Table Of ContentThis 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
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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
