Glutamine and Glutamate Mammals Volume I - 1st Edition
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PREFACE
The present comprehensive volume, which is based on the joint effort of a great many
top scientists and covering most aspects of the metabolism and function of glutamine and
glutamate in mammals, is a result of what we felt was a specific demand. Thus, the majority
of previous books and review articles on glutamine and glutamate are confined to limited
areas (e.g., energy metabolism, nervous transmission, etc.) or organs (e.g., brain, kidney,
liver, etc.). This is not surprising in view of the vast amount of recent publications in each
field, but it contributes to some sort of compartmentalization - to use a popular word -
that creates barriers and subspecialization. The present volumes intend to act as a carrier
between the various compartments. Similar to biological carriers, this one must be selective,
since every discovery claimed to be done cannot be and does not deserve to be conveyed.
However, what should be included will always be a matter of different opinion. Anyway,
to communicate essential information from the many interrelated subfields appears to be
necessary, since quite a few recent publications reflect the lack of knowledge of relevant
findings in neighboring fields.
In addition to breaking down artificial barriers between subjects and fields, this volume
also serves another purpose, namely to transmit different views on controversial matters.
For that reason each author has been allowed to speak with his own voice and present his
personal opinion on problems under debate. The careful reader will therefore discover that
in spite of considerable overlapping in problems to be discussed, the flavor of the discussions
may be different. Furthermore, although the reader may feel that he knows what is worth
knowing about a subject after having read the relevant chapter, he may change his mind
following the study of other chapters touching upon the same subject. However, the present
volumes do not pretend to give the final answer to the many problems presented, but it
intends to give a cross-section of a process under continuous development, and I wish to
convey my sincere thanks to the authors who have all contributed to approach this goal.
Elling Kvamme
THE EDITOR
Dr. Elling Kvamme is professor of neurochemistry at the Oslo University and Head of
the Neurochemical Laboratory.
In 1947, Dr. Kvamme received an M.D. at the Oslo University. Thereafter, he studied
organic and physical chemistry, and in 1959 he received the scientific degree, Dr. med., at
the Oslo University. After 3 years of service at Dikemark Hospital, Asker, and a l-year
internship (internal medicine and surgery) at the Ullevil Hospital, Oslo, he received a
FulbrightlSmith Mundt Fellowship and worked as a Research Fellow at the Sloan-Kettering
Institute for Cancer Research in New York from 1952 to 1954, and at the Public Health
Research Institute of the City of New York, Department of Biochemistry, from 1954 to
1955. From 1955 to 1962, Dr. Kvamme was appointed Assistant Head of the Central
Laboratory, Ullevdl Hospital. Thereafter, he was appointed Head of the newly formed
Neurochemical Laboratory at the Oslo University Psychiatric Clinic and, in 1966, appointed
professor of Neurochemistry at the Oslo University. He is currently teaching neurochemistry
to medical students and organizing postgraduate courses.
In 1962, Dr. Kvamme spent 6 months as a Technical Assistant Expert at the National
Institute of Cancer, Rio de Janeiro, being appointed by the International Atomic Energy
Agency, Vienna.
Dr. Kvamme has presented numerous papers at international meetings, as well as guest
lectures at various universities and institutes in Europe and the U.S. He has also taken an
active part in organizing many national and international meetings. Dr. Kvamme has served
as the President of the Norwegian Biochemical Society from 1976 to 1978, the Treasurer
of the International Society for Neurochemistry (ISN) from 1977 to 1981, the Chairman of
ISN from 1981 to 1983, and the Chairman of the Policy Advisory Committee of ISN from
1985 to 1987.
Dr. Kvamme's main interest includes the metabolism and function of amino acids, in
particular with regard to glutamine and glutamate. He has published a great number of
scientific articles in international journals, in addition to several review articles in handbooks
and scientific journals.
