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Supplement

Glutamine: The Emperor or His Clothes?¹

Vernon R. Young^*,2 and Alfred M. Ajami^**

^* Laboratory of Human Nutrition, School of Science and Clinical Research Center, Massachusetts Institute of Technology, Cambridge, MA 02139; Shriners Burns Hospital, Boston, MA 02114; and ^** Phenome Sciences, Incorporated, Woburn, MA 01801

²To whom correspondence should be addressed.

	ABSTRACT

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
In this introduction to the Proceedings of the Symposium on Glutamine, we consider various lines of evidence that might potentially lead to an answer to the question posed in the title. We begin with a short summary of the multiple functions of glutamine, which are extensive and, superficially at least, equally as impressive as those of glutamate. However, each of these amino acids may serve an equivalent role in some of these functions due to their ready metabolic interconversion. We raise the question whether glutamine is of primordial or rudimentary significance or whether it is a product of somebody else’s existence. Thus, there is a short account of the prebiotic events of evolution that led to the appearance of glutamine and life on Earth. In doing this, it then appears that glutamine is a rather schizophrenic molecule, stable and thermodynamically reliable in biochemical environments, but labile in chemical ones. We then turn to the involvement of glutamine in mammalian N (nitrogen) commerce, with initial emphasis on the nitrogen cycle on Earth, then N transport and N excretion, before assessing its contribution to carbon/energy or C/E commerce. We hypothesize that, in addition to its utilization in immune cell function and in normal intestinal tissues, glutamine is a particularly key anapleurotic and energy-yielding substrate in conditions of hypoxia, anoxia and dysoxia. It also serves as a quantitatively important gluconeogenic metabolite under normal postabsorptive conditions. We postulate that in certain conditions, this carbon-energy econometric function might be by-passed with ornithine. In conclusion, the answer to the question above depends on the context, and this point will receive elaboration in many of the individual contributions that collaborate to form these Proceedings.

KEY WORDS: • glutamine • glutamate • fluxes • nitrogen cycle • transport • carbon metabolism

	INTRODUCTION

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
The goals of this introductory contribution to the Symposium on Glutamine are to overview the physiochemical properties and then summarize the multiple functions of glutamine, which are extensive and, superficially at least, equally as impressive as those of glutamate (Young and Ajami 2000 ). However, each amino acid (glutamine, glutamate) may serve the same role in some of these functions due to their ready metabolic interconversion. We then raise the question whether glutamine is of primordial or rudimentary significance or whether it is a product of somebody else’s existence. Hence, we shall provide a short account of the prebiotic events in early evolution that led to the appearance of glutamine and life on Earth. In the current metaphor of the Internet, we then turn to the involvement of glutamine in mammalian N(nitrogen)-commerce, with initial emphasis on the nitrogen cycle on Earth, then N transport and N excretion, before assessing its contribution to carbon/energy or C/E-commerce. We will emphasize that glutamine is a particularly key anapleurotic and energy-yielding substrate in hypoxia, anoxia and dysoxia and point out that it also serves as a key gluconeogenic metabolite under normal postabsorptive conditions. We speculate that this carbon-energy econometric function might be by-passed with other 5-C metabolites, including ornithine, before reaching our summary and conclusions.

