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*
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202-5122
2To whom correspondence should be addressed. E-mail: shutson{at}wfubmc.edu.
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INTRODUCTION |
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 TOP INTRODUCTION REFERENCES |
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Activation of signaling pathways is now recognized to be an important nonprotein function of amino acids. This can be and often is studied with amino acid mixtures. In most instances, however, the indispensable branched-chain amino acid leucine can exert the same effects as amino acid mixtures. For this reason, the symposium focused primarily on leucine as a signaling molecule.
Historically, leucine has always seemed special and more important than
the other two branched-chain amino acids, isoleucine and valine.
The early work of Harper and collaborators (1954) first
demonstrated the adverse effects on growing animals fed a
low-protein diet containing an inordinately large amount of an
individual amino acid. Both food intake and growth were depressed. This
antagonism is most readily observed with leucine versus isoleucine and
valine (reviewed in Harper et al. 1970
). We have long
known that leucine is ketogenic and is specific among the
branched-chain amino acids in its ability to stimulate insulin
release from the islet cells of the pancreas (Panten et al. 1974
). Cochrane and coworkers (1956) first
reported that leucine precipitated hypoglycemic episodes in infants
with "idiopathic hypoglycemia," and Fajans et al.
(1963) suggested the description amino acid-induced
hyperinsulinemia. As discussed by Harper et al. (1970),
the uniqueness of leucine probably stems from the fact that
1) being ketogenic leucine cannot counterbalance the
hypoglycemic effect of insulin and 2) the
leucine-induced insulin release is presumably magnified in the
congenital hypoglycemia case noted above and in conditions where islet
cells are activated (Fajans et al. 1963
).
The first paper, "Regulation of Branched-Chain 
-Keto Acid
Dehydrogenase Kinase Expression" by Robert A. Harris, reviews the
molecular mechanisms by which leucine catabolism is controlled at the
level of the branched-chain -keto acid dehydrogenase complex.
Evidence is presented for nutrient and hormonal regulation of
expression of the branched-chain -keto acid dehydrogenase
kinase. The hypothesis is put forth for the involvement of thyroid
hormone in the regulation of the expression of this gene in animals fed
low-protein diets.
The second paper, "Function of Leucine in Excitory Neurotransmitter
Metabolism in the Central Nervous System" by Susan M. Hutson,
addresses the role of branched-chain amino acids in metabolism in the
central nervous system. The hypothesis is advanced that
branched-chain amino acids have an important role as donors of
nitrogen for dispensable amino acid biosynthesis, analogous to their
role in glutamine and alanine synthesis in skeletal muscle developed in
the 1970s (Odessey et al. 1974
, Chang and Goldberg 1978
, Garber et al. 1976
). Evidence
that BCAA nitrogen is required for formation of the neurotransmitter
glutamate are reviewed (Yudkoff et al. 1996
,
Bixel et al. 1997
, Hutson et al. 1998
)
and new findings on the special role of branched-chain amino acids
in neurotransmitter metabolism in the central nervous system are
presented.
The third paper, "Molecular Mechanisms in the Brain Involved in the
Anorexia of Branched-Chain Amino Acid Deficiency" by Dorothy W.
Gietzen, provides insight into the molecular mechanism underlying the
anorexia. Reports of anorexia with indispensable amino acid
deficiencies date from the early 1900s (Wilcock and Hopkins 1906
), and evidence for decreased appetite with deficiencies of
BCAA were reported by Rose (1957). Early work using
limiting diets, popularized by Harper (reviewed in Harper et al. 1970
), and animals with specific brain lesions (Leung and Rogers 1971
) suggested that the anterior piriform cortex is
the primary sensor of amino acid deficiency. This paper provides
evidence that conditioned taste aversion in response to amino acid
deficiency involves synaptic reorganization resulting from changes in
gene expression.
The unique ability of leucine to regulate protein synthesis in muscle
was first documented in the 1970s (Buse and Reid 1975
,
Fulks et al. 1975
, Li and Jefferson 1978
). Only recently, however, has great insight been gained
with respect to molecular mechanisms involved in the stimulatory
effects of leucine on protein translation (Hara et al. 1998
, Patti et al. 1998
, Kimball et al. 1999
, Anthony et al. 2000
) and multicellular
clustering of adipocytes (Fox et al. 1998a
,
1998b). The fourth paper, "Signaling Pathways Involved
in Translational Control of Protein Synthesis in Skeletal Muscle by
Leucine" by Leonard S. Jefferson, demonstrates stimulation of protein
synthesis by leucine is the result of enhancement of the activity and
synthesis of proteins involved in mRNA translation. Leucine signals
increased translation initiation by a mechanism involving the protein
kinase mammalian target of rapamycin (mTOR), a component of the
signaling cascade by which insulin likewise promotes protein synthesis.
The final paper, "Role of Leucine in the Regulation of mTOR by Amino
Acids: Revelations from Structure–Activity Studies" by Christopher
J. Lynch, extends the discussion of leucine regulation of the mTOR
signaling pathway to adipocytes and other cell types. Evidence
suggesting amino acids activate mTOR by more than one pathway is
presented.