CONTRIBUTORS
Arthur J. L. Cooper Elling Kvamme
Associate Professor Professor
Departments of Neurology and Neurochemical Laboratory
Biochemistry University of Oslo
Cornell University Medical College Oslo, Norway
New York. New York
Chin-Tarng Lin
Ivan Couee Department of Pathology
Department of Biochemistry National Taiwan University
Trinity College Taipei, Taiwan
Dublin, Ireland
A. M. Pujaras Crane C. M. Maillet
Department of Immunology Department of Biochemistry
Baylor College of Medicine University of Texas Health Science
Houston, Texas Center
Houston, Texas
Larry A. Denner
Department of Cell Biology J. D. McGivan
Baylor College of Medicine Department of Biochemistry
Houston, Texas University of Bristol
Bristol, England
Alan J. Garber
Professor of Medicine, Biochemistry, and
William J. Nicklas
Cell Biology
Professor
Baylor College of Medicine
Department of Neurology
and
Robert Wood Johnson Medical School
Chief
University of Medicine and Dentistry of
Diabetes Metabolism Unit
New Jersey
The Methodist Hospital
Piscataway, New Jersey
Houston, Texas
Peter J. Hanson Dennis S. Parsons
Division of Biology, Molecular Sciences Department of Physiology
University of Aston Oxford University
Birmingham, England Oxford, England
Nils-Erik Huseby David P. Simpson
Department of Clinical Chemistry Professor
Institute of Medical Biology Department of Medicine
University of Tromso University of Wisconsin
Tromso, Norway Madison, Wisconsin
Bang Hwang Gerd Svenneby
Indiana University Neurochemical Laboratory
Terre Haute Center for Medical Education University of Oslo
Terre Haute, Indiana Oslo, Norway
J. Tyson Tildon Ingeborg Aasland Torgner
Professor Neurochemical Laboratory
Department of Pediatrics University of Oslo
Department of Biological Chemistry Oslo, Norway
University of Maryland
Baltimore, Maryland Jang-Yen Wu
Professor
Keith F. Tipton Department of Physiology
Department of Biochemistry Milton S. Hershey Medical Center
Trinity College Pennsylvania State University
Dublin, Ireland Hershey, Pennsylvania
H. Ronald Zielke
Associate Professor
Department of Pediatrics
University of Maryland
Baltimore, Maryland
TABLE OF CONTENTS
Volume I
Chapter 1
Glutamate and Glutamine in Mammals: An Overview.. ..................................1
William J. Nicklas
ENZYMES IN GLUTAMINE AND GLUTAMATE METABOLISM
Chapter 2
Glutamine Synthetase .................................................................... 7
Arthur J. L. Cooper
Chapter 3
Glutamine Aminotransferases and w-Amidases .......................................... 33
Arthur J. L. Cooper
Chapter 4
Glutaminases ............................................................................ 53
Elling Kvamme, Gerd Svenneby, and Ingeborg Aasland Torgner
Chapter 5
Transglutaminases ....................................................................... 6 9
Elling Kvamme
Chapter 6
Glutamate Dehydrogenase ............................................................... 81
Keith F. Tipton and Ivan Couee
Chapter 7
Glutamate Decarboxylase.. ............................................................. 101
Jang-Yen Wu, Larry A. Denner, Chin-Tarng Lin, and Bang Hwang
Chapter 8
(L-Glutamate-2-Oxoglutarate) Aminotransferases ...................................... . l 2 3
Arthur J. L. Cooper
Chapter 9
y-Glutamyltransferase .................................................................. 153
Nils-Erik Huseby
EXTRANERVOUS METABOLISM OF GLUTAMINE AND GLUTAMATE
Chapter 10
Glutamine: An Energy Source for Mammalian Tissues. ................................167
J. Tyson Tildon and H. Ronald Zielke
Chapter 11
Metabolism of Glutamine and Glutamate in Liver - Regulation and Physiological
Significance ............................................................................