	Physiochemical properties

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
The functions of glutamine, relative to those of glutamate or to other amino acids that could be included in a so-called "glutamine family" (e.g., the 4- and 6-carbon homologs and functional group analogs), might be better understood and possibly predicted in the first instance from a knowledge of the physiochemical properties of these amino acids (Sandberg et al. 1998 ). Beyond determination of "constitutional" properties, such as solubility and melting point, the characterization of amino acids in terms of their quantum chemical reactivities has become routine practice with the aid of modeling and simulation environments that correlate quantitatively the structure of molecules with some of their various biological activities. The field of structure-activity estimation of amino acids and their peptidomimetics has burgeoned in recent years, in step with the vast expansion of therapeutic agents now derived from peptides. Thus, it is possible to obtain rankings with relative ease for whole families of amino acids in simulated harsh environments (i.e., hydrolyzing or dehydrating) or within their docking relationship and microenvironment as ligands and substrates under a variety of thermodynamic conditions (Karelson 2000 ). We have summarized in Table 1 a number of physical and chemical properties of the amino acids we have chosen to include in this analysis. The principal descriptors, which were obtained in the HyperChem modeling environment (Hypercube, Gainesville, FL, http://www.hyper.com) and over a range of energy minimization scenarios are as follows: 1) thermodynamic and these relate to the hydrogen bonding, accepting and other energy orbitals, 2) lypophilicity and 3) polarity. In addition, we compare values for these descriptors computed in the un-ionized state to the conditions that are most probable in biological settings in which dissociation and noncovalent bonding within a matrix is a conformational norm. From this summary, it may be seen that there are major differences among the amino acids when they are in ionic form at a physiologic pH. For example, the binding energy from complete neglect of differential overlap (E_CNDO)³ analysis, and the corresponding orbital energies of the highest occupied (E_HOMO) and lowest unoccupied (E_LUMO) molecular orbitals change dramatically as a function of ionization state, principally in the case of the basic and acidic analogs such as glutamic acid and ornithine. The same order of change is observable in the quantitative estimation of polarity and polarizability, such as the LogP lipophilicity index, and the hydrogen acceptor, hydrogen donor and dipole moment descriptors. Asparagine, glutamine and homoglutamine are notable as a series of homologs because their properties, which govern the probability of molecular associations and subsequent reactivity, are relatively constant and independent of ionization state. That is, the homologous series of neutral molecules in the glutamine family can be considered to represent thermodynamically stable forms of molecular "currency." If their purpose is to carry and donate nitrogen in the form of a terminal amide, then it can be said that they are the more suited to do so under the greatest diversity of conditions in molecular evolution.

	Physiologic functions

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
However, it is not possible to take the foregoing data much further at this point, in terms of our interest in predicting the relative importance in nutrition and metabolism of the two 5-carbon amino acids, glutamate and glutamine. We will speculate on this later as we recall some of these properties, but it is now worth listing the functions of glutamine, given in Table 2 .

In addition to this protein substrate and structural role of glutamine, this amino acid has been termed a "competence factor" by Rhoads (1999) in that it serves to stimulate protein synthesis (Hammerqvist et al. 1989 , Hickson et al. 1995 , MacLennan et al. 1987 , Smith 1990 ) by a mechanism(s) that is still not fully understood, as well as other systems including intestinal/fluid electrolyte absorption, intestinal cell proliferation and the mitogenic response to growth factors. Its role in nitrogen metabolism and as a source of fuel in various tissues and under various conditions will be considered, in brief, below. Thus, in a general context, this listing of the functions of glutamine might be compared with those of glutamate as summarized by us earlier (Young and Ajami 2000 ); both amino acids fulfill numerous and important functions, some of which may be met by either one due to their ready metabolic interconversion, although a number of functions are unique to the specific amino acid. For example, this latter point applies to the role of glutamate as a taste substance (Fernstrom and Garattini 2000 , Halpern 2000 , Yamaguchi and Ninomiya 2000 ), which is not shared by glutamine. Similarly, the interorgan nitrogen transport function is unique to glutamine, at least in comparison with glutamate, although glutamate-derived alanine is also an important vehicle for moving nitrogen from muscle to the liver (Elia and Livesey 1983 , Elia et al. 1985 ). We will also return to this function as well as a number of others below as we continue to develop our answer to the question posed in the title of this paper. Nevertheless, the breadth of the involvement of both amino acids in cell function and metabolism is reflected by Purich (1998) who stated: "Few would quarrel with the assertion that glutamine is a phenomenally versatile metabolite ... ." Brosnan (2000 ) states in reference to glutamate: "No other amino acid displays such remarkable versatility!"

