DOCSLIB.ORG

Sattler Wsu 0251E 12373.Pdf (2.595Mb)

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Sattler Wsu 0251E 12373.Pdf (2.595Mb) STRUCTURAL AND MECHANISTIC CHARACTERIZATION OF ENZYMES IN PERSULFIDE OXIDATION AND MONOLIGNOL BIOSYNTHESIS PATHWAYS By STEVEN ANDREW SATTLER A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY WASHINGTON STATE UNIVERSITY School of Molecular Biosciences MAY 2018 © Copyright by STEVEN ANDREW SATTLER, 2018 All Rights Reserved © Copyright by STEVEN ANDREW SATTLER, 2018 All Rights Reserved To the Faculty of Washington State University: The members of the Committee appointed to examine the dissertation of STEVEN ANDREW SATTLER find it satisfactory and recommend that it be accepted. ChulHee Kang, Ph.D., Chair Susan Wang, Ph.D. Luying Xun, Ph.D. Margaret Black, Ph.D. ii ACKNOWLEDGMENT There are many people who I would like to thank for helping place me in a position to earn this degree. Foremost, I would like to thank my academic advisors, friends, and family for their guidance, support, and patience while I spent several years as an undergraduate and doctoral student. Most of my achievements are attributed to your respective influences on my education or disposition, and for that I will always be grateful. Even if you are not mentioned by name in this acknowledgment, know that your influence is appreciated. I would first like to thank my doctoral advisor, Dr. ChulHee Kang, for providing me with an opportunity to earn this degree. His guidance and willingness to listen to my ideas were crucial to my development as a scientist and prepared me for a professional career in theoretical work. I would also like to thank Dr. Luis Matos, who provided me with my first research opportunity as an undergraduate. I partially owe any success that I have had as a graduate student to his guidance. The final academician I would like to recognize by name is Susan Wick Johnson. As a teacher and friend, she was the first person to guide me in understanding the rewards of scholastic success. To members of my graduate research group, both past and present, I would like to thank Abigail Green, Robert Hayes, Kevin Lewis, Timothy Moural, Alexander Walker, Se-Young Jun, and Shin-Hwa Wu. The alliances we have developed through the years are both personal and professional in nature, and I would like to thank all of you for your friendship and collaboration as we were all trying to make difficult transitions in our lives. I will never forget the impact that that our relationships had and continue to have on my development as a scientist and person. To my family and close friends, the ways and magnitudes of how you have affected my life for the better are immeasurable. I would like to thank my parents, Scott and Stacie Sattler and Roni and Bill Jarrell, my grandparents Richard and Sandy Stone and Edith and Larry Sattler, and iii my siblings Chris Sattler, Brian Sattler, Brook Sattler, J.R. Jarrell, Carlee Jarrell, Austin Sattler, and Corey Jarrell. I would also like to thank April Frers, Rahul Dhal, Rob Jones, Josh Swider, Justin Johnson, Jason Price, Deborah Bohnen, Enrique Alvarado, and Brett Vanderwurff. I have always greatly appreciated your friendship, love and support, and have learned valuable lessons from each of you. Finally, I would like to thank the administrative staff of the School of Molecular Biosciences, particularly Kelly McGovern and Tami Breske. I never missed a deadline because of them. iv STRUCTURAL AND MECHANISTIC CHARACTERIZATION OF ENZYMES IN PERSULFIDE OXIDATION AND MONOLIGNOL BIOSYNTHESIS PATHWAYS Abstract by Steven Andrew Sattler, Ph.D. Washington State University May 2018 Chair: ChulHee Kang We conducted investigations of the structural and biochemical properties of two distinct types of enzyme from different pathways: cinnamoyl-CoA reductases (CCRs) and the persulfide dioxygenases (PDOs). CCR is an enzyme of the monolignol biosynthesis pathway in plants that uses NADPH to reduce any of three major hydroxycinnamoyl-CoA thioesters, thus catalyzing the formation of hydroxycinnamaldehydes. These aldehydes are further reduced by cinnamyl alcohol dehydrogenase (CAD) to form the alcohol substrates required for lignin biosynthesis. One CCR, SbCCR1, was crystallized in the presence of NADPH and the structure was determined at 2.9 Å resolution. It was determined—through site-directed mutagenesis, ITC, molecular docking, and kinetics assays—that not only is feruloyl-CoA the preferred