DOCSLIB.ORG

Small Molecule Modulation of GLUT1-Mediated Glucose Transport

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Small Molecule Modulation of GLUT1-Mediated Glucose Transport University of Massachusetts Medical School eScholarship@UMMS GSBS Dissertations and Theses Graduate School of Biomedical Sciences 2017-12-21 Small Molecule Modulation of GLUT1-Mediated Glucose Transport Ogooluwa A. Ojelabi University of Massachusetts Medical School Let us know how access to this document benefits ou.y Follow this and additional works at: https://escholarship.umassmed.edu/gsbs_diss Part of the Biochemistry, Biophysics, and Structural Biology Commons Repository Citation Ojelabi OA. (2017). Small Molecule Modulation of GLUT1-Mediated Glucose Transport. GSBS Dissertations and Theses. https://doi.org/10.13028/M2R69F. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/950 Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial 4.0 License This material is brought to you by eScholarship@UMMS. It has been accepted for inclusion in GSBS Dissertations and Theses by an authorized administrator of eScholarship@UMMS. For more information, please contact [email protected]. SMALL MOLECULE MODULATION OF GLUT1-MEDIATED GLUCOSE TRANSPORT A Dissertation Presented By OGOOLUWA ADEGOKE OJELABI Submitted to the Faculty of the University of Massachusetts Graduate School of Biomedical Sciences, Worcester in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY December 21, 2017 Department of Biochemistry and Molecular Pharmacology SMALL MOLECULE MODULATION OF GLUT1-MEDIATED GLUCOSE TRANSPORT A Dissertation Presented By OGOOLUWA ADEGOKE OJELABI Dissertation Defense Committee Members Mary Munson, Ph.D. Biochemistry and Molecular Pharmacology Silvia Corvera, M.D. Program in Molecular Medicine William Kobertz, Ph.D. Biochemistry and Molecular Pharmacology Chair of Dissertation Committee Reid Gilmore, Ph.D. Biochemistry and Molecular Pharmacology External Dissertation Committee Member Paul Pilch, Ph.D. Professor, Boston University School of Medicine Thesis Advisor Anthony Carruthers, Ph.D. Biochemistry and Molecular Pharmacology Student Program Biochemistry and Molecular Pharmacology December 21, 2017 iii DEDICATION To Ife and Ola I hope the efforts of your mom and I to attain excellence in our endeavors will always inspire you to work hard to acquire the skills that will bring you success Ecclesiastes 10:10 iv ACKNOWLEDGEMENTS I am eternally grateful to my advisor and mentor, Dr. Anthony Carruthers, for his loving support, guidance, encouragement, and help all through this graduate program. Tony always made time for me in spite of his busy schedule and he made sure I had everything I needed to succeed. He always encourages me to do my best work, and is truly excited about my progress. Thank you, Tony, for believing in me and for genuinely caring about the well-being of my family and I. When I first spoke to Tony about joining his lab, he told me that he and the members of his lab will do everything in their power to see that I succeed, and that is exactly what Tony and the Carruthers’ lab have done! I am grateful to the all members of Carruthers lab, both past and present, for creating a great working environment, and for their help. Particularly, I would like to thank Dr. Julie De Zutter for her help with experiments and for her true interest in my success. I also want to thank Dr. Anthony Cura, who mentored me when I first rotated in the lab, and taught me the fundamentals I so much needed. Special thanks to Dr. Jay Sage, Andrew Simon and Kenny Lloyd for their help and amazing support. I appreciate the support of my TRAC members – Dr. Reid Gilmore, Dr. Silvia Corvera and Dr. Mary Munson. I am grateful for their valuable suggestions and insights toward my thesis research, and for their sincere interests in my success and progress. I would also like to thank Dr. Bill Kobertz for agreeing to serve on my dissertation committee, and for his many signatures and support as the director of the department’s graduate program. I sincerely want to thank Dr. Paul Pilch for accepting our invitation to serve as the external member of my dissertation committee, and for his time and input. v I would like to thank Navitor Pharmaceuticals for providing the navitor compounds used in this study and for funding the navitor compounds project. I especially will like to thank Drs. Sengupta, Saiah