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Department of Surgery, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA 02115 and * Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
2To whom correspondence should be addressed. E-mail: dwilmore{at}partners.org.
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INTRODUCTION |
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 TOP INTRODUCTION LITERATURE CITED |
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Considerable new knowledge is emerging from these studies, particularly with reference to investigations of the dispensable or nonessential amino acids. This group of compounds has characteristically been considered secondary to the essential or indispensable group. Yet, the nonessential amino acids must be extremely important, for they have survived evolutionary selection, and their synthetic mechanisms have been preserved by the body to maintain key metabolic processes and ensure survival.
Recent research suggests that during a variety of life stresses and
diseases, several of these so-called dispensable amino acids may
become conditionally essential because their consumption within the
body outstrips endogenous production (Lacey and Wilmore 1990
). Other investigators have reported that single amino
acids exert specific pharmacologic effects, which may enhance cell or
organ functions, often to aid resolution of a disease (Efron and Barbul 2000
).
Research on the amino acid glutamine (GLN) is a prime example of the benefits that have been accrued from such focused investigations. This five-carbon compound carrying two nitrogens was thought of as a low priority substrate for many years, in part because it was relatively ubiquitous, somewhat unstable in the liquid phase (which generally precluded its use in feeding formulas) and difficult to measure. Yet, in retrospect, all of the signs were present that this was an amino acid with great potential.
First isolated in 1883 in beet juice (Schulze and Bosshard 1883
), glutamine was later found in abundance in wheat gliadin
(Damodaran et al. 1932
). In 1935, Krebs (1980)
described the synthesis of glutamine from ammonium and
glutamate using the guinea pig and rat kidney. Further work by this and
other laboratories demonstrated its central role in acid-base
homeostasis, its use as a precursor in nucleic acid and nucleotide
biosynthesis, its role in the synthesis of amino sugars and its
singular importance in intraorgan transport. Krebs noted that, although
"most amino acids have multiple functions, GLN appears to be the most
versatile" (Krebs 1980
).
In the 1950s, Eagle et al. (1956)
, while working at the
NIH, found that GLN was an essential substrate to support dividing
cells in culture. Growth would not occur if GLN was excluded from the
culture media. Later, Windmueller, a pharmacologist, set out to develop
a perfused small bowel segment that would maintain near normal
metabolism so that he could study intestinal drug kinetics. He found
that the experimental segments could not be sustained using the
standard perfusates, and he designed studies to determine what
substrates were essential to normal small bowel metabolism. GLN ranked
highest on the list (Windmueller and Spaeth 1980
).
But technical problems also posed major challenges to investigators who
had to determine GLN concentrations in biological tissues. When
processing amino acids for chromatographic analysis, an acid filtrate
was usually prepared. This acid environment favored GLN degradation
with destabilization of the amide nitrogen. In addition, glutamine
could not be separated from asparagine (Stein and Moore 1954
). Thus, many of the fundamental animal and human studies
performed in this last half century failed to quantitate GLN and
determine its importance as a quantitative intraorgan nitrogen carrier
or an organ-specific fuel [for example, see Felig et al. (1969)
]. However, when protocols were devised to accurately
determine concentrations of GLN in fluids and tissues
(Mulhbacher et al. 1984
, Smith and Panico 1985
), the importance of this amino acid in nutritional
biochemistry and integrative metabolism began to unfold
(Muhlbacher et al. 1984
).
Since then, the quantity of published information on GLN has grown
exponentially and these data have fascinated workers in biochemical,
nutritional and medical fields. Experts have described the importance
of glutamine in a variety of areas, including skeletal-muscle
protein synthesis, intestinal structure and function, glucose
regulation, antioxidant metabolism and enhancement of immune function.
Important preliminary studies also suggest a role for GLN
supplementation to preserve lean tissue in persons with human
immunodeficiency virus (HIV) infection (Shabert et al. 1999
), propose the use of GLN treatment for individuals with
sickle cell anemia (Nihara et al. 1998
) and suggest a
place for this amino acid in the management of insulin-resistant
states (Borel et al. 1998
), such as obesity and diabetes
mellitus.
Because of this tremendous growth of new information concerning GLN, it
was timely for a group of authoritative investigators to come together
to update the data and place these findings within a context of other
biochemical and nutritional information. Other symposia have been held
on this topic (Abumrad et al. 1989
, Carter 1996
, Okada and Wilmore 1999
, Souba 1990
) and readers are encouraged to review their proceedings to
gain a perspective on the development of the GLN field.
In this symposium, both basic and clinical research was presented. Lively discussion helped focus the presentations, clarify issues and integrate the data. The proceedings follow the general format of the symposium.