	Origins of glutamine

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
It might be asked, therefore, given the multiple roles played by glutamine and glutamate 1) when and how did they arise during the evolution of Life? and 2) which one may have been of more primordial origin and/or central to the eventual appearance and organization of the nitrogen economy of the mammalian system? Thus, as reviewed by Orgel (1998) , the Earth is estimated to be slightly >4.5 billion years old, whereas life originated 3.8 or more billion years ago. Three hypotheses have been proposed to explain the origin of small organic molecules, including amino acids, as follows: 1) synthesis in a reducing environment via the electrical discharge reaction. Glycine and several other naturally occurring amino acids are prominent products but none of the "Urey-Miller" type of experiments appear to yield glutamine as a product, presumably due to its chemical instability as discussed above. Amino acid polymers may also be detected depending upon the conditions (Harada 1974 ); 2) preformed organic material including amino acids (e.g., Irion 2000 ) delivered to earth by meteorites and comets, the so-called popular impact theory; and 3) low-molecular-weight constituents were of hydrothermal origin and arose in an iron-sulfur world in which, for example, the reaction between iron (II) sulfide and hydrogen sulfide could provide the free energy necessary for reduction of carbon dioxide to molecules capable of supporting the origin of life. Wachterschaüser (1992 and 1994) has been a strong proponent of this theory for which there appears to be increasing experimental support (Cody et al. 2000 , Huber and Wachterschaüser 1998 ), including demonstration of the conversion of carbon monoxide to peptides via a number of individual reaction steps in the iron-sulfur world (Wachterschaüser 2000 ). Although none of these theories can be rejected and it is possible that there may have been more than one source of organic molecules during the predawn of life, it is very likely, in the context of this paper, that glutamate came before glutamine.

In contrast to the foregoing theories for which some experimental support has been accumulated, the situation with respect to the evolution of a self-replicating system in which glutamine and other amino acids were players is even more tenuous because of the virtual absence of experimental data (Orgel 1998 ). In brief, it is generally accepted that there was an RNA world in which RNA molecules functioned as both genetic materials and enzyme-like catalysts (Freelund et al. 1999 ) and that this RNA world gave rise to the DNA/protein world in which biochemical reactions are catalyzed by DNA-encoded protein enzymes. Joyce (2000) offers the view that RNA molecules are lacking when it comes to chemical diversity of their subunits and that riboenzymes (RNA molecules that behave as enzymes) cannot match proteins in their catalytic sophistication, possibly accounting for the replacement of the RNA world by a genetic system based on DNA and protein. It is also possible that the RNA world was preceded by a simpler peptide nucleic acid (Böhler et al. 1995 ) or an (L)--threofuranosyl oligonucleotide world (Schöning et al. 2000 ) and that metabolism, or substantial organization of reaction sequences (Morowitz et al. 2000 ), may have preceded genetics as we know it today.

	The carbon and nitrogen cycles

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
If it can be accepted, for purposes of this presentation, that glutamate arose earlier than glutamine, then perhaps we can now fast-track to the "appearance" of glutamate and glutamine in the carbon and nitrogen economy of the present biosphere. Although glutamate might have preceded glutamine during the prebiotic phase of the Earth’s past, it could be speculated that glutamine emerged as a player in the fast-moving RNA world because we know that glutamine participates in the nucleotide metabolism of extant organisms. Thus, we turn now to glutamine/glutamate in reference to the cycling of carbon and nitrogen here on Earth, including the atmosphere.

As depicted in Figure 1 , living organisms can be divided into two large groups according to how they obtain carbon from the environment; many autotrophs fix carbon dioxide from the atmosphere via photosynthesis (plants; photosynthetic bacteria) whereas heterotrophs, including humans, obtain carbon in more complex forms, which are used as nutrients, and they return CO₂ to the atmosphere. All organisms require nitrogen; thus, as in the case of carbon, a nitrogen cycle also operates, in which gaseous nitrogen makes up 80% of the atmosphere. There are some organisms capable of fixing atmospheric nitrogen into ammonia, and plants are able to use either the ammonia or soluble nitrates (that are reduced to ammonia) produced by nitrifying bacteria; vertebrates must obtain some nitrogen in the form of amino acids and other N-containing organic compounds. Because glutamate and glutamine provide a critical entry of the ammonia into the plant and animal worlds of amino acids and other nitrogen compounds, it is pertinent to examine, in the context of this nitrogen cycle and the amino acid economy of the mammalian organism, the contribution that each amino acid makes.