and Vlasuk for their support and encouragement. I have enjoyed a remarkable support from all the members of the BMP department. I am thankful for their encouragement, support and for making this place a friendly and collaborative environment for science. I would like to acknowledge my friends here at UMass Medical School who truly understand and share in the travails of biomedical research, and with whom I have shared the joys of our progress in science and outside of science. Special thanks to Chido Kativhu, Zach Maben, Ken Aryee, Amena Arif, and Eugene Bah for been my solid support system. I am grateful to my friends, the members of my church, and my family for their unconditional love, prayers and support over the years. Words cannot express enough how much I appreciate you all. Thank you, I am grateful. To the love of my life, Ayomi, thank you for loving me. Your unconditional love provides the much-needed drive to get through each day. Thank you for your encouragement, your prayers, your patience, your understanding, and for taking care of me and the kids too. I cannot imagine going through this journey without you. Thank you for making it worthwhile. Finally, to Ife and Ola, thank you for your understanding, and for honing my ability to focus and to maximize the use of my time away from home. As this program ends, I hope to create more time for you both and to be truly there for you. vi ABSTRACT The glucose transport protein, GLUT1, is highly expressed in rapidly proliferating cells, including cancer cells, while decreased GLUT1 levels are found in diseases such as GLUT1 deficiency syndrome and Alzheimer’s. There is increased interest in developing GLUT1 inhibitors as novel anticancer therapeutics, and the discovery of compounds that directly stimulate GLUT1 function. This work investigates how small molecules stimulate and/or inhibit GLUT1-mediated glucose transport, either directly or through the AMPK pathway. Using sugar transport assays and docking analyses to explore Ligand–GLUT1 interactions and specificity of binding, we show that: 1) Ligands inhibit GLUT1 by competing with glucose for binding to the exofacial or endofacial sugar binding sites; 2) Subsaturating inhibitor concentrations stimulate sugar uptake; 3) Ligands inhibit GLUT1–, GLUT3– and GLUT4–mediated sugar uptake in HEK293 cells; and 4) Inclusion of a benzonitrile head group on endofacial GLUT1 inhibitors confers greater inhibitory potency. Furthermore, we investigated AMPK-regulated GLUT1 trafficking in cultured blood-brain barrier endothelial cells, and show that inhibition of GLUT1 internalization is not responsible for increased cell surface levels of GLUT1 observed with AMPK activation in these cells. This study provides a framework for screening candidate GLUT1 inhibitors for specificity, and for optimizing drug design and delivery. Our data on transport stimulation at low inhibitor concentrations support the idea that GLUT1 functions as a cooperative oligomer of allosteric alternating access subunits. vii TABLE OF CONTENTS DEDICATION ................................................................................................................. iii ACKNOWLEDGEMENTS ............................................................................................... iv ABSTRACT .................................................................................................................... vi TABLE OF CONTENTS ................................................................................................ vii LIST OF TABLES ............................................................................................................ x LIST OF FIGURES ......................................................................................................... xi LIST OF PUBLISHED MATERIALS PRODUCED BY THE AUTHOR ........................... xiv LIST OF ABBREVIATIONS ........................................................................................... xv CHAPTER I .................................................................................................................... 1 Introduction .................................................................................................................... 1 Solute transport across cell membranes ......................................................................... 