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FOOTNOTES |
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REFERENCES |
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|
TOPINTRODUCTIONREFERENCES |
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1.
Anthony J. C., Gautsch Anthony T., Kimball S. R., Vary T. C., Jefferson L. S. Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. J. Nutr. 2000;130:139-145
2.
Bixel M. G., Hutson S. M., Hamprecht B. Cellular distribution of branched-chain amino acid aminotransferase isoenzymes among rat brain glial cells in culture. J. Histochem. Cytochem. 1997;45:685-694
3. Buse M. G., Reid S. S. Leucine: a possible regulator of branched chain amino acids on the ribosomal cycle in muscles of fasted rats. Horm. Metab. Res. 1975;11:289-292
4.
Chang T. W., Goldberg A. L. The metabolic fates of amino acids and the formation of glutamine in skeletal muscle. J. Biol. Chem. 1978;253:3685-3693
5. Cochrane W. A., Payne W. W., Simpkiss M. J., Woolf L. I. Familial hypoglycemia precipitated by amino acids. J. Clin. Invest. 1956;35:411-422
6. Fajans S. S., Knopf R. F., Floyd J. C., Power L., Conn J. W. The experimental induction in man of sensitivity to leucine hypoglycemia. J. Clin. Invest. 1963;42:216-229[Medline]
7.
Fox H. L., Kimball S. R., Jefferson L. S., Lynch C. J. Amino acids stimulate phosphorylation of p70S6k and organization of rat adipocytes into multicellular clusters. Am. J. Physiol. Cell Physiol. 1998a;274:C206-C213
8.
Fox H. L., Pham P. T., Kimball S. R., Jefferson L. S., Lynch C. J. Amino acid effects on translational repressor 4E-BP1 are mediated primarily by L-leucine in isolated adipipocytes. Am. J. Physiol. Cell Physiol. 1998b;275:C1232-C1238
9.
Fulks R. M., Li J. B., Goldberg A. L. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J. Biol. Chem. 1975;250:290-298
10.
Garber A. J., Karl I. E., Kipnis D. M. Alanine and glutamine synthesis and release from skeletal muscle. II. The precursor role of amino acids in alanine and glutamine synthesis. J. Biol. Chem. 1976;251:836-843
11.
Hara K., Yonezawa K., Weng Q.-P., Kozolwski M. T., Belham C., Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 1998;273:14484-14494
12.
Harper A. E., Benevenga N. J., Wohlheuter R. M. Effects of ingestion of disproportionate amounts of amino acids. Physiol. Rev. 1970;50:428-558
13. Harper A. E., Benton D. A., Winje M. E., Elvehjem C. A. Leucine-isoleucine antagonism in the rat. Arch. Biochem. Biophys. 1954;57:1-12
14. Hutson S. M., Berkich D. A., Drown P., Xu B., LaNoue K. F. Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism. J. Neurochem. 1998;71:863-874[Medline]
15.
Kimball S. R., Shantz L. M., Horetsky R. L., Jefferson L. S. Leucine regulates translation of specific mRNAs in L6 myoblasts through mTOR-mediated changes in availability of eIF4E and phosphorylation of ribosomal protein S6. J. Biol. Chem. 1999;274:11647-11652
16.
Leung P.M.B., Rogers Q. R. Importance of prepyriform cortex in food-intake response of rats to amino acids. Am. J. Physiol. 1971;221:929-935
17. Li J. B., Jefferson L. S. Influence of amino acid availability on protein turnover in perfused skeletal muscle. Biochim. Biophys. Acta 1978;544:351-359[Medline]
18. Odessey R., Khairallah E. A., Goldberg A. L. Origin and possible significance of alanine production by skeletal muscle. J. Biol. Chem. 1974;250:290-298
19. Panten U., Christians J., Kriegstein E., Von Poser W., Hasselblatt A. Studies on the mechanism of L-leucine-and alpha-ketoisocaproic acid-induced insulin release from perifused isolated pancreatic islets. Diabetologia 1974;10:149-154[Medline]
20. Patti M.-E., Brambilla E., Luzi L., Landaker E. J., Kahn C. R. Bidirectional modulation of insulin action by amino acids. J. Clin. Invest. 1998;101:1519-1529[Medline]
21. Rose W. C. The amino acid requirement of adult man. Nutr. Abstr. Rev. 1957;27:631-647
22. Wilcock E. G., Hopkins F. G. The importance of individual amino-acids in metabolism; observations on the effect of adding tryptophane to a diet in which zein is the sole nitrogenous constituent. J. Physiol. (Lond.) 1906;25:88-102
23. Yudkoff M., Daikhin Y., Grunstein L., Nissim I., Stern J., Pleasure D., Nissim I. Astrocyte leucine metabolism: significance of branched-chain amino acid transamination. J. Neurochem. 1996;66:378-385[Medline]
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