Glycerol. Storage: Store at 4°C short term and -20°C long term. Avoid freeze-thaw cycles. Note: For research use only, not for use in diagnostic procedure. Data: Gene Universal Technology Co. Ltd www.universalbiol.com Tel: 0550-3121009 E-mail: [email protected] Efficient Professional Protein and Antibody Platforms Sample: Raw264.7 Cell Lysate at 40 ug A431 Cell Lysate at 40 ug Primary: Anti-ALOX12 at 1/300 dilution Secondary: IRDye800CW Goat An- ti-Rabbit IgG at 1/20000 dilution Predicted band size: 73 kD Observed band size: 73 kD Gene Universal Technology Co.
    [Show full text]
  • Mechanistic Study of Cysteine Dioxygenase, a Non-Heme
    MECHANISTIC STUDY OF CYSTEINE DIOXYGENASE, A NON-HEME MONONUCLEAR IRON ENZYME by WEI LI Presented to the Faculty of the Graduate School of The University of Texas at Arlington in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY THE UNIVERSITY OF TEXAS AT ARLINGTON August 2014 Copyright © by Student Name Wei Li All Rights Reserved Acknowledgements I would like to thank Dr. Pierce for your mentoring, guidance and patience over the five years. I cannot go all the way through this without your help. Your intelligence and determination has been and will always be an example for me. I would like to thank my committee members Dr. Dias, Dr. Heo and Dr. Jonhson- Winters for the directions and invaluable advice. I also would like to thank all my lab mates, Josh, Bishnu ,Andra, Priyanka, Eleanor, you all helped me so I could finish my projects. I would like to thank the Department of Chemistry and Biochemistry for the help with my academic and career. At Last, I would like to thank my lovely wife and beautiful daughter who made my life meaningful and full of joy. July 11, 2014 iii Abstract MECHANISTIC STUDY OF CYSTEINE DIOXYGENASE A NON-HEME MONONUCLEAR IRON ENZYME Wei Li, PhD The University of Texas at Arlington, 2014 Supervising Professor: Brad Pierce Cysteine dioxygenase (CDO) is an non-heme mononuclear iron enzymes that catalyzes the O2-dependent oxidation of L-cysteine (Cys) to produce cysteine sulfinic acid (CSA). CDO controls cysteine levels in cells and is a potential drug target for some diseases such as Parkinson’s and Alzhermer’s.
    [Show full text]
  • Unique Coupling of Mono- and Dioxygenase Chemistries in a Single Active Site Promotes Heme Degradation
    Unique coupling of mono- and dioxygenase chemistries in a single active site promotes heme degradation Toshitaka Matsuia,1, Shusuke Nambua, Celia W. Gouldingb,c, Satoshi Takahashia, Hiroshi Fujiid, and Masao Ikeda-Saitoa,1 aInstitute of Multidisciplinary Research for Advanced Materials, Tohoku University, Katahira, Aoba, Sendai 980-8577, Japan; bDepartment of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697; cDepartment of Pharmaceutical Sciences, University of California, Irvine, CA 92697; and dDepartment of Chemistry, Graduate School of Humanities and Sciences, Nara Women’s University, Kitauoyanishi, Nara 630-8506, Japan Edited by Harry B. Gray, California Institute of Technology, Pasadena, CA, and approved February 26, 2016 (received for review November 26, 2015) − + Bacterial pathogens must acquire host iron for survival and colo- RH + O2 + 2e + 2H → ROH + H2O, [1] nization. Because free iron is restricted in the host, numerous pathogens have evolved to overcome this limitation by using a R + O → RðOÞ . [2] family of monooxygenases that mediate the oxidative cleavage of 2 2 heme into biliverdin, carbon monoxide, and iron. However, the Biological heme degradation proceeds through a unique self- etiological agent of tuberculosis, Mycobacterium tuberculosis, ac- oxidation mechanism where the substrate heme activates O complishes this task without generating carbon monoxide, which 2 potentially induces its latent state. Here we show that this unusual molecules. The canonical enzyme, heme oxygenase (HO), de- heme degradation reaction proceeds through sequential mono- grades heme into ferrous iron, carbon monoxide (CO), and bil- and dioxygenation events within the single active center of MhuD, iverdin by three successive monooxygenation reactions (Fig. 1A) a mechanism unparalleled in enzyme catalysis.