substrate for SbCCR1, but residues Thr154 and Tyr310 are essential to binding functional groups about the aromatic ring of the substrate. Production of a T154Y mutant of SbCCR1 resulted in significant reduction in substrate preference for feruloyl-CoA over p-coumaroyl-CoA, providing support for the hypothesis that substitutions can be made at this position leading to favorable reductions in or softening of lignin v content in S. bicolor. Furthermore, confirmed the existence of an additional CCR in S. bicolor through multiple-sequence alignment and kinetics analyses. PDOs catalyze the oxidation of a sulfane sulfur on glutathione persulfide (GSSH) or higher glutathione polysulfanes (GSSnH, where n > 1) during the process of detoxifying dihydrogen sulfide (H2S). In this study, the structures of PDOs from M. xanthus (MxPDO1) and P. putida (PpPDO2) were determined in the presence of a catalytic iron, as well as in the presence of both iron and product molecule glutathione for the PDO from P. putida. Structure alignments with other PDOs, in addition to the 1.46 Å PpPDO2/GSH complex structure, revealed key substrate-binding residues and provided a basis for activity differences between PDOs and a closely related group of enzymes, the glyoxalases II. Static light scattering further showed that, despite high identity to the glyoxalases II, PDOs are likely dimeric. In summary, we described interactions between PDOs and GSH, as well as provided information as to how two highly related groups of enzymes could differ in form and function. vi TABLE OF CONTENTS Page ACKNOWLEDGMENT................................................................................................................ iii ABSTRACT .....................................................................................................................................v LIST OF TABLES ......................................................................................................................... ix LIST OF FIGURES .........................................................................................................................x CHAPTERS CHAPTER ONE: INTRODUCTION ..................................................................................1 1.1 General Overview ....................................................................................................1 1.2 Function of CCR ......................................................................................................1 1.3 Mutations to Monolignol Biosynthetic Enzymes and the “Lignin Problem” ..........1 1.4 Function of PDOs ....................................................................................................2 1.5 PDOs and Ethylmalonic Encephalopathy (EE) .......................................................3 1.6 Structural and Evolutionary Relationships between PDOs and the Glyoxalases II ................................................................................................................3 1.7 Chapter Summaries ..................................................................................................5 1.8 References ..............................................................................................................10 CHAPTER TWO: CHARACTERIZATIONS OF TWO PERSULFIDE DIOXYGENASES OF THEMETALLO-β-LACTAMASE SUPERFAMILY .................14 2.1 Contributions..........................................................................................................14 2.2 Abstract ..................................................................................................................14 2.3 Introduction ............................................................................................................15 2.4 Materials and Methods ...........................................................................................17 2.5 Results ....................................................................................................................21 vii 2.6 Discussion ..............................................................................................................24 2.7 Acknowledgments..................................................................................................28 2.8 References ..............................................................................................................43 CHAPTER THREE: STRUCTURAL AND BIOCHEMICAL CHARACTERIZATION OF CINNAMOYL-COA REDUCTASES ........................................................................47 3.1 Contributions..........................................................................................................47 3.2 Abstract ..................................................................................................................47 3.3 Introduction ............................................................................................................48 3.4 Materials and Methods ...........................................................................................51 3.5 Results ....................................................................................................................56 3.6 Discussion
Load more

Recommended publications
  • Child Neurology: Ethylmalonic Encephalopathy
    Published Ahead of Print on February 28, 2020 as 10.1212/WNL.0000000000009144 RESIDENT & FELLOW SECTION Child Neurology: Ethylmalonic encephalopathy Periyasamy Govindaraj, PhD, Bindu Parayil Sankaran, FRACP, Madhu Nagappa, DM, Correspondence Hanumanthapura R. Arvinda, DM, Sekar Deepha, MSc, J.N. Jessiena Ponmalar, MSc, Sanjib Sinha, DM, Dr. Parayil Sankaran Narayanappa Gayathri, PhD, and Arun B. Taly, DM Bindu.parayilsankaran@ health.nsw.gov.au Neurology® 2020;94:e1-e4. doi:10.1212/WNL.0000000000009144 Ethylmalonic encephalopathy (EE; OMIM #602473) is an autosomal recessive disorder char- MORE ONLINE acterized by (1) progressive neurologic impairment, including global developmental delay with Video periods of regression during illness, progressive pyramidal and extrapyramidal signs, and seizures; and (2) generalized microvascular damage, including petechial purpura and chronic hemorrhagic diarrhea. It leads to premature death. EE is caused by mutations in ethylmalonic encephalopathy protein 1 (ETHE1), and more than 60 different mutations have been reported.1,2 ETHE1 encodes a mitochondrial sulfur dioxygenase involved in the catabolism of hydrogen sulfide 2 fi (H2S). Impairment of sulfur dioxygenase leads to the accumulation of hydrogen sul de and its fl derivatives (thiosulphate) in various body uids and tissues. Higher concentration of H2Sistoxic and induces direct damage to cell membranes. It inhibits cytochrome c oxidase (COX), increases lactic acid and short-chain acyl-COA dehydrogenase, and leads to elevation of ethyl malonate and C4/C5 acylcarnitine in muscle and brain.2 We describe the clinical phenotype and MRI, path- ologic, and biochemical findings of a patient with EE from India who had a novel homozygous c.493 G>C (p.D165H) variation in ETHE1.
    [Show full text]
  • 10.1136/Jmg.2005.036210 J Med Genet: First Published As 10.1136/Jmg.2005.036210 on 23 September 2005
    JMG Online First, published on September 23, 2005 as 10.1136/jmg.2005.036210 J Med Genet: first published as 10.1136/jmg.2005.036210 on 23 September 2005. Downloaded from ETHE1 mutations are specific to Ethylmalonic Encephalopathy V. Tiranti1*, E. Briem 1*, E. Lamantea1, R. Mineri1, E. Papaleo2, L. De Gioia2, F. Forlani3, P. Rinaldo4, P. Dickson5, B. Abu-Libdeh6, L. Cindro-Heberle7, M. Owaidha8, R.M. Jack9, E. Christensen10, A. Burlina11, M. Zeviani1 1Unit of Molecular Neurogenetics – Pierfranco and Luisa Mariani Center for the Study of Children’s Mitochondrial Disorders, National Neurological Institute “C. Besta”, Milan, Italy; 2Department of Biotechnology and Biosciences. University of Milan-Bicocca, Italy; 3Dipartimento di Scienze Molecolari Agro-Alimentari, Facoltà di Agraria, State University of Milan, Italy; 4Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Biochemical Genetics Laboratory, Rochester, MN, USA; 5Harbor-UCLA Medical Center, Division of Medical Genetics, Torrance, CA, USA; 6Makassed Hospital, Mount of Olives, Jerusalem, Israel; 7Paediatric Neurology Unit, Al Sabah Hospital, Kuwait; 8Al-Jahra Hospital, Kuwait; 9Biochemical Genetics lab, Children’s Hospital, Sand Point Way NE, Seattle, WA USA: 10Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark; 11Division of Inborn Metabolic Diseases, Department of Pediatrics, University of Padua, Italy Correspondence to: Massimo Zeviani, MD, PhD Unit of Molecular Neurogenetics National Neurological Institute “Carlo Besta” Via Temolo 4, 20133 Milan, Italy FAX +39-02-23942619 Phone +39-02-23942630 E-mail: [email protected] [email protected] http://jmg.bmj.com/ URL: www.mitopedia.org *The first two authors should be regarded as joint First Authors. on September 24, 2021 by guest.