View larger version (24K): [in this window] [in a new window]   Figure 1. The cycling of carbon and nitrogen in the biosphere. Combined from Lehninger et al. (1993) .

(1)

and 2) the glutamate dehydrogenase reaction:

(2)

However, because the K_m for NH⁺₄ in this reaction is high or >1 mmol/L, this reaction is thought to make only a modest contribution to net ammonia assimilation in the mammalian organism [see Katagiri and Nakamura (1999) ].

Hence, we need to ask now about net glutamate synthesis. In bacteria and plant chloroplasts, glutamate is produced by the action of glutamate synthase, according to the reaction:

(3)

The sum of the glutamate synthase ^{(Eq. 3)} and glutamine synthetase ^{(Eq. 1)} reactions is, therefore:

(4)

Hence, the two reactions combined ^{(Eq. 4)} give a net synthesis of one molecule of glutamate. But, because glutamate synthetase is not present in animal tissues, a net incorporation of ammonia nitrogen via this nitrogen cycle arises primarily from glutamate rather than from glutamine. A net accumulation of glutamine would be achieved via the glutamine synthetase reaction that uses ammonia, which would be derived from various sources including glutamate, other amino acids or via hydrolysis of urea. Thus, in reference to mammalian nutrition, glutamate is primary to glutamine in the context of a net accumulation of ammonia nitrogen from the nitrogen cycle.

A net incorporation of ammonia could also be achieved via the glycine synthetase (glycine cleavage) reaction, as follows:

The glycine formed might then be incorporated into proteins and used, for example, for glutathione, creatine or porphyrin synthesis; via the serine hydroxymethyl transferase reaction, it would also be converted to serine. The nitrogen of serine would then either be available for cysteine (and taurine) synthesis or released as ammonia via the serine dehydratase reaction. Thus, in theory, the glycine-serine pathway of ammonia incorporation into the amino acid economy of the organism would have a limited effect on the net input of nitrogen from ammonia. In any case, the physiologic significance of the glycine cleavage system appears to be related more to glycine catabolism than to glycine synthesis (Kikuchi 1973 ).

If glutamate is the ruler in the context of making net amino nitrogen available to the mammalian organism via plant proteins, two issues arise. First, does the glutamine that is also present in these food sources serve a specific, indispensable and/or functional role beyond that of serving as a source of utilizable nitrogen? This is a major topic for subsequent presentations to answer but we are unaware of any evidence that there is a specific dietary requirement for glutamine in healthy humans. Second, given the role of glutamate as a nitrogen portal for bringing atmospheric nitrogen into mammalian metabolism, is there an additional and specific dietary need for glutamate provided sufficient dietary amino nitrogen as alanine and aspartate, for example, is available for transamination reactions and thus for glutamate (and then glutamine) synthesis? This question cannot be answered unequivocally at present, but it is clear that indispensable amino acids alone, or when in high concentration relative to the dispensable amino acids, will not support adequate growth in experimental animals (Rogers and Harper 1965 , Young and Zamora 1968 ) or human infants (Snyderman et al. 1962 ). Hence, we conclude that a source of preformed -amino nitrogen from other than the indispensable amino acids is required by the mammalian organism. Whether glutamate is actually needed or possibly serves as a more efficient source of this nitrogen, compared with its homologs (Young and Ajami 2000 ) remains to be determined. However, Reeds (2000) has reviewed a number of findings revealing that diets completely devoid of glutamine and glutamate result in poorer growth in rats and pigs. This is suggestive of a dietary requirement for glutamate. However, the new concept that we offer here is that a dietary -amino N source is needed beyond that supplied by the indispensable amino acids and that glycine would not effectively meet this role for reasons alluded to above. This concept is firmly based on the question of glutamate synthesis in animals that was raised recently by Katagiri and Nakamura (1999) .

