Biochemical and Pharmacological Roles of Adenosylmethionine and the Central Nervous System. Proceedings of an International Round Table on Adenosylmethionine and the Central Nervous System, Naples, Italy, May 1978 PDF
Preview Biochemical and Pharmacological Roles of Adenosylmethionine and the Central Nervous System. Proceedings of an International Round Table on Adenosylmethionine and the Central Nervous System, Naples, Italy, May 1978
This book was edited by Dr Usdin in his private capacity. No Official support or endorsement by the NIMH is intended or should be inferred. BIOCHEMICAL AND PHARMACOLOGICAL ROLES OF ADENOSYLMETHIONINE AND THE CENTRAL NERVOUS SYSTEM Proceedings of on International Round Table on Aderosylmethionine and the Central Nervous System NoplesJtaly. May 1978 Editors VINCENZO ZAPPIA University of Naples Naples, Italy EARL USDIN National Institute of Mental Health Rockville, Maryland, USA FRANCESCO SALVATORE University of Naples Naples. Italy PERGAMON PRESS OXFORD · NEW YORK · TORONTO · SYDNEY · PARIS · FRANKFURT U.K. Pergamon Press Ltd., Headlngton Hill Hall. Oxford OX3 OBW, England U.S.A. Pergamon Press Inc., Maxwell House. Fairview Park, Elmsford. New York 10523. U.S.A. CANADA Pergamon of Canada, Suite ş04,150 Consumers Road, Willowdale, Ontario M2J 1P9, Canada AUSTRALIA Pergamon Press (Aust.) Pty. Ltd., P.O. Box 544, Potts Point, N.S.W. 2011 Australia FRANCE Pergamon Press SARL, 24 rue des Ecoles, 75240 Paris, Cedex 05, France FEDERAL REPUBLIC Pergamon Press GmbH, 6242 Kronberg-Taunus, OF GERMANY Pferdstrasse I Federal Republic of Germany Copyright ©1979 Pergamon Press Ltd. All Rights Reserved. No part of this publication may be reproduced, stored h á retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writirig from the publishers. First editiom979 British Library Cataloguing in Publication Data Adenosylmettiionine and the Central Nervous System (conference). Naples, 1978 Biochemical and pharmacological roles of adenosylmethionirje and the central nervous system. 1. Neurochemistry 2. Central nervous system. 3. Adenosylmethionine I. Title II. Zappia. Vincenzo III. Usdin. Earl IV. Salvatore. Francesco 612'.8 QP356.3 79-40691 ISBN 0-08-024929-9 In order to make this volume available as ecoromically and as rapidly as possible the authors' typescripts have been reproduced in their original forms. This method urv fortunately has its typographical limitations but it is hoped that they in no way distract ttie reader. Printed and bound at William Clowes & Sons Limited Beccles and London Preface This volume contains thirteen contributions by experts on the biochemical and pharmacological roles of S-adenosylmethionine (SAM), with particular emphasis on trie functions of this compound in the central nervous syste m(CNS). The reports were presented at a round-table meeting held in Naples (Italy) on May 2, 1978. This specialized meeting was organized in response to the rapid expansion of this field. The organizers regretted that it was impossible to accomodate othe rout standing investigators within the program of the meeting and hope this volume will allow others interested in the role of SAM in the CNS to profit from the presenta tions. The Editors wish to express their thanks to the speakers, the discussants, the section chairmen and to the other participants. The meeting was sponsored by the "Accademia di Scienze Mediche di Napoli" and the Editors wish to express their ap preciation to Professor L. Donatelli, Secretary of the Accademia, for his cooper ation. They also acknowledge the generous hospitality at the Villa Pignatelli of the "Sovraintendenza delle Belle Arti di Napoli" as well as the support received from Dr. L. Camozzi of the Bio-Research Laboratories and from the "Azienda di Soggioinoe Cura di Napoli". Meetings on SAM were initiated in 1964 when Drs. Shapiro and Schlenk organized the first one at the Argonne National Laboratory in