Table Of ContentMAMMALIAN
AMINO ACID
TRANSPORT
Mechanisms and Control
MAMMALIAN
AMINO ACID
TRANSPORT
Mechanisms and Control
Edited by
Michael S. Kilberg
UniversityofFlorida
Gainesville,Florida
and
Dieter Haussinger
MedizinischeUniversitiitsklinik
Freiburgim Breisgau, Germany
Springer Science+Business Media, LLC
Library of Congress Cataloging in Publication Data
Mammalian amino acid transport: mechanisms and control /edited by Michael S.
Kilberg and Dieter Haussinger.
p. em.
Includes bibliographical references and index.
1. Amino acids-Physiological lransport-Congresscs. I. Kilbcrg, Michael S. II.
Haussinger, D. (Dieter), date.
QP561.M35 1993 92-37711
599'.0875-dc20 CIP
Cover art courtesy of Cell Press, Cambridge, Massachusetts.
From K. E. Smith etal., 1992, "Cloning and Expression ofa Glycine
Transporter Reveal Colocalization with NMDA Receptors," Neuron, 8:927-935.
ProceedingsofaGermanSocietyofBiologicalChemistryconferenceon
CoordinateRegulationbetweenTransportand MetabolismofGlutamine,Glutamate,
andGamma-GlutamylCompounds,held May 13-16,1990,
inTitisee,Germany
ISBN978-1-4899-1163-6 ISBN978-1-4899-1161-2(eBook)
DOI10.1007/978-1-4899-1161-2
© SpringerScience+BusinessMediaNewYork1992
OriginallypublishedbyPlenumPress,NewYorkin1992.
Softcoverreprintofthehardcover1stedition 1992
Allrights reserved
Nopartofthis bookmaybe reproduced,storedinaretrievalsystem,ortransmittedin
anyform orbyany means,electronic,mechanical,photocopying,microfilming, record
ing,orotherwise,withoutwrittenpermissionfrom the Publisher
FOREWORD
Amino acid transport is a part of each of two larger subjects, amino acid
metabolism and the biomembrane transport of various .small molecules and ions.
Nevertheless in this volume we treat amino acid transport as more than a fragment of
eitherofthesetwolargersubjects. Amorecomprehensiveapproach isjustified whenwe
remember two historic and ongoing aspects of the title subject.
First,amino acid transport had its beginning and acquired a distinct momentum
(even if somewhat interrupted from 1913 until about 1945) as amino acid metabolism
with the central and pioneer work of Van Slyke and Meyer in 1913. The reviews in this
volume will show that it steadily becomes a larger aspect of amino acid metabolism,
broadly perceived. These chapters will show for how many organelles, cells, tissues,
organs and organ systems, the transmembrane compartmentations and flows of amino
acids play very large parts in their fundamental biological relations. The authors here
are tending collectively to evaluate an understanding of amino acid flows across
biomernbranes, and the regulation of these flows, as necessary to an ultimate
understandingofthefull rangeofdevelopmentand metabolism. Suchan understanding
goesfar beyondthe purelysubstrate-destabilizingcontributionsby enzymes,whichhave
often been arbitrarily limited to that conceptualentity,"the cell", and which for solong
a splendid time had most of biochemical research attention.
Secondly, the title interest had another beginning, which it embraced tightly for
at least two decades and to which it steadily returns. This beginning encompassed the
full range of the phenomenon of the membrane transport of small molecules and ions,
whether organic or inorganic. The historic selection of the amino acids for that attack
arosenotsomuch fromtheiruniquebiologicalinterestasfromtheadvantagestheyoffer
for such studies through their wide ranges of structure, shape, configuration, and
distribution of charge and polarity. (An attendant tragedy is the circumstance that
probably half of the biological world blinds itself to the real electrolytic nature of the
amino acids by seeing them as RCH(NH2)COOH rather than RCH(NH3+)COO- greatly
handicaps exploitation of this advantage). These features undoubtedly underlie their
biologicalimportancetoo, butthey havemadepertinent,toawiderangeofotherorganic
molecules,thebiologicalmeans by whichtheirtransmembraneflowsaredeterminedand
expressed. This range includes various other metabolites,hormones, small peptides and
their analogs, drugs, and other environmental factors. The relationship of their
transmembrane flows to linked movements of inorganic ions speaks also to the
fundamental breadth of our subject. .
Thisseriesof reviews will be found to progress through thissuccession ofcentral
interests. At least some of these chapters will be seen quite appropriately to reflect
directly on the phenomenon of membrane transport for itsown sake,a subject that still
needs finishing while we reach forward to try to understand the whole pattern of the
flows of metabolism. Furthermore, as the possibility emerges of identifying and
characterizing the proteins catalyzing and regulating these events, the importance of
accurately characterizingeach participating membrane transport system increases. But
for this aspectalso,the biologyof membrane transport has moved far beyond the naked
concept of permeability and its interruption, once supposed to occur solely by enzyme
v
action, or to be mediated by lipids, or to be energized in isolation from other cellular
energy transduction. Instead it has grown to be tightly associated with almost all other
metabolic events.
Oneshouldnot introduceourtitlesubjectwithoutattemptingtoconstructabridge
crossingthe interveningchaptersto the concludingessay entitledInterorganAminoAcid
Nutrition, which I have the privilegealso to offer. It isan admitted bias to regard that
subject as our principal and ultimate target: how are the flows of the amino acids and
their metabolites, along with the linked flows of inorganic ions, all ultimately to be
integrated intotheir places,to understand the overall flows of biological function? The
concept of that overall flow of metabolism led Peter Mitchell to a striking, if perhaps
slightlyexaggerateddictum:"itiseasiertounderstandbiochemistryin termsoftransport,
than it is to understand transport in terms of biochemistry." Recent work suggests that
transport receptor sites may have proved attractive for secondary exploitations as cell
surface receptors for viruses. Thus, perhaps allowing viral infections to contribute as
they do to nutritional problems, and transport abnormalities to influence viral
pathogenesis (Kim sa lll., 1991; Wang sa lll., 1991). Will the discrimination between
transporters per se from associated transport regulators present further problems? How
far will the emergingtendencyof transport mediators toformproteinsuperfamilies go?