1 Simple diffusion ....................................................................................................... 1 Protein-mediated transport ...................................................................................... 2 Passive versus active transport ............................................................................... 3 Clinical relevance of membrane transport proteins .................................................. 3 Glucose transport across cell membranes ...................................................................... 4 The glucose transporter (GLUT) proteins ................................................................ 5 The Na+–dependent glucose cotransporter (SGLT) proteins.................................... 7 SWEET proteins ...................................................................................................... 9 Kinetic and
Load more

Recommended publications
  • Screening and Identification of Key Biomarkers in Clear Cell Renal Cell Carcinoma Based on Bioinformatics Analysis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. 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. Screening and identification of key biomarkers in clear cell renal cell carcinoma based on bioinformatics analysis Basavaraj Vastrad1, Chanabasayya Vastrad*2 , Iranna Kotturshetti 1. Department of Biochemistry, Basaveshwar College of Pharmacy, Gadag, Karnataka 582103, India. 2. Biostatistics and Bioinformatics, Chanabasava Nilaya, Bharthinagar, Dharwad 580001, Karanataka, India. 3. Department of Ayurveda, Rajiv Gandhi Education Society`s Ayurvedic Medical College, Ron, Karnataka 562209, India. * Chanabasayya Vastrad [email protected] Ph: +919480073398 Chanabasava Nilaya, Bharthinagar, Dharwad 580001 , Karanataka, India bioRxiv preprint doi: https://doi.org/10.1101/2020.12.21.423889; this version posted December 23, 2020. 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. Abstract Clear cell renal cell carcinoma (ccRCC) is one of the most common types of malignancy of the urinary system. The pathogenesis and effective diagnosis of ccRCC have become popular topics for research in the previous decade. In the current study, an integrated bioinformatics analysis was performed to identify core genes associated in ccRCC. An expression dataset (GSE105261) was downloaded from the Gene Expression Omnibus database, and included 26 ccRCC and 9 normal kideny samples. Assessment of the microarray dataset led to the recognition of differentially expressed genes (DEGs), which was subsequently used for pathway and gene ontology (GO) enrichment analysis.
    [Show full text]
  • (Glut1ds): Methylxanthines Potentiate GLUT1 Haploinsufficiency in Vitro
    0031-3998/01/5002-0254 PEDIATRIC RESEARCH Vol. 50, No. 2, 2001 Copyright © 2001 International Pediatric Research Foundation, Inc. Printed in U.S.A. Glucose Transporter Type 1 Deficiency Syndrome (Glut1DS): Methylxanthines Potentiate GLUT1 Haploinsufficiency In Vitro YUAN-YUAN HO, HONG YANG, JÖRG KLEPPER, JORGE FISCHBARG, DONG WANG, AND DARRYL C. DE VIVO Department of Neurology, Columbia University, New York, New York 10032, U.S.A. [Y.Y.H., H.Y., D.W., D.C.D.]; Department of Pediatrics, University of Essen, Essen, Germany 45122 [J.K.]; and Departments of Physiology and Cellular Biophysics, and Ophthalmology, Columbia University, New York, New York 10032, U.S.A. [J.F.] ABSTRACT Methylxanthines such as caffeine and theophylline are known substrate for Glut1. The combined effects of caffeine (3 mM) and to inhibit glucose transport. We have studied such inhibition in phenobarbital (10 mM) on glucose transport, as determined in the glucose transporter type 1 deficiency syndrome (Glut1DS) by patient 15 and the maternal control, show no additive or syner- erythrocyte glucose transport assays. Data from four patients gistic inhibition. These data indicate that caffeine and phenobar- with individual mutations in the GLUT1 gene are discussed: bital have similar Glut1 inhibitory properties in these two sub- patient 1 (hemizygosity), 3 (S66F), 15 (368Ins23), and 17 jects. Our study suggests that Glut1DS patients may have a (R333W). Zero-trans influx of 14C-labeled 3-O-methyl glucose reduced safety margin for methylxanthines. Consumption of (3-OMG) into erythrocytes of patients is reduced (patient 1, 51%; methylxanthine-containing products may aggravate the neuro- 3, 45%; 15, 31%; 17, 52%) compared with maternal controls.