    [Show full text]
  • Original Article Genetic Variants of Aloxs Genes in Polyunsaturated Fatty Acid/Arachidonic Acid Metabolism Associated with Type-2 Diabetes Development
    Int J Clin Exp Med 2018;11(12):13797-13805 www.ijcem.com /ISSN:1940-5901/IJCEM0077987 Original Article Genetic variants of ALOXs genes in polyunsaturated fatty acid/arachidonic acid metabolism associated with type-2 diabetes development Jim Jinn-Chyuan Sheu1,3,4,5*, Ying-Ju Lin1,3*, Cherry Yin-Yi Chang2, Shih-Yin Chen1,3, Wen-Ling Liao1,4, Jai-Sing Yang1, Ming-Tsung Lai6, Chih-Mei Chen1, Chun-Cheng Tseng4, Tritium Hwang4, Ping-Ho Chen7, Fuu-Jen Tsai1,3 1Human Genetic Center, 2Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan; 3School of Chinese Medicine, China Medical University, Taichung, Taiwan; 4Institute of Biomedical Sci- ences, National Sun Yat-sen University, Kaohsiung, Taiwan; 5Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan; 6Department of Pathology, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 7School of Dentistry, Kaohsiung Medical University, Kaohsiung, Taiwan. *Equal contributors. Received April 16, 2018; Accepted July 24, 2018; Epub December 15, 2018; Published December 30, 2018 Abstract: Poly-unsaturated fatty acids (PUFAs)/arachidonic acids (AAs) and their derived eicosanoids play potent roles in triggering inflammation during obesity and diabetes development. Recent studies have indicated functional roles of ALOX5, ALOX12, ALOX12B, and ALOX15 in the development of insulin resistance and islet β-cell dysfunc- tion. However, the impact of their genetic variants on type 2 diabetes (T2D) development in Asian patients remains unclear. In this study, 1,682 healthy controls and 788 patients with T2D were enrolled for genotyping those four ALOX genes by the TaqMan method. A total of eight Han Chinese-specific SNPs (two SNps for each gene) were selected for this study.
    [Show full text]
  • Structural Enzymology of Sulfide Oxidation by Persulfide Dioxygenase and Rhodanese
    Structural Enzymology of Sulfide Oxidation by Persulfide Dioxygenase and Rhodanese by Nicole A. Motl A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biological Chemistry) in the University of Michigan 2017 Doctoral Committee Professor Ruma Banerjee, Chair Assistant Professor Uhn-Soo Cho Professor Nicolai Lehnert Professor Stephen W. Ragsdale Professor Janet L. Smith Nicole A. Motl [email protected] ORCID iD: 0000-0001-6009-2988 © Nicole A. Motl 2017 ACKNOWLEDGEMENTS I would like to take this opportunity to acknowledge the many people who have provided me with guidance and support during my doctoral studies. First I would like to express my appreciation and gratitude to my advisor Dr. Ruma Banerjee for the mentorship, guidance, support and encouragement she has provided. I would like to thank my committee members Dr. Uhn-Soo Cho, Dr. Nicolai Lehnert, Dr. Stephen Ragsdale and Dr. Janet Smith for their advice, assistance and support. I would like to thank Dr. Janet Smith and members of Dr. Smith’s lab, especially Meredith Skiba, for sharing their expertise in crystallography. I would like to thank Dr. Omer Kabil for his help, suggestions and discussions in various aspects of my study. I would also like to thank members of Dr. Banerjee’s lab for their suggestions and discussions. Additionally, I would like to thank my friends and family for their support. ii TABLE OF CONTENTS ACKNOWLEDGEMENTS ii LIST OF TABLES viii LIST OF FIGURES ix ABBREVIATIONS xi ABSTRACT xii CHAPTER I. Introduction:
    [Show full text]
  • Functional Characterization of Genetic Enzyme Variations in Human Lipoxygenases