    [Show full text]
  • Supplementary Materials
    Supplementary Materials COMPARATIVE ANALYSIS OF THE TRANSCRIPTOME, PROTEOME AND miRNA PROFILE OF KUPFFER CELLS AND MONOCYTES Andrey Elchaninov1,3*, Anastasiya Lokhonina1,3, Maria Nikitina2, Polina Vishnyakova1,3, Andrey Makarov1, Irina Arutyunyan1, Anastasiya Poltavets1, Evgeniya Kananykhina2, Sergey Kovalchuk4, Evgeny Karpulevich5,6, Galina Bolshakova2, Gennady Sukhikh1, Timur Fatkhudinov2,3 1 Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, Moscow, Russia 2 Laboratory of Growth and Development, Scientific Research Institute of Human Morphology, Moscow, Russia 3 Histology Department, Medical Institute, Peoples' Friendship University of Russia, Moscow, Russia 4 Laboratory of Bioinformatic methods for Combinatorial Chemistry and Biology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia 5 Information Systems Department, Ivannikov Institute for System Programming of the Russian Academy of Sciences, Moscow, Russia 6 Genome Engineering Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia Figure S1. Flow cytometry analysis of unsorted blood sample. Representative forward, side scattering and histogram are shown. The proportions of negative cells were determined in relation to the isotype controls. The percentages of positive cells are indicated. The blue curve corresponds to the isotype control. Figure S2. Flow cytometry analysis of unsorted liver stromal cells. Representative forward, side scattering and histogram are shown. The proportions of negative cells were determined in relation to the isotype controls. The percentages of positive cells are indicated. The blue curve corresponds to the isotype control. Figure S3. MiRNAs expression analysis in monocytes and Kupffer cells. Full-length of heatmaps are presented.
    [Show full text]
  • Electronic Supplementary Material (ESI) for Metallomics
    Electronic Supplementary Material (ESI) for Metallomics. This journal is © The Royal Society of Chemistry 2018 Uniprot Entry name Gene names Protein names Predicted Pattern Number of Iron role EC number Subcellular Membrane Involvement in disease Gene ontology (biological process) Id iron ions location associated 1 P46952 3HAO_HUMAN HAAO 3-hydroxyanthranilate 3,4- H47-E53-H91 1 Fe cation Catalytic 1.13.11.6 Cytoplasm No NAD biosynthetic process [GO:0009435]; neuron cellular homeostasis dioxygenase (EC 1.13.11.6) (3- [GO:0070050]; quinolinate biosynthetic process [GO:0019805]; response to hydroxyanthranilate oxygenase) cadmium ion [GO:0046686]; response to zinc ion [GO:0010043]; tryptophan (3-HAO) (3-hydroxyanthranilic catabolic process [GO:0006569] acid dioxygenase) (HAD) 2 O00767 ACOD_HUMAN SCD Acyl-CoA desaturase (EC H120-H125-H157-H161; 2 Fe cations Catalytic 1.14.19.1 Endoplasmic Yes long-chain fatty-acyl-CoA biosynthetic process [GO:0035338]; unsaturated fatty 1.14.19.1) (Delta(9)-desaturase) H160-H269-H298-H302 reticulum acid biosynthetic process [GO:0006636] (Delta-9 desaturase) (Fatty acid desaturase) (Stearoyl-CoA desaturase) (hSCD1) 3 Q6ZNF0 ACP7_HUMAN ACP7 PAPL PAPL1 Acid phosphatase type 7 (EC D141-D170-Y173-H335 1 Fe cation Catalytic 3.1.3.2 Extracellular No 3.1.3.2) (Purple acid space phosphatase long form) 4 Q96SZ5 AEDO_HUMAN ADO C10orf22 2-aminoethanethiol dioxygenase H112-H114-H193 1 Fe cation Catalytic 1.13.11.19 Unknown No oxidation-reduction process [GO:0055114]; sulfur amino acid catabolic process (EC 1.13.11.19) (Cysteamine
    [Show full text]
  • Anti-ETHE1 Antibody (ARG57432)
    Product datasheet [email protected] ARG57432 Package: 100 μl anti-ETHE1 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes ETHE1 Tested Reactivity Hu, Ms, Rat Tested Application WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name ETHE1 Antigen Species Human Immunogen Recombinant protein of Human ETHE1. Conjugation Un-conjugated Alternate Names Sulfur dioxygenase ETHE1; EC 1.13.11.18; HSCO; Ethylmalonic encephalopathy protein 1; Persulfide dioxygenase ETHE1, mitochondrial; YF13H12; Hepatoma subtracted clone one protein Application Instructions Application table Application Dilution WB 1:200 - 1:1000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control Mouse liver Calculated Mw 28 kDa Properties Form Liquid Purification Affinity purification with immunogen. Buffer PBS (pH 7.3), 0.02% Sodium azide and 50% Glycerol. Preservative 0.02% Sodium azide Stabilizer 50% Glycerol Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. Note For laboratory research only, not for drug, diagnostic or other use. www.arigobio.com 1/2 Bioinformation Gene Symbol ETHE1 Gene Full Name ethylmalonic encephalopathy 1 Background This gene encodes a sulfur dioxygenase that localizes within the mitochondrial matrix. The enzyme functions in sulfide catabolism. Mutations in this gene result in ethylmalonic encephalopathy.[provided by RefSeq, May 2009] Function Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix.