183
J. D. McGivan
Chapter 12
Renal Glutamine Metabolism.. ........................................................ ,203
David P. Simpson
Chapter 13
Cyclic Nucleotide Regulation of Glutamine Metabolism in Skeletal Muscle.. . . . . . . . . . .221
C. M. Maillet, A. M. Pujaras Crane, and A. J. Garber
Chapter 14
Transport and Metabolism of Glutamine and Glutamate in the Small Intestine ........ .235
Peter J. Hanson and Dennis S. Parsons
INDEX.. .............................................................................. ,255
Volume I1
GLUTAMINE AND GLUTAMATE IN THE CENTRAL NERVOUS SYSTEM
Chapter 15
Glutamate as a Neurotransmitter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Richard P. Shank and M. H. Aprison
Chapter 16
Uptake and Release of Glutamate and Glutamine in Neurons and Astrocytes in Primary
Cultures ................................................................................. 21
Arne Shousboe, JBrgen Drejer, and Leif Hertz
Chapter 17
Metabolism of Glutamate and Glutamine in Neurons and Astrocytes in Primary
Cultures .................................................................................39
Leif Hertz and Arne Shousboe
Chapter 18
Transmitter Glutamate in Mammalian Hippocampus and Striatum ...................... 57
Frode Fonnum
Chapter 19
Glutamine and its Neuroactive Derivatives in the Retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Mary J. Voaden
Chapter 20
Exciting Amino Acid Receptors.. .......................................................
89
J ~ r g e nDrejer and Tage Honore
PATHOLOGY OF GLUTAMINE AND GLUTAMATE
Chapter 21
Glutamine, Glutamate, and GABA in Human Diseases ................................ 113
Thomas L. Perry
Chapter 22
Pathology of Glutamate Dehydrogenase ................................................ 127
Andreas Plaitakis and Soll Berl
Chapter 23
Excitatory Amino Acids in Epilepsy ................................................... 143
Henry F. Bradford and Dale W. Peterson
Chapter 24
Experimental and Clinical States of Hyperammonia: Alterations in Glutamate and
Glutamine .............................................................................. 165
Oliver W. Cass and Leslie Zieve
INDEX. ................................................................................ 177
Volume I 1
Chapter 1
GLUTAMATE AND GLUTAMINE IN MAMMALS: AN OVERVIEW
William J. Nicklas
Glutamate and glutamine are key amino acids in mammalian intermediary metabolism,
intimately associated with aerobic metabolism via the tricarboxylic acid cycle and with
ammonia metabolism. In addition they are involved in the synthetic pathways of numerous
biologically important compounds.' Research in various aspects of the metabolism and
function of these amino acids has been continuous since the earliest days of modem bio-
chemical ~ t u d i e s The
. ~ various contributions to this monograph attest to the vitality and
conceptual depth of current research efforts. The direction of these studies has traced a path
through the traditional biochemical methodologies and now encompasses other powerful
techniques such as immunohistochemistry and molecular biology.
What is emerging from these multidisciplinary studies on different organ systems is a
pattern of greater complexity and heterogeneity than previous work might have suggested.
Not only does one find the expected intracellular and interorgan diversity, but intercellular
heterogeneity is becoming a more commonly accepted phenomenon. Nowhere is this com-
plexity and heterogeneity more apparent, nor has it been more intensely studied, than in the
nervous ~ y s t e m . In ~ central nervous system (CNS), glutamate and its decarboxylation
~ -the
product, 4-aminobutyrate (GABA), may well function as important neurotransmitter sub-
s t a n c e ~Thus
. ~ superimposed on the "normal" role of glutamate and glutamine in cellular
metabolism with its accompanying transport systems and enzymes is the further complication
of specific membrane-associated receptor proteins and the associated ion-channel systems.