    Redox Biology 1 (2013) 566–577 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox Functional characterization of genetic enzyme variations in human lipoxygenases Thomas Horn a,n, Kumar Reddy Kakularam b, Monika Anton a, Constanze Richter c, Pallu Reddanna b,d, Hartmut Kuhn a a Institute of Biochemistry, University Medicine Berlin—Charité, Charitéplatz 1, D-10117 Berlin, Germany b Department of Animal Sciences, School of Life Sciences, University of Hyderabad, Gachibowli, Hyderabad 500046, Andhra Pradesh, India c Institute of Nutrition Technology and Nutrition Chemistry, TU Berlin, Gustav-Meyer-Allee 25, D-13355 Berlin, Germany d National Institute of Animal Biotechnology, Hyderabad 500046, Andhra Pradesh, India article info abstract Article history: Mammalian lipoxygenases play a role in normal cell development and differentiation but they have also been Received 28 October 2013 implicated in the pathogenesis of cardiovascular, hyperproliferative and neurodegenerative diseases. As lipid Accepted 1 November 2013 peroxidizing enzymes they are involved in the regulation of cellular redox homeostasis since they produce lipid hydroperoxides, which serve as an efficient source for free radicals. There are various epidemiological Keywords: correlation studies relating naturally occurring variationsinthesixhumanlipoxygenasegenes(SNPsorrare Eicosanoids mutations) to the frequency for various diseases in these individuals, but for most of the described variations no Leukotrienes functional data are available. Employing a combined bioinformatical and enzymological strategy, which Lipoxygenases included structural modeling and experimental site-directed mutagenesis, we systematically explored the Gene polymorphism structural and functional consequences of non-synonymous genetic variations in four different human SNP lipoxygenase genes (ALOX5, ALOX12, ALOX15, and ALOX15B) that have been identified in the human 1000 genome project.
    [Show full text]
  • Positive Allosteric Modulation of Indoleamine 2,3-Dioxygenase 1
    Positive allosteric modulation of indoleamine 2,3- dioxygenase 1 restrains neuroinflammation Giada Mondanellia, Alice Colettib, Francesco Antonio Grecob, Maria Teresa Pallottaa, Ciriana Orabonaa, Alberta Iaconoa, Maria Laura Belladonnaa, Elisa Albinia,b, Eleonora Panfilia, Francesca Fallarinoa, Marco Gargaroa, Giorgia Mannia, Davide Matinoa, Agostinho Carvalhoc,d, Cristina Cunhac,d, Patricia Macielc,d, Massimiliano Di Filippoe, Lorenzo Gaetanie, Roberta Bianchia, Carmine Vaccaa, Ioana Maria Iamandiia, Elisa Proiettia, Francesca Bosciaf, Lucio Annunziatof,1, Maikel Peppelenboschg, Paolo Puccettia, Paolo Calabresie,2, Antonio Macchiarulob,3, Laura Santambrogioh,i,j,3, Claudia Volpia,3,4, and Ursula Grohmanna,k,3,4 aDepartment of Experimental Medicine, University of Perugia, 06100 Perugia, Italy; bDepartment of Pharmaceutical Sciences, University of Perugia, 06100 Perugia, Italy; cLife and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; dICVS/3B’s–PT Government Associate Laboratory, 4704-553 Braga/Guimarães, Portugal; eDepartment of Medicine, University of Perugia, 06100 Perugia, Italy; fDepartment of Neuroscience, University of Naples Federico II, 80131 Naples, Italy; gDepartment of Gastroenterology and Hepatology, Erasmus Medical Centre–University Medical Centre Rotterdam, 3015 GD Rotterdam, The Netherlands; hEnglander Institute of Precision Medicine, Weill Cornell Medicine, New York, NY 10065; iDepartment of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065; jDepartment of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065; and kDepartment of Pathology, Albert Einstein College of Medicine, New York, NY 10461 Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved January 16, 2020 (received for review October 21, 2019) L-tryptophan (Trp), an essential amino acid for mammals, is the or necessary to contain the pathology (20).
    [Show full text]