    [Show full text]
  • Hydrogen Sulfide Metabolite, Sodium Thiosulfate
    International Journal of Molecular Sciences Review Hydrogen Sulfide Metabolite, Sodium Thiosulfate: Clinical Applications and Underlying Molecular Mechanisms Max Y. Zhang 1,2, George J. Dugbartey 1,2,3, Smriti Juriasingani 1,3 and Alp Sener 1,2,3,4,* 1 Matthew Mailing Center for Translational Transplant Studies, London Health Sciences Center, Western University, London, ON N6A 5A5, Canada; [email protected] (M.Y.Z.); [email protected] (G.J.D.); [email protected] (S.J.) 2 London Health Sciences Center, Multi-Organ Transplant Program, Western University, London, ON N6A 5A5, Canada 3 London Health Sciences Center, Department of Surgery, Division of Urology, Western University, London, ON N6A 5A5, Canada 4 Department of Microbiology & Immunology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON N6A 3K7, Canada * Correspondence: [email protected]; Tel.: +1(519) 6633352 Abstract: Thiosulfate in the form of sodium thiosulfate (STS) is a major oxidation product of hydrogen sulfide (H2S), an endogenous signaling molecule and the third member of the gasotransmitter family. STS is currently used in the clinical treatment of acute cyanide poisoning, cisplatin toxicities in cancer therapy, and calciphylaxis in dialysis patients. Burgeoning evidence show that STS has antioxidant and anti-inflammatory properties, making it a potential therapeutic candidate molecule that can target multiple molecular pathways in various diseases and drug-induced toxicities. This review Citation: Zhang, M.Y.; Dugbartey, discusses the biochemical and molecular pathways in the generation of STS from H2S, its clinical G.J.; Juriasingani, S.; Sener, A. usefulness, and potential clinical applications, as well as the molecular mechanisms underlying these Hydrogen Sulfide Metabolite, clinical applications and a future perspective in kidney transplantation.
    [Show full text]
  • Springer Handbook of Enzymes
    Dietmar Schomburg and Ida Schomburg (Eds.) Springer Handbook of Enzymes Volume 25 Class 1 • Oxidoreductases X EC 1.9-1.13 co edited by Antje Chang Second Edition 4y Springer Index of Recommended Enzyme Names EC-No. Recommended Name Page 1.13.11.50 acetylacetone-cleaving enzyme 673 1.10.3.4 o-aminophenol oxidase 149 1.13.12.12 apo-/?-carotenoid-14',13'-dioxygenase 732 1.13.11.34 arachidonate 5-lipoxygenase 591 1.13.11.40 arachidonate 8-lipoxygenase 627 1.13.11.31 arachidonate 12-lipoxygenase 568 1.13.11.33 arachidonate 15-lipoxygenase 585 1.13.12.1 arginine 2-monooxygenase 675 1.13.11.13 ascorbate 2,3-dioxygenase 491 1.10.2.1 L-ascorbate-cytochrome-b5 reductase 79 1.10.3.3 L-ascorbate oxidase 134 1.11.1.11 L-ascorbate peroxidase 257 1.13.99.2 benzoate 1,2-dioxygenase (transferred to EC 1.14.12.10) 740 1.13.11.39 biphenyl-2,3-diol 1,2-dioxygenase 618 1.13.11.22 caffeate 3,4-dioxygenase 531 1.13.11.16 3-carboxyethylcatechol 2,3-dioxygenase 505 1.13.11.21 p-carotene 15,15'-dioxygenase (transferred to EC 1.14.99.36) 530 1.11.1.6 catalase 194 1.13.11.1 catechol 1,2-dioxygenase 382 1.13.11.2 catechol 2,3-dioxygenase 395 1.10.3.1 catechol oxidase 105 1.13.11.36 chloridazon-catechol dioxygenase 607 1.11.1.10 chloride peroxidase 245 1.13.11.49 chlorite O2-lyase 670 1.13.99.4 4-chlorophenylacetate 3,4-dioxygenase (transferred to EC 1.14.12.9) .