	Nitrogen transport

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
The plasma fluxes of glutamine together with those of glutamate and alanine as reported in some representative studies, mainly in healthy adults, are presented in Table 3 . It may be seen that the nitrogen flux of glutamine is considerably higher than that of alanine and glutamate. This would be even more dramatic if the data had been expressed in reference to the molar flux of nitrogen because the value for the glutamine molecule would be double that shown in this table. Glutamine fluxes may (Yarasheski et al. 1998 ) or may not (Jackson et al. 1999 , van Acker et al. 1999 ) increase catabolic stress and we should also point out that difficulties arise in estimating whole-body glutamine flux by means of the constant tracer infusion paradigm (van Acker et al. 1998 ). Also, although the major source of both glutamine (Nurjhan et al. 1995 ) and alanine (Consoli et al. 1990 ) entering the plasma compartment is muscle, these two amino acids respond differently to different nutritional status. For example, glutamine and not alanine is the major amino group carrier leaving the human forelimb after a protein meal (Elia and Livesey 1983 ) but alanine release is reduced by glucose, whereas glutamine is not (Elia et al. 1985 ).

This further raises the thought that the transport function of glutamine is not restricted to the flow of nitrogen between organs or simply from the periphery to the splanchnic region. The major transmitters at excitatory synapses in the central nervous system are glutamate and acetyl choline, whereas inhibitory signals are carried by glycine and -amino butyric acid. This amino acid function might have evolved >1 billion years ago (Walker et al. 1996 ), and it is now abundantly clear that there is a glutamate-glutamine cycle in the brain; glutamine serves to return the glutamate that is removed from the synaptic cleft by astrocytes back to the presynaptic neuron (Fig. 2 ). Two points should be made here, given the more extensive discussion by Behar and Rothman (2001) elsewhere in these Proceedings. First, it appears that the glutamate/glutamine cycle is a major metabolic flux in rats (Sibson et al. 1998 ). In the human cortex (Table 4) and in the resting human brain cycle, it seems to account for 80% of glucose oxidation (Rothman et al. 1999 , Shulman and Rothman 1998 ). Second, it is likely that the schema shown in Figure 2 is incomplete and that a more elaborate picture of synaptic information flow should now depict glial/neuronal networks because the two different types of glial cells, astrocytes and oligodendrocyte precursor cells, appear to be involved in glutamate-mediated neuronal signaling (LoTurco 2000 ). In spite of these newer details, the involvement of glutamine in the cycle of release and re-uptake of the excitatory neurotransmitter glutamate appears to be an established feature of mammalian brain function.

View larger version (18K): [in this window] [in a new window]   Figure 2. Schematic of glutamate-glutamine cycling in the brain. Adapted from Daikhin and Yudkoff (2000) .

The energy cost of transporting nitrogen as asparagine (the lower homolog) would be higher than this because asparagine synthetase uses the amide of glutamine for formation of asparagine from aspartic acid, as follows:

Therefore, not only is ATP required for the asparagine synthetase reaction with formation of AMP and PP_i, but ATP is used for synthesis of the amide group of glutamine before its use in this reaction. In sum, this greatly increases the energy cost of transporting the nitrogen as the amide group of this lower homolog of glutamine. 2) Glutamine is a neutral amino acid and can penetrate cell membranes more easily than can charged glutamate. 3) The formation of glutamine for N transport would, in effect, spare the 5-carbon skeleton of glutamate and, presumably, -ketoglutarate for supporting tricarboxylic acid cycle function. 4) Glutamine synthesis scavenges ammonia more effectively than does the synthesis of glutamate, via glutamic acid dehydrogenase (GDH). We might remind the reader that use of reduced NAD(P)H in the GDH reaction means that the energy equivalent of three ATP is involved because the three electron pairs from NAD(P)H would produce three ATP via the oxidative phosphorylation reactions. Evidently, it would not be efficient from an energetic standpoint to use glutamate as the N-transporting vehicle, a point that reconfirms the inferences drawn from the earlier discussion of glutamate’s thermodynamic properties. Nevertheless, this matter in no way minimizes the importance of GDH in body function. A recent example of its significance is emphasized by the report of a new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia caused by mutations in the GDH gene that impair the control of GDH enzyme activity (Stanley et al. 1998 ).