Furthermore, glutamate and related neuroexcitatory substances are also potentially neuro-
toxic. The pharmacological and toxicological consequences of multiple receptor types for
excitatory dicarboxylic amino acids are only now being understood and e~ploited.'.~ It is
clear from this that exquisite regulatory mechanisms must be present to separate these various
functions of ubiquitously distributed amino acids such as glutamate and glutamine. The
homeostatic regulation of the neuroactive amino acids is associated with a heterogeneity of
enzyme distribution among the neurons and glial cells that make up the nervous ~ y s t e m . ~
Most current evidence would suggest that transmitter pools of glutamate are formed in
glutamatergic synaptic endings from glutamine via the activity of phosphate-activated glu-
taminase [EC 3.5.1.21, which catalyzes the hydrolytic cleavage of glutamine to glutamate
and ammonia. It is doubtful that this enzyme is localized principally in such neurons but
there may be some relative enrichment. Regulation probably occurs via product inhibition
and presence of other effectors, such as Ca2+. ' O s ' ' Glutamine synthesis in the brain appears
to be principally associated with the activity of glutamine synthetase [EC 6.3.1.21 which
catalyzes the ATP-dependent amidation of glutamate. '* This also serves to remove ammonia
from the circulation since the urea cycle is inoperative in brain. Early experiments in which
animals were injected with radioactive precursors suggested that glutamine synthesis in the
brain was compartmented. For example, when rats were injected intracistemally (thus avoid-
ing problems with the blood-brain bamer) with I4C-glutamate and the total pools of brain
glutamate and glutamine acid-extracted, it was found that within minutes the radiospecific
activity of the total glutamine was severalfold higher than that of the total brain glutamate.13
This indicated that the radioactive extracellular glutamate was metabolized in a biochemical
compartment in which glutamine was synthesized before the radioactive glutamate could
mix with the bulk of tissue glutamate. Based on a great deal of similar in vivo and in vitro
data, Balazs et a1.14 suggested the "compartment" in which glutamine was actively syn-
2 Glutamine and Glutamate in Mammals
thesized was the astroglial cells of the brain. The subsequent immunohistochemical locali-
zation of glutamine synthetase in astrocytes in the brain15 has definitively shown this
interpretation based on biochemical studies to be correct. These findings immediately suggest
problems of regulation of transport and metabolism which would not be so obvious in a less
complex model. However, this complexity also allows for the separate regulation of the role
of these amino acids in "normal" metabolism and their possible role in neurotransmission.
From these studies emerged a concept of a "glutamine cycle" between glia and nerve
ending^.^.'^ In this hypothesis, glutamate and GABA levels within their respective nerve
terminals are maintained by glutamine derived from the extracellular space which in turn
can be replenished by synthesis in the glia via glutamine synthetase. In a series of studies
we attempted to answer the question as to whether this really o c ~ u r r e d One. ~ consistent
finding that emerged from the many earlier studies done with radioactive precursors of
glutamate/glutamine was that radioactive acetate (either I4C- or 3H-labeled) is preferentially
metabolized in the glutamine-synthesizing compartment of the brain, i.e., the astrocyte,
whereas radioactively labeled glucose is metabolized in all compartments. l6 Numerous stud-
ies have shown that when various CNS preparations are allowed to metabolize labeled glucose
and/or acetate and then efflux of synaptic contents initiated by depolarization stimuli, there
is a preferential efflux of glucose-labeled gl~tamate.~,",'~ In a series of experiment^,^ tissue
slice preparations from rat brains were incubated with a mixture of '4C-glucose and 3H-
acetate to label endogenous pools of amino acids. The alkaloid veratridine was used to cause
the efflux of synaptic glutamate and GABA. The proposed flow pathway from glutamine
synthesis in glia to glutamine utilization in the nerve endings was blocked by using 6-diazo-
5-0x0-L-norleucine (DON), an inhibitor of glutaminase, or L-methionine sulfoximine, an
inhibitor of glutamine synthetase. These treatments decreased the veratridine-induced release
of acetate-labeled glutamate and GABA preferentially. Therefore, glutamate and GABA
labeled from radioactive acetate metabolism (i.e., from glial metabolism) did indeed enter
transmitter pools of these amino acids via g l ~ t a m i n eMoreover,
.~ the contribution of glu-
tamine metabolism to the maintenance of transmitter amino acid levels seemed to be quan-
titatively important. The above studies were performed with in vitro preparations. Rothstein
and TabakoffI9 have come to a similar conclusion after in vivo inhibition of glutamine
synthetase. Methionine sulfoximine was administered to rats intraventricularly and the glu-
tamergic system of the striatum was studied. Striatal glutamine synthetase activity and
glutamine levels were decreased substantially for days with no change in total glutamate
levels. In addition, the Ca2+-dependent, K+-stimulated release of glutamate from striatal
slices of treated animals was diminished by 50%. When glutamine was present in the
perfusion medium in which release was measured, there was no difference in glutamate
efflux between slices from control or treated animals. The same authors had previously
reported that treatment of rats with intraventricular methionine sulfoximine decreased the
activity of dopaminergic terminals in the ~triaturn.~' This is of physiological interest because
it has been suggested that corticostriatal glutamergic inputs presynaptically facilitate the
release of doparnine from nigrostriatal nerve endings. At the present time, there is every
reason to conclude that the "glutamine cycle" is operative in the CNS and is of quantitative
and qualitative importance in the regulation of glutamate homeostasis.