(Gibson et aI., 1991). As James H. Schwartz remarks, "the amount of functional
information the can be derived from protein structure is astonishing."
The participating authors have sought to review the subject broadly, rather than
to limit attention to studies made in a particular laboratory. We depend, however, on
each authorship for sensitivity to the personal knowledge growing out of that area of
participation, and we are also aware that some of the subjects are so new that the
corresponding chapters arise for the moment from rather few labs.
REFERENCES
Gibson, A.L., Wagner, L.M.,Collins, F.S.and Oxender, D.L., 1991,Science 254:109.
Kim,J.W.,Closs, E.I., Albritton, L.M.and Cunningham, J.M., 1991,Nature 352:725.
Van Slyke, D.D.and Meyer, G.M., 1913, J.BioI.Chern. 16:197.
Wang, H., Kavanaugh, M.P.,North, R.A.and Kabat, D., 1991, Nature 352:728.
H.N. Christensen
vi
PREFACE
Transport of amino acids or their derivatives across biological membranes is a
highly controlled process. Nature has evolved more or less specific transport systems
whichallowaminoacid transfer betweendifferentsubcellularcompartmentson the one
hand and between the cellular interior and its extracellular environment on the other.
However,it would bean oversimplificationtoview the role ofaminoacid transportonly
as asubstratetranslocation from one sideofa membrane to the other. Forexample,flux
through many amino acid-metabolizing pathways is controlled by transmembrane and
interorgan amino acid transport,rendering transportas an importantsite for control of
aminoacid metabolism. More recently,it has becomeclear thatenergy-dependentamino
acid transporters can build up osmotic gradients across the plasma membrane,resulting
in alterationsofcellular volumeand cellularfunction,such as protein turnover and cell
growth. Thus, amino acid transport also must receive attention in terms of inter-and
intracellular signalling.
Recent advances in knowledge are presented here in an indepth treatment by
experts in this active research area from the viewpoint of physiology, biochemistry,
molecular biology and medicine. This includes the methodological aspects for assessing
amino acid transport systems, their energetics, the specific features of amino acid
transportin differentsubcellularorganellesandtissues,thefunctionalconsequencesand
physiological importance, ontogenetic aspects, as well as intercellular and interorgan
transport. Thus, the book is not only of interest to biochemists, physiologists, and cell
biologists, but also for the interested student and physician.
Finally,it isa pleasuretothank the manycolleagueswho havecontributed to this
project by giving their advice and critique. We are especially thankful to Dr. H.N.
Christensen for overtaking the task to summarize the recent advances in physiological
interorgan flows of the amino acids. His professional life has been dedicated to the
subject of amino acid transport and his contributions to the field are innumerable. We
also are indebted toMs.Maria Chan for preparing the layoutof the book and for help in
compiling the entries to the subject index, and to our secretaries Ms. Vanessa Garrison
and Ms. Petra Ochsenfarth for their patient efforts on our behalf. Wehope that this
extensive and integrating account of present knowledge will provide a useful platform
for further research in this field.
February 1992 DieterHaussinger
Michael Kilberg
vii
CONTENTS
PART A: GENERAL ASPECTS
Amino Acid Transporters: Systematic Approach and
Principles of ControL.................................................................................................... 3
G.G.Guidotti and G.C.Gazzola
Energetics of Amino Acid Transport................................................................................ 31
A.A.Eddy
Techniques Used in the Study of Plasma Membrane
Amino Acid Transport................................................................................................... 51
J.D.McGivan
Molecular Biological Approaches for Amino Acid Transport............................... 65
R.M.Williamson, T.Z.Su and D.L.Oxender
Amino Acid Transport During Embryogenesis............................................................ 75
L.J.Van Winkle
Amino Acid Transport by Lysosomes................................................................................ 89
R.L.Pisoni and J.A.Schneider
Amino Acid Transport in Mitochondria.......................................................................... 101
J.D. McGivan
Amino Acid Transport,Cell Volume and Regulation
of Cell Growth................................................................................................................... 113
D.Haussinger, F. Lang and M.S. Kilberg
PART B: TISSUE SPECIFIC TRANSPORT AND FUNCTIONAL IMPLICATIONS
Amino Acid Transport in Liver........................................................................................... 133
M.S.Kilberg and D.Haussinger
Amino Acid Transport in Intestine.................................................................................... 149
B.R.Stevens
Amino Acid Transport in Brain........................................................................................... 165
Q.R.Smith and A.J.L.Cooper
Muscle Amino Acid Metabolism and Transport........................................................... 195
B.Mackenzie, A.Ahmed and M.J.Rennie
ix
Amino Acid Transport in the Kidney............................................................................... 233
J.S.Schwegler, S.Sibernagl, B.K.Tamarappoo
and T.C.WeIbourne
Amino Acid Transport in Lymphocytes........................................................................... 261
G.B.Segel
Transport of Cysteinyl Leukotrienes................................................................................ 275
D.Keppler, M.Maller and T.Ishikawa
Interorgan Glutathione Transport...................................................................................... 283
T.P.M.Akerboom and H. Sies
Interorgan Amino Acid Nutrition...................................................................................... 295
H.N. Christensen
INDEX............................................................................................................................................. 305
x
PART A
GENERAL ASPECTS