the United States. Then after a rather long break two meetings followed in close succession: one at Gif-sur-Yvette (France), organized by Drs. Lederer and Cantoni in 1973, and one in 1974 in Rome (Italy) through the efforts of Drs. Salvatore, Borek, Zappia, Williams-Ashman and Schlenk. In addition to the Naples meeting on SAM in the CNS in 1978, there is also scheduled a Conference on Transmethylation for October in Bethesda (U.S.A.), organ ized by Usdin, Borchardt and Creveling. The reports in this volume include an introductory review on some novel biochemical aspects of SAM and seven papers concerned with several chemical and biochemical properties of this molecule, with special reference to its roles in the CNS. The five papers which follow deal with pharmacological aspects of SAM within the CNS and also with attempted clinical use of this compound. The clinical utility of SAM would be of remarkable interest, if it can be confirmed by further studies. viii Preface The Editors would like to recall that the trial of the topics of this symposium was opened by the studies of Dr. Julius Axelrod: the discovery in the CNS of methylating enzymes which metabolize catecholamines and other aromatic compounds. The trial continues to be lighted today by his studies on protein methylation and the role of SAM in the excitation-secretion coupling at the level of the outer surface of the chromaffin vesicle. Thus, we dedicate this volume to the work of Julius Axelrod. Vlncmzo ΖαρμΙα ΕοΛί Íl¿dín F^anceóco SaívcutoKo, Abbreviations ACTH = adrenocorticotrophic hormone 5-HT = serotonin Ado-Hcy cf SAH GABA = γ -aminobutyric acid ADO-MET cf SAM HnRNP = heterogenous nuclear ribonucleo AP = anterior pituitary protein asDMArg = N^,N^-di(asymmetric)arginine HVA = homovanillic acid ATP = adenosine 5'-triphosphate INMT = indoleamine N-methyltransferase BBB = blood-brain barrier LH = luteinizine hormone CEEG = coommppuut erized EEG LSD = lysergic acid diethylamide CHίFH^ = NN5^--methyltetrahydrofolate MAO = monoamine oxidase CNS = central nervous system ME = median eminence COMT = catechol 0-methyltransferase m^FH^ = N^-methyltetrahydrofolate CPT = protein carboxy transferase MHPG-SO, = 3-methoxy-4-hydroxyphenyl- CPZ = chlorpromazine glycol sulfate DBN = 2,3,4,6,7,8-hexahydro-pyrrolo M.I.T. = MIT = Massachusetts Insti [l,2-a]pyrimidine tute of Technology deca SAM = decarboxylated SAM = S-adenosyl- MMArg = N^-(mono)methylarginine 5'-methylthiopropylamine MTA = methylthioadenosine DMT = N,N-dimethyltryptamine MTHF = methyltetrahydrofolate DNA = deoxyribonucleic acid NADPH = NAD(P)H = reduced triphospho- DOPA = Dopa = dopa = 3,4-dihydroxyphenyl- pyridine nucleotide alanine NE = norepinephrine dTMP = deoxythymidine monophosphate ΝΕΑ = neuro-endocrine axis dUMP = deoxyuridine monophosphate NIMH = (U.S.) National Institute of Ε. coli = Escherichia coli Mental Health EEG = electroencephalograph NMT = N-methyltryptamine 3-EP = 3-endorphin nor^^CPZ = N-demethyl CPZ FAD = favin adenine dinucleotide nor2CPZ = di-N-demethyl CPZ FH/ = tetrahydrofolate PCMB = p-chloromercuribenzoic acid FSH = follicle stimulating hormone Pi = inorganic phosphate GH = growth hormone PIF = prolactin inhibitory factor GLC = gas-liquid chromatography PLP = pyridoxal-5'-phosphate GTP = guanosine-5'-triphosphate PNMT = phenylethanolamine N-methyl Η = histamine transferase HHPRLA = hypothalamic-hypophyseal-prolac PRL = prolactin tin axis RNA = ribonucleic acid 5-HIAA = HIAA = 5-hydroxyindoleactic acid SAH = S-adenosylhomocysteine HIF = hypothalamic inhibitory factor SAM = S-adenosylmethionine HIMT cf HIOMT sDMArg = NG,N'^-di(symmetric)arginine HIOMT = hydroxyindole 0-methyltransferase SMM = S-methylmethionine HMT = histamine N-methyltransferase TIDA = tubero-infundibular system HNMT - cf HMT TLC = thin-layer chromatography HPLC = high (performance or pressure) tRNA = transfer RNA liquid chromatography TSH = thyrotropin