	Glutamine, urea synthesis and N excretion

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
The amide nitrogen of glutamine is transported from peripheral tissues (principally from muscle and lung) to the central organs and appears 1) in portal blood alanine and aspartate if the glutamine is taken up and metabolized by the intestine and 2) in urea if the liver is the immediate site of uptake of the transported glutamine amide N. The first nitrogen for urea synthesis, which is inserted via the mitochondrial enzyme carbamoyl phosphate synthetase (CPSI) occurs as follows:

This enzyme is allosterically activated by N-acetylglutamate and, from this standpoint, glutamine might be regarded as a regulator of urea synthesis. There is, in mammalian tissues, another isoform of CPS (CPS II), which is a large multifunctional cytosolic protein (Hewagama et al. 1999 ) that catalyzes formation of carbamoyl phosphate, as follows:

This reaction is involved in the synthesis of the N3 atom of pyrimidine nucleotides, whereas the amide of glutamine is used directly for the formation of the N3 and N9 atoms of purines.

There is a third form of this enzyme (CPS III) that is similar to CPSI, except glutamine is the N-donor. Apparently the role of this enzyme in invertebrates and ureoosmotic elasmobranch fish (sharks, skates, rays) is in the urea cycle (Zalkin and Smith 1998 ).

Purine and pyrimidine metabolism referred to above in relation to CPS II will be mentioned again but here we raise some issues about glutamine N transport with reference to urea N production. First, there is zonation of metabolism in the liver; glutamine is taken up by the periportal cells of the liver in which there is relatively high glutaminase activity, with the ammonia being directed toward carbamoyl phosphate synthesis. It is to be noted that acid-base status profoundly affects the flux of nitrogen from glutamine to ammonia and urea through the modulation of phosphate-dependent glutaminase activity (Nissim et al. 1996 , Nissim 1999 ). Glutamine formation and release from the liver occurs principally in the perivenous region; the hepatocytes in this area are rich in glutamine synthetase (Häussinger 1990 , Häussinger et al. 1992 , Watford 2000 ) (Fig. 3 ). Also included in this figure of the zonation of glutamine metabolism in the liver is the finding of and speculation made by O’Sullivan et al. (1998) concerning arginine metabolism in the liver. These investigators proposed that dietary arginine, a portion of which is converted to ornithine in the intestine, repletes the urea cycle with intermediates in the periportal hepatocytes, whereas the excess becomes available for catabolism in the perivenous hepatocytes. This is an interesting speculation and it serves to nicely integrate glutamine and arginine metabolism with emphasis on the primacy of ammonia detoxification.

View larger version (28K): [in this window] [in a new window]   Figure 3. Schematic to illustrate the zonation of glutamine and arginine metabolism in the mammalian liver. Adapted from Häussinger (1990) and O’Sullivan et al. (1998) .

Thus, when ¹⁵NH₄Cl was given to healthy adults daily for 5 d before a 24-h tracer study, during which time the ¹⁵NH₄Cl was continued, we (Metges, C. C., Petzke, K. J. and Young, V. R., unpublished data 2000) observed that there was considerable labeling of one of the N atoms of urea (m + 1 urea) with relatively little labeling of both N atoms (m + 2 urea). Although this does not prove that there is tight channeling of the ammonia derived from glutamine into carbamoyl phosphate because this differential labeling of the urea could arise by virtue of the fact that there is a differential labeling of the relevant precursor pools (Brosnan et al. 1996 ), it is certainly indicative of a preferential movement of the ammonia N into carbamoyl phosphate for urea synthesis. Channeling of intermediates occurs throughout most of the urea cycle (Watford 1989 ) and there is also little doubt that substrate channeling occurs in a number of enzyme systems (Miles et al. 1999 , Ovadi and Srere 2000 ). Indeed this process (in which two or more sequential enzymes in a pathway interact to transfer a metabolite, or intermediate, from one enzyme site to another without allowing free diffusion of the metabolite into bulk solvent) may be, according to Anderson (1999) , a general feature of biochemistry and of fundamental importance to the overall control and catalytic efficiency of multifunctional enzymes and enzyme complexes. Parenthetically, the physiologic importance of enzyme location and specific enzyme interactions is illustrated dramatically by the work of Wojtas et al. (1997), reviewed by Srere and Knull (1998) , showing that mutations in the Drosophila melanogaster glycerol phosphate dehydrogenase (GPDH) gene yield a flightless phenotype and that this is due to cellular mislocation of GPDH, aldolase and glyceraldehyde 3-phosphate dehydrogenase.