    [Show full text]
  • Sulfur Oxygenase Reductases - a Structural and Biochemical Perspective
    Sulfur Oxygenase Reductases - A Structural and Biochemical Perspective vom Fachbereich Biologie der Technischen Universität Darmstadt zur Erlangung des akademischen Grades eines Doctor rerum naturalium genehmigte Dissertation vorgelegt von Dipl. Biol. Andreas Veith aus Seeheim-Jugenheim 1. Referent: Dr. habil. Arnulf Kletzin 2. Referent: Prof. Dr. Felicitas Pfeifer Eingereicht am 21.07.2011 Tag der mündlichen Prüfung: 16.09.2011 Darmstadt 2011 D 17 "Trying to determine the structure of a protein by UV spectroscopy was like trying to determine the structure of a piano by listening to the sound it made while being dropped down a flight of stairs." -- Francis Crick Die vorliegende Arbeit wurde als Promotionsarbeit am Institut für Mikrobiologie und Genetik des Fachbereichs Biologie der Technischen Universität Darmstadt unter Leitung von Herrn Dr. Arnulf Kletzin in der Abteilung von Frau Prof. Felicitas Pfeifer im Zeitraum von Mai 2007 bis Juli 2011 angefertigt. Ein Teil der vorliegenden Arbeit wurde in Portugal am Instituto de Tecnologia Químicia e Biológica, Universidade Nova de Lisboa (ITQB/UNL), Oeiras, Portugal in der Arbeitsgruppe von Dr. Carlos Frazão, Dr. Cláudio M. Gomes und Prof. Miguel Teixeira im Rahmen einer Kooperation durchgeführt. Ehrenwörtliche Erklärung Ich erkläre hiermit ehrenwörtlich, dass ich die vorliegende Arbeit selbstständig angefertigt habe. Sämtliche aus fremden Quellen direkt oder indirekt übernommenen Gedanken sind als solche kenntlich gemacht. Die Arbeit wurde bisher keiner anderen Prüfungsbehörde vorgelegt und noch nicht veröffentlicht. Darmstadt, den 21.07.2011 Andreas Veith Acknowledgements First and foremost I would like to thank my supervisor Dr. Arnulf Kletzin for giving me the opportunity to step into the fascinating world of proteins.
    [Show full text]
  • H2S) Metabolism in Ethylmalonic Encephalopathy
    Downloaded from http://cshperspectives.cshlp.org/ on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Altered Sulfide (H2S) Metabolism in Ethylmalonic Encephalopathy Valeria Tiranti and Massimo Zeviani Pierfranco and Luisa Mariani Center for Research on Children’s Mitochondrial Disorders, Unit of Molecular Neurogenetics, Institute of Neurology “Carlo Besta,” Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Foundation, Milan, Italy Correspondence: [email protected]; [email protected] Hydrogen sulfide (sulfide, H2S) is a colorless, water-soluble gas with a typical smell of rotten eggs. In the past, it has been investigated for its role as a potent toxic gas emanating from sewers and swamps or as a by-product of industrial processes. At high concentrations, H2S is a powerful inhibitor of cytochrome c oxidase; in trace amounts, it is an important signaling molecule, like nitric oxide (NO) and carbon monoxide (CO), together termed “gasotransmitters.” This review will cover the physiological role and the pathogenic effects of H2S, focusing on ethylmalonic encephalopathy, a human mitochondrial disorder caused by genetic abnormalities of sulfide metabolism. We will also discuss the options that are now conceivable for preventing genetically driven chronic H2S toxicity, taking into account that a complete understanding of the physiopathology of H2S has still to be achieved. ecause of its fame as a deadly gas, the phys- 4.2.1.22) and cystathionine g-lyase (CSE, EC Biological role of H2S had been long over- 4.4.1.1), which both utilize L-cysteine as a sub- looked, until Abe and Kimura in 1996 (Abe strate (Stipanuk and Beck 1982; Hosoki et al.