stimulating hormone HRF = hypothalamic releasing factor VMA = vanillylmandelic acid HRS = Hamilton Rating Scale (for Depression) Contributors Algeri, Sergio Delia Pietra, Gennaro Institute of Pharmacological Research Department of Biochemistry "Mario Negri", Via Eritrea 62 1st Medical School 20157 Milano, Italy University of Naples Via Costantinopoli 16 Amati, Amato 80138 Napoli, Italy Department of Psychiatry 1st Medical School Del Vecchio, Mario University of Naples Department of Psychiatry 80100 Napoli, Italy 1st Medical School Baldessarini, Ross J. University of Naples Mailman Laboratories for 80100 Napoli, Italy Psychiatric Research McLean Division of Eloranta, Terho E. Massachusetts General Hospital Department of Biochemistry Belmont, Massachusetts 20178 USA University of Kuopio P.O.B. 138 Benzi, Gianni SF-70101 Institute of Pharmacology Kuopio 10, Finland University of Pavia Facolta di Scienze Esposito, Carla 27100 Pavia, Italy Department of Biochemistry 1st Medical School Cacciapuoti, Giovanna University of Naples Department of Biochemistry Via Costantinopoli 16 1st Medical School 80138 Napoli, Italy University of Naples Via Costantinopoli 16 Famiglietti, Luciana A. 80138 Napoli, Italy Department of Psychiatry 1st Medical School Catto, Emilia University of Naples Institute of Pharmacological Research 80100 Napoli, Italy "Mario Negri" Via Eritrea 62 20157 Milano, Italy Fiecchi, Alberto Department of Chemistry Celani, Tiziana Medical School Department of Psychiatry University of Milan 1st Medical School Via Saldini, 50 University of Naples 20133 Milano, Italy 80100 Napoli, Italy Galletti, Patrizia Clementi, Giuseppe Department of Biochemistry Department of Pharmacology 1st Medical School School of Medicine University of Naples University of Catania Via Costantinopoli, 16 95125 Catania, Italy 80138 Napoli, Italy Curcio, Maria Kemali, Dargut Institute of Pharmacological Research Department of Psychiatry "Mario Negri", Via Eritrea 62 1st Medical School 20157 MUano, Italy University of Naples 80100 Napoli, Italy Contributors Kim, Sangduk Salvatore, Francesco Fels Research Institute Department of Biochemistry Temple University School of Medicine 2nd Medical School Philadelphia, Pennsylvania 19140, USA University of Naples Via Sergio Pansini 5 Lipinski, Joseph F. 80131 Napoli, Italy Department of Psychiatry Harvard Medical School Scapagnini, Umberto Boston, Massachusetts, USA Department of Pharmacology School of Medicine Mason, Robert J. University of Catania Department of Biochemistry Catania, Italy University of Leeds 9 Hyde Terrace Schatz, Robert A. Leeds LS 2 9LS, England Laboratory of Neurochemlstry Mental Health Research Institute Paik, Woon Ki University of Michigan Medical Center Fels Research Institute Ann Arbor, Michigan 48109, USA Temple University School of Medicine Philadelphia, Pennsylvania 19140, USA Sellinger, Otto Z. Laboratory of Neurochemlstry Pearson, Andrew G.M. Mental Health Research Institute Department of Biochemistry University of Michigan Medical Center University of Leeds Ann Arbor, Michigan 48109, USA 9 Hyde Terrace Leeds LS2 9LS, England Stramentinoli, Giorgio Department of Biochemistry Ponzio, Franca Bio-Research Co. Institute of Pharmacological Research 20060 Liscate (Milan), Italy "Mario Negri", Via Eritrea 62 20157 Milano, Italy Turner, Anthony J. Department of Biochemistry Porcelli, Marina University of Leeds Department of Biochemistry 9 Hyde Terrace 1st Medical School Leeds LS2 9LS, England University of Naples Via Costantinopoli 16 Usdin, Earl 80138 Napoli, Italy Psychopharmacology Research Branch National Institute of Mental Health Porta, Raffaele Rockville, Maryland 20857, USA Department of Biochemistry 1st Medical School Vacca, Lucio University of Naples Department of Psychiatry Via Costantinopoli 16 1st Medical School 80138 Napoli, Italy University of Naples 80100 Napoli, Italy Prato, Agata Department of Pharmacology