Finally, with respect to glutamine and nitrogen excretion, humans, as for other terrestrial vertebrates, are ureotelic, in which the principal route of nitrogen loss is via urea formation and elimination. Aquatic animals, for which water is more plentiful, are ammonotelic or ammonia excreting. However, in birds or terrestrial reptiles, excess nitrogen is eliminated via purine synthesis and then uric acid formation (uricotelic) (Lehninger et al. 1993 ). In this last-mentioned case, glutamine is a major intermediate in the elimination of nitrogen, whereas in humans, this route of N loss is a relatively minor one. Hence, this is not a major intermediary function of glutamine in reference N homeostasis in humans although important in other species.

	Glutamine and C-commerce

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
As listed earlier (Table 2) glutamine is involved in the C- or energy-commerce of humans and although this topic is considered in more detail by others in these Proceedings, it is worth emphasizing that glutamine appears to serve a much more important role as a gluconeogenic precursor than has perhaps been generally recognized. Thus, as summarized in Table 5 , Stumvoll et al. (1998 and 1999) have shown that glutamine is as important as lactate in contributing to net gluconeogenesis in the postabsorptive state. Furthermore, the gluconeogenesis from glutamine occurs principally in the kidney, whereas alanine conversion is essentially limited to the liver (Stumvoll et al. 1998 ). Renal gluconeogenesis contributes 20–25% of whole-body glucose production (Stumvoll et al. 1999 ). Overall, glutamine gluconeogenesis was responsible for 5% of systemic glucose appearance, and renal production of glucose from glutamine accounted for nearly 75% of all glucose derived from glutamine. The kidney accounts for 40–50% of overall gluconeogenesis under postabsorptive conditions (Gerich et al. 2000 ). In addition, a significant fraction of the glutamine that serves as substrate for gluconeogenesis originates via its release from muscle proteins (Nurjhan et al. 1995 ). This is in contrast to alanine, which is a major gluconeogenic precursor for liver glucose production. In the case of this latter amino acid, however, a significant fraction is formed from pyruvate, produced via the utilization of glucose in muscle. In this context, there is a relatively higher recycling of alanine carbon (via its return to muscle as glucose) in the production of glucose than in the case of glutamine carbon. On the basis of these newer findings, which have been described more extensively by Bier (unpublished data), we depict in Figure 4 the possible relationships between the alanine-glucose and glutamine-glucose cycles, which raises the question whether glutamine is more important in whole-body glucose homeostasis than is alanine, for example.

View larger version (27K): [in this window] [in a new window]   Figure 4. A depiction of a glucose-alanine-glutamine cycle. Adapted from Lehninger et al. (1993) .

This brings us to another point, namely, the speculation that glutamine exists to deliver glutamate for 5 C-commerce. We further would argue the following: 1) this function is especially important under conditions of increased energy need and in which anoxia, hypoxia or dysoxia exists, that is, conditions that cause fluctuations in intracellular pH and bicarbonate ion; and 2) glutamine would meet this role better than glutamate, again with reference to its relative thermodynamic constancy relative to ionization state. Further, because glutamine can enter the cell against a proton gradient, it would not interfere with cyst(e)ine and sulfur amino acid metabolism, as discussed by Dröge and Holm (1997) . Indeed, there is some limited evidence that glutamine serves as a key anapleurotic and energy-yielding substrate in hypoxia, anoxia and dysoxia. For example, Khogali et al. (1998) , using a cardiac ischema-reperfusion model (Rennie et al. 1996 ), showed a reduced cardiac flow, decreased ATP and glutamate concentrations and increased lactate when the perfusion medium did not contain glutamine and that addition of the amino acid prevented these changes. In anoxia, mitochondria change from being ATP producers to powerful ATP consumers (St. Pierre et al. 2000 ). Thus, Weinberg et al. (2000) found that the mitochondrial lesion, membrane permeability transit and cytochrome C leakage in ischemic/hypoxic cell injury was prevented by citric acid cycle metabolites that anaerobially generate ATP via substrate-level phosphorylation. The substrates they examined included -ketoglutarate and aspartic acid. It seems likely, therefore, that glutamine could serve as the source of -ketoglutarate in relation to this process.