    [Show full text]
  • Regulation of Myocardial Glucose Transporters GLUT1 and GLUT4 in Chronically Anemic Fetal Lambs
    0031-3998/05/5804-0713 PEDIATRIC RESEARCH Vol. 58, No. 4, 2005 Copyright © 2005 International Pediatric Research Foundation, Inc. Printed in U.S.A. Regulation of Myocardial Glucose Transporters GLUT1 and GLUT4 in Chronically Anemic Fetal Lambs J. CARTER RALPHE, PETER N. NAU, CHRISTOPHER E. MASCIO, JEFFREY L. SEGAR, AND THOMAS D. SCHOLZ Department of Pediatrics [J.C.R., P.N.N., J.L.S., T.D.S.], Department of Surgery [C.E.M.], University of Iowa, Iowa City, Iowa 52242 ABSTRACT Little is known about the chronic adaptations that take place steady state, GLUT4 protein localized to the sarcolemma mem- in the fetal heart to allow for increased substrate delivery in brane. These findings suggest that the glucose transporters are response to chronic stress. Because glucose is an important fuel post-transcriptionally regulated in myocardium of chronically for the fetal cardiomyocytes, we hypothesized that myocardial anemic fetal sheep with changes that mimic normal postnatal glucose transporters 1 and 4 (GLUT1 and GLUT4, respectively) development. Unlike the postnatal heart, localization of GLUT4 are up-regulated in the fetal sheep heart that is chronically to the cell membrane suggests the importance of GLUT4 in basal stressed by anemia. Fetal sheep at 128 d gestation underwent glucose uptake in the stressed fetal heart. (Pediatr Res 58: daily isovolumic hemorrhage and determination of myocardial 713–718, 2005) blood flow, oxygen consumption, and substrate utilization. At the endof3or7dofanemia, myocardial levels of GLUT1 and Abbreviations GLUT4 mRNA and protein were measured and subcellular ERK, extracellular-regulated kinase localization was determined. Despite stable heart rate and blood GLUT1(4), glucose transporter 1 (4) pressure, anemia caused a nearly 4-fold increase in right and left HIF-1␣, hypoxia-inducible factor 1␣ ventricular (RV and LV) free wall blood flow.
    [Show full text]
  • Regulation of Skeletal Muscle Glucose Transport and Glucose Metabolism by Exercise Training
    nutrients Review Regulation of Skeletal Muscle Glucose Transport and Glucose Metabolism by Exercise Training Parker L. Evans 1,2,3, Shawna L. McMillin 1,2,3 , Luke A. Weyrauch 1,2,3 and Carol A. Witczak 1,2,3,4,* 1 Department of Kinesiology, East Carolina University, Greenville, NC 27858, USA; [email protected] (P.L.E.); [email protected] (S.L.M.); [email protected] (L.A.W.) 2 Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA 3 East Carolina Diabetes & Obesity Institute, East Carolina University, Greenville, NC 27834, USA 4 Department of Biochemistry & Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA * Correspondence: [email protected]; Tel.: +1-252-744-1224 Received: 8 September 2019; Accepted: 8 October 2019; Published: 12 October 2019 Abstract: Aerobic exercise training and resistance exercise training are both well-known for their ability to improve human health; especially in individuals with type 2 diabetes. However, there are critical differences between these two main forms of exercise training and the adaptations that they induce in the body that may account for their beneficial effects. This article reviews the literature and highlights key gaps in our current understanding of the effects of aerobic and resistance exercise training on the regulation of systemic glucose homeostasis, skeletal muscle glucose transport and skeletal muscle glucose metabolism. Keywords: aerobic exercise; blood glucose; functional overload; GLUT; hexokinase; insulin resistance; resistance exercise; SGLT; type 2 diabetes; weightlifting 1. Introduction Exercise training is defined as planned bouts of physical activity which repeatedly occur over a duration of time lasting from weeks to years.
    [Show full text]
  • Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice
    pharmaceutics Review Mechanisms of CYP450 Inhibition: Understanding Drug-Drug Interactions Due to Mechanism-Based Inhibition in Clinical Practice Malavika Deodhar 1, Sweilem B Al Rihani 1 , Meghan J. Arwood 1, Lucy Darakjian 1, Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (M.D.); [email protected] (S.B.A.R.); [email protected] (M.J.A.); [email protected] (L.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Received: 5 August 2020; Accepted: 31 August 2020; Published: 4 September 2020 Abstract: In an ageing society, polypharmacy has become a major public health and economic issue. Overuse of medications, especially in patients with chronic diseases, carries major health risks. One common consequence of polypharmacy is the increased emergence of adverse drug events, mainly from drug–drug interactions. The majority of currently available drugs are metabolized by CYP450 enzymes. Interactions due to shared CYP450-mediated metabolic pathways for two or more drugs are frequent, especially through reversible or irreversible CYP450 inhibition. The magnitude of these interactions depends on several factors, including varying affinity and concentration of substrates, time delay between the administration of the drugs, and mechanisms of CYP450 inhibition. Various types of CYP450 inhibition (competitive, non-competitive, mechanism-based) have been observed clinically, and interactions of these types require a distinct clinical management strategy. This review focuses on mechanism-based inhibition, which occurs when a substrate forms a reactive intermediate, creating a stable enzyme–intermediate complex that irreversibly reduces enzyme activity.