    [Show full text]
  • (Riscs) in Acidithiobacillus Thiooxidans
    ARTICLE Stoichiometric Modeling of Oxidation of Reduced Inorganic Sulfur Compounds (Riscs) in Acidithiobacillus thiooxidans Roberto A. Bobadilla Fazzini,1 Maria Paz Corte´s,2,3 Leandro Padilla,1 Daniel Maturana,2,3 Marko Budinich,2,3 Alejandro Maass,3,4 Pilar Parada1 1 BioSigma ‘S.A.’, Loteo Los Libertadores, Lote 106, Colina, Chile; telephone: 56-2-437 9030; fax: 56-2-460 0416; e-mail: [email protected], [email protected] 2 Laboratory of Bioinformatics and Mathematics of the Genome, Center for Mathematical Modeling (UMI2807-CNRS) and FONDAP Center for Genome Regulation, Santiago, Chile 3 Faculty of Mathematical and Physical Sciences, University of Chile, Santiago, Chile 4 Department of Mathematical Engineering, Center for Mathematical Modeling (UMI2807-CNRS) and FONDAP Center for Genome Regulation, Santiago, Chile dioxygenase as the main catalyzer and a moderate function ABSTRACT: The prokaryotic oxidation of reduced inorgan- of tetrathionate hydrolase in elemental sulfur catabolism, ic sulfur compounds (RISCs) is a topic of utmost impor- demonstrating that this model constitutes an advanced tance from a biogeochemical and industrial perspective. instrument for the optimization of At. thiooxidans biomass Despite sulfur oxidizing bacterial activity is largely known, production with potential use in biohydrometallurgical and no quantitative approaches to biological RISCs oxidation environmental applications. have been made, gathering all the complex abiotic and Biotechnol. Bioeng. 2013;110: 2242–2251. enzymatic stoichiometry involved. Even though in the ß 2013 Wiley Periodicals, Inc. case of neutrophilic bacteria such as Paracoccus and Beggia- KEYWORDS: At. thiooxidans; reduced Inorganic sulfur toa species the RISCs oxidation systems are well described, compounds (RISCs); chemolithoautotrophic oxidation there is a lack of knowledge for acidophilic microorganisms.
    [Show full text]
  • Ethylmalonic Encephalopathy
    Ethylmalonic encephalopathy Description Ethylmalonic encephalopathy is an inherited disorder that affects several body systems, particularly the nervous system. Neurological signs and symptoms include delayed development and the loss of previously acquired skills (developmental regression), weak muscle tone (hypotonia), seizures, and abnormal movements. The body's network of blood vessels (the vascular system) is also affected. Children with this disorder often develop rashes of tiny red spots (petechiae) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood (acrocyanosis). Chronic diarrhea is another common feature of ethylmalonic encephalopathy. The signs and symptoms of ethylmalonic encephalopathy are apparent at birth or begin in the first few months of life. Problems with the nervous system typically worsen over time, and most affected individuals survive only into early childhood. Frequency About 70 individuals with this condition have been identified worldwide, mostly in Mediterranean and Arab populations. Although ethylmalonic encephalopathy appears to be very rare, researchers suggest that some cases have been misdiagnosed as other neurological disorders. Causes Ethylmalonic encephalopathy results from mutations in the ETHE1 gene. This gene provides instructions for making an enzyme that is active in mitochondria, which are the energy-producing centers in cells. The ETHE1 enzyme is part of a pathway that breaks down sulfide (H2S), a molecule that is critical at very low levels for normal cell functioning but is toxic at high levels. Excess sulfide interferes with numerous cell activities, including mitochondrial energy production. Mutations in the ETHE1 gene lead to the production of a nonfunctional version of the enzyme or prevent any enzyme from being made.
    [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]