Finally, the question might be raised whether the role of glutamine in reference to 5 C-commerce might be by-passed. Here, we speculate that ornithine might substitute for glutamine in this role, under certain conditions. It is known that the -ketoglutarate salt of ornithine improves N homeostasis, sustains muscle glutamine and increases plasma glutamine in surgical patients (Cynober et al. 1987 , Cynober 1999 , DeBandt et al. 1998 ). Further, we have shown that ornithine is readily oxidized in healthy adults (Castillo et al. 1994 ) and in severely burned patients (Yu et al. 2001 ), leading to a suggestion that this amino acid might be an effective substitute for glutamine with respect to its role in 5 C-commerce. This will require additional investigation under defined conditions of tissue oxygen availability and ATP status.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 
The purpose of this introductory paper is to raise a number of issues related to glutamine in metabolism and nutrition that are either of more basic or more applied and clinical importance. Further light is focused on these various issues in the succeeding papers to these Proceedings. In summary, and with reference to whether glutamine is the Emperor or his clothes [or alternatively a possible "pretender to the throne" according to the editorial by Abcouwer and Souba (1999) ], it is clear that the answer will depend on the context. Hence, our conclusions are as follows: 1) glutamate appeared on Earth before glutamine and the latter is quite unstable when present in simple solution or medium but is a robust and aggressive molecule when introduced into the complex environment of living tissues. We find glutamine to be rather schizophrenic; 2) glutamate and glutamine are both involved in ammonia fixation but a net appearance of N from the atmosphere occurs initially via glutamate; 3) glutamine is a preferred interorgan and intercellular vehicle for N transport for physiochemical and energetic reasons; 4) glutamate is the more important facile player in intracellular N metabolism; 5) glutamine regulates urea N production; 6) in normal mammalian N nutrition, glutamate is of greater primary nutritional significance than is glutamine; 7) glutamine exists to deliver 5-C for anapleurotic and ATP synthesis functions, especially under conditions of oxygen limitation; 8) glutamine is a quantitative contributor to whole-body glucose homeostasis, whereas glutamate is not, and alanine somewhat less; and, finally, 9) in cases in which whole-body homeostasis has been severely compromised by infection, physical injury, invasive therapy or during rapid growth and repair, the need for or advantage of glutamine vs. glutamate as substrates in the support of N and C commerce might become more clear upon reviewing the evidence presented elsewhere in these Proceedings.

	FOOTNOTES

 
¹ Presented at the International Symposium on Glutamine, October 2–3, 2000, Sonesta Beach, Bermuda. The symposium was sponsored by Ajinomoto USA, Incorporated. The proceedings are published as a supplement to The Journal of Nutrition. Editors for the symposium publication were Douglas W. Wilmore, the Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School and John L. Rombeau, the Department of Surgery, the University of Pennsylvania School of Medicine.

³ Abbreviations used: CPSI, carbamoyl phosphate synthetase; GDH, glutamic acid dehydrogenase; GPDH, glycerol phosphate dehydrogenase; HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital.

	LITERATURE CITED

TOP ABSTRACT INTRODUCTION Physiochemical properties Physiologic functions Origins of glutamine The carbon and nitrogen... Nitrogen transport Glutamine, urea synthesis and... Glutamine and C-commerce CONCLUSIONS LITERATURE CITED

 

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