This symposium was sponsored by Ajinomoto U.S.A., Inc. The program was planned and administered by a steering committee consisting of Drs. Dennis M. Bier (Baylor College of Medicine), Alfred E. Harper (retired, University of Wisconsin), Wiley W. Souba (Pennsylvania State University College of Medicine), Vernon R. Young (Massachusetts Institute of Technology) and Douglas W. Wilmore (Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School). The committee would like to thank Dr. Sadahiko Ogihara, Mr. Hiroyuki Miyake and Mr. Richard Bonnette of Ajinomoto U.S.A., Inc., and Mr. Tadao Toki of Ajinomoto Co., Inc., for their encouragement, thoughtful advice and enthusiastic organizational support of the symposium. The editorial assistance of Mrs. Maureen Rombeau is gratefully acknowledged.
We hope that these proceedings transmit useful new information and advance the field. Moreover, it is our hope that new knowledge will evolve and be applied for the human good.
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FOOTNOTES |
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LITERATURE CITED |
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TOPINTRODUCTIONLITERATURE CITED |
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1. Abumrad N. N. Adibi S. A. Lochs H. Roth E. eds. Glutamine metabolism Metabolism 38 (suppl.):1-92 .
2.
Borel M. J., Williams P. E., Jabbour K., Levenhagen D., Katzer E. & Flakoll P. J. (1998) Parenteral glutamine infusion alters insulin-medicated glucose metabolism. J. Parent. Enteral Nutr. 22:280-285.
3. Carter E. eds. Glamin launch symposium Nutrition 12:S67-S86 .
4. Damodaran M., Jaaback G. & Chibnal A. C. (1932) The isolation of glutamine from an enzymic digest of gliadin. Biochem. J. 26:1704-1713.[Medline]
5.
Eagle H., Oyama V. I., Levy M., Horton C. L. & Fleischman R. (1956) The growth response of mammalian cells in tissue culture to L-glutamine and L-glutamic acid. J. Biol. Chem. 218:607-616.
6. Efron D. & Barbul A. (2000) Role of arginine in immunonutrition. J. Gastroenterol. 35(suppl. 12):20-23.
7. Felig F., Owen O. E., Warren J. & Cahill G. F., Jr (1969) Amino acid metabolism during prolonged starvation. J. Clin. Investig. 48:584-594.
8. Krebs H. (1980) Special lecture: glutamine metabolism in the animal body. Mora J. Palacios R. eds. Glutamine Metabolism Enzymology and Regulation 1980:319-329 Academic Press New York, NY. .
9. Lacey J. M. & Wilmore D. W. (1990) Is glutamine a conditionally essential amino acid?. Nutr. Rev. 48:297-309.[Medline]
10.
Muhlbacher F., Kapadia C. R., Colpoys M. F., Smith R. J. & Wilmore D. W. (1984) Effects of glucocorticoids on glutamine metabolism in skeletal muscle. Am. J. Physiol. 247:E75-E83.
11. Nihara Y., Zerez C. R., Akiyama D. S. & Tanaka K. R. (1998) Oral L-glutamine therapy for sickle cell anemia: 1. Subjective clinical improvement and favorable change in red cell NAD redox potential. Am. J. Hematol. 58:117-121.
12. Okada A. Wilmore D. W. eds. International symposium: growth factors and nutrients in intestinal health and disease J. Parent. Enteral Nutr 23 (suppl. 5):S1-S127 .
13. Schulze E. & Bosshard E. (1883) Weber das glutamin. Landwirtsh. Vers. Sta. 29:295-307.
14. Shabert J. K., Winslow C., Lacey J. M. & Wilmore D. W. (1999) Glutamine-antioxidant supplementation increased body cell mass in AIDS patients with weight loss: a randomized, double-blind controlled trial. Nutrition 15:860-864.[Medline]
15. Smith R. J. & Panico K. A. (1985) Automated analysis of o-phthalaldehyde derivatives of amino acids in physiological fluids by reversed phase high performance liquid chromatography. J. Liq. Chromatogr. 8:1783-1795.
16. Souba W. W. eds. Glutamine J. Parent. Enteral Nutr 14 (suppl. 4):S1-S108 .
17.
Stein W. H. & Moore S. (1954) The free amino acids of human blood plasma. J. Biol. Chem. 211:915-925.
18.
Windmueller H. G. & Spaeth A.E. (1980) Respiratory fuels and nitrogen metabolism in vivo in small intestine of fed rats: quantitative importance of glutamine, glutamate and aspartate. J. Biol. Chem. 255:107-112.
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