When the first studies on amino acid metabolism in the brain were reported 2 decades
ago, there was a good deal of skepticism in the traditional biochemical community. Some
of this attitude was probably due to the perception of a relative homogeneity of amino acid
metabolism in other organs, for example, in the liver which was the benchmark for com-
parison. Another important reason, perhaps, was a lack of awareness of how to properly
interpret studies with tracer-radioactive precursors and the role played by high affinity active
transport systems for substances such as glutamate when tracer amounts are utilized in such
studies. In any case, doubts were slowly buried under an ever-increasing amount of data
Volume I 3
culminating in the immunohistochemical localization studies. In the meantime, the perception
of the homogeneity of glutamate metabolism in organs such as the liver has been replaced
by more recent, broadening concepts of its heterogeneity.
The early studies with isotopically labeled precursors administered intravenously to animals
also suggested a compartmentation of glutamate/glutamine/ammonia metabolism in other
organs such as the liver.I3 This was not pursued at the time. It is now clear that ammonia
metabolism in the liver is heterogeneous. Glutamine synthetase appears to be localized in
a small layer of perivenous cells2' which results in a heterogeneity in glutamine and ammonia
metabolism as studied by steady-state anterograde and retrograde perfusion experiment^.^^
Thus, there is a periportal location of urea synthesis and a perivenous location for glutamine
synthesis in the liver. Each of these processes is subject to regulation and the resulting
studies have been most fruitful in better understanding ammonia metabolism in the liver and
its response to various physiological effectors.23Haussinger2' has proposed an intercellular
"glutamine cycle" operating in the liver during ureogenesis which is to some extent rem-
iniscent of the "glutamine cycle" of the brain. The disparate distribution of glutamine
synthetase and the resulting heterogeneity of ammonia metabolism also impacts on the in
situ activity of other enzymes which may be more homogeneously distributed, such as
glutamate dehydrogenase [EC 1.4.1.31, an oxidoreductase which catalyses the NAD(P)-
dependent deamination of glutamate to 2-oxoglutarate as well as the reverse reaction, the
amination of 2-oxoglutarate to glutamate. The direction of the reaction can be different in
different organs and under different conditions within the same organ. In the brain, the
contribution of this enzyme to amino acid metabolism is not well understood but is under
active in~estigation.~~ Studies in the brain might well profit from what has been found in
experiments with other organs such as the liver. As pointed out by Sies and H a u ~ s i n g e r , ~ ~
ammonia production from catabolism of endogenous sources implies an increased oxidative
deamination of glutamate by glutamate dehydrogenase in the periportal lobule of the liver.
Conversely, perivenous glutamine synthesis from ammonia released from periportal hepa-
tocytes requires increased glutamate formation by glutamate dehydrogenase to maintain
glutamate levels. Here again there is an interesting analogy to studies in the nervous system.
Berl et al.'3725in their pioneering studies on 15N-NH, metabolism in the brain found an
increased synthesis of glutamate which occurred via glutamate dehydrogenase when gluta-
mine synthesis was stimulated by increased ammonia levels. Concomitantly, to maintain 2-
oxoglutarate levels, fixation of carbon dioxide via pyruvate carboxylase was also stimulated.
The astrocyte is fixed as the site where these effects occur by the fact that I4C-HCO, behaves
like acetate as a glutamine precursor in vivoZ5and in ~ i t r o , 'and~ pyruvate carboxylase
appears to be a glial enzyme.27
The above discussion illustrates the complexities of the regulation of glutamate metabolism
in different organs. It also serves to illustrate the differences and similarities in approach
which can be taken in such studies. Hopefully, the present volume will allow even more
"borrowing" between investigators in this field. This interdisciplinary sharing will become
even more important as research begins on the molecular biology of glutamate function and
metabolism and the novel revelations expected from those studies.
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Enzvmes in Glutamine and Glutamate Metabolism