    [Show full text]
  • WES Gene Package Multiple Congenital Anomalie.Xlsx
    Whole Exome Sequencing Gene package Multiple congenital anomalie, version 5, 1‐2‐2018 Technical information DNA was enriched using Agilent SureSelect Clinical Research Exome V2 capture and paired‐end sequenced on the Illumina platform (outsourced). The aim is to obtain 8.1 Giga base pairs per exome with a mapped fraction of 0.99. The average coverage of the exome is ~50x. Duplicate reads are excluded. Data are demultiplexed with bcl2fastq Conversion Software from Illumina. Reads are mapped to the genome using the BWA‐MEM algorithm (reference: http://bio‐bwa.sourceforge.net/). Variant detection is performed by the Genome Analysis Toolkit HaplotypeCaller (reference: http://www.broadinstitute.org/gatk/). The detected variants are filtered and annotated with Cartagenia software and classified with Alamut Visual. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved Phenotype description including OMIM phenotype ID(s) OMIM median depth % covered % covered % covered gene symbol gene ID >10x >20x >30x A4GALT [Blood group, P1Pk system, P(2) phenotype], 111400 607922 101 100 100 99 [Blood group, P1Pk system, p phenotype], 111400 NOR polyagglutination syndrome, 111400 AAAS Achalasia‐addisonianism‐alacrimia syndrome, 231550 605378 73 100 100 100 AAGAB Keratoderma, palmoplantar,
    [Show full text]
  • Is Retinal Metabolic Dysfunction at the Center of the Pathogenesis of Age-Related Macular Degeneration?
    International Journal of Molecular Sciences Review Is Retinal Metabolic Dysfunction at the Center of the Pathogenesis of Age-related Macular Degeneration? Thierry Léveillard 1,*, Nancy J. Philp 2 and Florian Sennlaub 3 1 . Department of Genetics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France 2 . Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA; [email protected] 3 . Department of Therapeutics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France; fl[email protected] * Correspondence: [email protected]; Tel.: +33-1-5346-2548 Received: 21 December 2018; Accepted: 5 February 2019; Published: 11 February 2019 Abstract: The retinal pigment epithelium (RPE) forms the outer blood–retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized via OXPHOS. Excess lactate in the RPE is transported across the basolateral membrane to the choroid. The uptake of glucose by cone photoreceptor cells is enhanced by rod-derived cone viability factor (RdCVF) secreted by rods and by insulin signaling. Together, the three cells act as symbiotes: the RPE supplies the glucose from the choroidal circulation to the photoreceptors, the rods help the cones, and both produce lactate to feed the RPE.
    [Show full text]
  • The Genetic Landscape of the Human Solute Carrier (SLC) Transporter Superfamily
    Human Genetics (2019) 138:1359–1377 https://doi.org/10.1007/s00439-019-02081-x ORIGINAL INVESTIGATION The genetic landscape of the human solute carrier (SLC) transporter superfamily Lena Schaller1 · Volker M. Lauschke1 Received: 4 August 2019 / Accepted: 26 October 2019 / Published online: 2 November 2019 © The Author(s) 2019 Abstract The human solute carrier (SLC) superfamily of transporters is comprised of over 400 membrane-bound proteins, and plays essential roles in a multitude of physiological and pharmacological processes. In addition, perturbation of SLC transporter function underlies numerous human diseases, which renders SLC transporters attractive drug targets. Common genetic polymorphisms in SLC genes have been associated with inter-individual diferences in drug efcacy and toxicity. However, despite their tremendous clinical relevance, epidemiological data of these variants are mostly derived from heterogeneous cohorts of small sample size and the genetic SLC landscape beyond these common variants has not been comprehensively assessed. In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entire SLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identifed, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conserva- tion, structural considerations, and functional genomics data revealed that each individual genome harbors 29.7 variants with putative functional efects, of which rare variants account for 18%. Inter-ethnic variability was found to be extensive, and 83% of deleterious SLC variants were only identifed in a single population.