Wurtman, Richard J. School of Medicine Laboratory of Neuroendocrine Regulation University of Catania Massachusetts Institute of Technology Catania, Italy Cambridge, Massachusetts, 02139, USA Ragusa, Nicola Zappia, Vincenzo Department of Pharmacology Department of Biochemistry School of Medicine 1st Medical School University of Catania University of Naples Catania, Italy Via Costantinopoli 16 80138 Napoli, Italy Rizza, Victor Department of Pharmacology School of Medicine University of Catania Catania, Italy Novel Aspects in the Biochemistry of Adenosylmethionine and Related Sulfur Compounds Vincenzo Zappia, Francesco Salvatore, Marina Porcelli and Giovanna Cacciapuoti Depxartments of Biochemistry, 1st and 2nd Medical School, University of Naples, Naples, Italy In recent years, since the Symposiiun on "The Biochemistry of Adenosylmethionine" held in Rome in 1974 (1), several new metabolic functions have been assigned to this important and widely occurring sulfonium compound. The number of enzymatic reactions in which it functions either as substrate or as modulator has signif icantly increased: few other molecules are indeed involved in so many different types of reactions within the cell. The only other sulfonium compound detectable in mammalian tissues is S-adenosyl-(5')-3-methylthiopropylamine, i.e., decarboxy- lated adenosylmethionine; the biological roles of the two compounds are summarized in Table 1. Table 1 BIOLOGICAL ROLES OF S-ADENOSYLMETHIONINE (I) AND ITS DECARBOXYLATED PRODUCT (II) • DONOR OF METHYL GROUP IN A WIDE VARIETY OF TRANSMETHYLATION REACTIONS (I). • DONOR OF PROPYLAMINE MOIETY IN THE BIOSYNTHESIS OF SPERMIDINE, SYM- NOR-SPERMIDINE, SPERMINE AND SYM-NOR-SPERMINE (II). t SUBSTRATE OF A SPECIFIC LYASE WHICH CONVERTS THE MOLECULE INTO 5'- METHYL-THIOADENOSINE AND HOMOSERINE (I). • DONOR OF THE AMINOBUTYRYL SIDE CHAIN TO tRNA (I). • DONOR OF THE SIDE CHAIN AMINO GROUP IN BIOTIN BIOSYNTHESIS (I). • ADENOSYL DONOR (I). • ACTIVATOR OF LYSINE-2,3-AMINO MUTASE, THREONINE SYNTHETASE, PYRUVATE- FORMATE-LYASE AND N^ -METHYLTETRAHYDROFOLATE-HOMOCYSTEINE METHYL- TRANSFERASE (I). • INHIBITOR OF RIBONUCLEASE H, METHYLENE TETRAHYDROFOLIC REDUCTASE AND ETHANOLAMINEPHOSPHATE CYTIDYLTRANSFERASE (I). • REQUIRED FOR BACTERIAL CHEMOTAXIS (I). f REQUIRED IN THE RESTRICTION AND MODIFICATION SYSTEM OF DNA IN PRO- KARYOTES AND EUKARYOTES (I). 2 V. Zappia et dl, TRANSMETHYLATION REACTIONS Transmethylation may be conaidered as the oldest example of biochemical group transfer and represents by far the largest and most widely studied group of alkyl transfer reactions (2). In mammalian systems adenosylmethionine (SAM) is the most versatile methyl donor, while N^-methyltetrahydrofolic acid (3), methylcobalamin (4) and betaine (5), are involved in transmethylations only in a few instances. S-adenosylmethionine N'-methyltetrahydrofolate o "NH Adenosyl^ ^Hj) Methyl cobalamin Fig. 1 Schematic representation of the biological methyl donors in mammalian systems Fig. 1 gives a schematic representation of these molecules; the methyl group is bound respectively: to the sulfur atom in the onium configuration in SAM, to the trivalent nitrogen in the folic acid derivative, to the nitrogen in the ammonium form in betaine, and to the cobalt ion coordinated by four nitrogen atoms in the cobalamine derivative. Whether the 5-N of methyltetrahydrofolate is quaternized (6) similarly to the nitrogen of betaine is matter of investigation. The non- polar environment of the enzyme active site could facilitate such a conformation. The chemical variety of acceptors of the methyl group from SAM is strikingly high: the attachment of the methyl group to the nitrogen atom is perhaps the most extensively studied, but sulfur, oxygen and carbon are also binding sites .As far as the central nervous system (CNS) is concerned, methyl transfer reactions are
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