    [Show full text]
  • Disease-Induced Modulation of Drug Transporters at the Blood–Brain Barrier Level
    International Journal of Molecular Sciences Review Disease-Induced Modulation of Drug Transporters at the Blood–Brain Barrier Level Sweilem B. Al Rihani 1 , Lucy I. Darakjian 1, Malavika Deodhar 1 , Pamela Dow 1 , Jacques Turgeon 1,2 and Veronique Michaud 1,2,* 1 Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Orlando, FL 32827, USA; [email protected] (S.B.A.R.); [email protected] (L.I.D.); [email protected] (M.D.); [email protected] (P.D.); [email protected] (J.T.) 2 Faculty of Pharmacy, Université de Montréal, Montreal, QC H3C 3J7, Canada * Correspondence: [email protected]; Tel.: +1-856-938-8697 Abstract: The blood–brain barrier (BBB) is a highly selective and restrictive semipermeable network of cells and blood vessel constituents. All components of the neurovascular unit give to the BBB its crucial and protective function, i.e., to regulate homeostasis in the central nervous system (CNS) by removing substances from the endothelial compartment and supplying the brain with nutrients and other endogenous compounds. Many transporters have been identified that play a role in maintaining BBB integrity and homeostasis. As such, the restrictive nature of the BBB provides an obstacle for drug delivery to the CNS. Nevertheless, according to their physicochemical or pharmacological properties, drugs may reach the CNS by passive diffusion or be subjected to putative influx and/or efflux through BBB membrane transporters, allowing or limiting their distribution to the CNS. Drug transporters functionally expressed on various compartments of the BBB involve numerous proteins from either the ATP-binding cassette (ABC) or the solute carrier (SLC) superfamilies.
    [Show full text]
  • The Genetic Relationship Between Paroxysmal Movement Disorders and Epilepsy
    Review article pISSN 2635-909X • eISSN 2635-9103 Ann Child Neurol 2020;28(3):76-87 https://doi.org/10.26815/acn.2020.00073 The Genetic Relationship between Paroxysmal Movement Disorders and Epilepsy Hyunji Ahn, MD, Tae-Sung Ko, MD Department of Pediatrics, Asan Medical Center Children’s Hospital, University of Ulsan College of Medicine, Seoul, Korea Received: May 1, 2020 Revised: May 12, 2020 Seizures and movement disorders both involve abnormal movements and are often difficult to Accepted: May 24, 2020 distinguish due to their overlapping phenomenology and possible etiological commonalities. Par- oxysmal movement disorders, which include three paroxysmal dyskinesia syndromes (paroxysmal Corresponding author: kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, paroxysmal exercise-induced dys- Tae-Sung Ko, MD kinesia), hemiplegic migraine, and episodic ataxia, are important examples of conditions where Department of Pediatrics, Asan movement disorders and seizures overlap. Recently, many articles describing genes associated Medical Center Children’s Hospital, University of Ulsan College of with paroxysmal movement disorders and epilepsy have been published, providing much infor- Medicine, 88 Olympic-ro 43-gil, mation about their molecular pathology. In this review, we summarize the main genetic disorders Songpa-gu, Seoul 05505, Korea that results in co-occurrence of epilepsy and paroxysmal movement disorders, with a presenta- Tel: +82-2-3010-3390 tion of their genetic characteristics, suspected pathogenic mechanisms, and detailed descriptions Fax: +82-2-473-3725 of paroxysmal movement disorders and seizure types. E-mail: [email protected] Keywords: Dyskinesias; Movement disorders; Seizures; Epilepsy Introduction ies, and paroxysmal dyskinesias [3,4]. Paroxysmal dyskinesias are an important disease paradigm asso- Movement disorders often arise from the basal ganglia nuclei or ciated with overlapping movement disorders and seizures [5].
    [Show full text]
  • Potent Inhibition of Monoamine Oxidase B by a Piloquinone from Marine-Derived Streptomyces Sp. CNQ-027
    J. Microbiol. Biotechnol. (2017), 27(4), 785–790 https://doi.org/10.4014/jmb.1612.12025 Research Article Review jmb Potent Inhibition of Monoamine Oxidase B by a Piloquinone from Marine-Derived Streptomyces sp. CNQ-027 Hyun Woo Lee1, Hansol Choi2, Sang-Jip Nam2, William Fenical3, and Hoon Kim1* 1Department of Pharmacy and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea 2Department of Chemistry and Nano Science, Ewha Womans University, Seoul 03760, Republic of Korea 3Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA 92093-0204, USA Received: December 19, 2016 Revised: December 27, 2016 Two piloquinone derivatives isolated from Streptomyces sp. CNQ-027 were tested for the Accepted: January 4, 2017 inhibitory activities of two isoforms of monoamine oxidase (MAO), which catalyzes monoamine neurotransmitters. The piloquinone 4,7-dihydroxy-3-methyl-2-(4-methyl-1- oxopentyl)-6H-dibenzo[b,d]pyran-6-one (1) was found to be a highly potent inhibitor of First published online human MAO-B, with an IC50 value of 1.21 µM; in addition, it was found to be highly effective January 9, 2017 against MAO-A, with an IC50 value of 6.47 µM. Compound 1 was selective, but not extremely *Corresponding author so, for MAO-B compared with MAO-A, with a selectivity index value of 5.35. Compound 1,8- Phone: +82-61-750-3751; dihydroxy-2-methyl-3-(4-methyl-1-oxopentyl)-9,10-phenanthrenedione (2) was moderately Fax: +82-61-750-3708; effective for the inhibition of MAO-B (IC = 14.50 µM) but not for MAO-A (IC > 80 µM).
    [Show full text]
  • Evidence of Pyrimethamine and Cycloguanil Analogues As Dual Inhibitors of Trypanosoma Brucei Pteridine Reductase and Dihydrofolate Reductase
    pharmaceuticals Article Evidence of Pyrimethamine and Cycloguanil Analogues as Dual Inhibitors of Trypanosoma brucei Pteridine Reductase and Dihydrofolate Reductase Giusy Tassone 1,† , Giacomo Landi 1,†, Pasquale Linciano 2,† , Valeria Francesconi 3 , Michele Tonelli 3 , Lorenzo Tagliazucchi 2 , Maria Paola Costi 2 , Stefano Mangani 1 and Cecilia Pozzi 1,* 1 Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018–2022, University of Siena, via Aldo Moro 2, 53100 Siena, Italy; [email protected] (G.T.); [email protected] (G.L.); [email protected] (S.M.) 2 Department of Life Science, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy; [email protected] (P.L.); [email protected] (L.T.); [email protected] (M.P.C.) 3 Department of Pharmacy, University of Genoa, Viale Benedetto XV n.3, 16132 Genoa, Italy; [email protected] (V.F.); [email protected] (M.T.) * Correspondence: [email protected]; Tel.: +39-0577-232132 † These authors contributed equally to this work. Abstract: Trypanosoma and Leishmania parasites are the etiological agents of various threatening Citation: Tassone, G.; Landi, G.; neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, Linciano, P.; Francesconi, V.; Tonelli, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to M.; Tagliazucchi, L.; Costi, M.P.; Trypanosoma brucei (Tb), have been achieved by the introduction of fexinidazole and the combination Mangani, S.; Pozzi, C. Evidence of therapy eflornithine–nifurtimox. Nevertheless, due to drug resistance issues and the exitance of Pyrimethamine and Cycloguanil animal reservoirs, the development of new NTD treatments is still required.
    [Show full text]