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      Glutamine and glutamate as vital metabolites

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          Abstract

          Glucose is widely accepted as the primary nutrient for the maintenance and promotion of cell function. This metabolite leads to production of ATP, NADPH and precursors for the synthesis of macromolecules such as nucleic acids and phospholipids. We propose that, in addition to glucose, the 5-carbon amino acids glutamine and glutamate should be considered to be equally important for maintenance and promotion of cell function. The functions of glutamine/glutamate are many, i.e., they are substrates for protein synthesis, anabolic precursors for muscle growth, they regulate acid-base balance in the kidney, they are substrates for ureagenesis in the liver and for hepatic and renal gluconeogenesis, they act as an oxidative fuel for the intestine and cells of the immune system, provide inter-organ nitrogen transport, and act as precursors of neurotransmitter synthesis, of nucleotide and nucleic acid synthesis and of glutathione production. Many of these functions are interrelated with glucose metabolism. The specialized aspects of glutamine/glutamate metabolism of different glutamine-utilizing cells are discussed in the context of glucose requirements and cell function.

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          Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection?

          Glutamine is normally considered to be a nonessential amino acid. However, recent studies have provided evidence that glutamine may become "conditionally essential" during inflammatory conditions such as infection and injury. It is now well documented that under appropriate conditions, glutamine is essential for cell proliferation, that it can act as a respiratory fuel and that it can enhance the function of stimulated immune cells. Studies thus far have determined the effect of extracellular glutamine concentration on lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities and neutrophil bacterial killing. Other cells of the immune system remain to be studied. The high rate of glutamine utilization and its importance to the function of lymphocytes, macrophages and neutrophils have raised the question "why glutamine?" because these cells have access to a variety of metabolic fuels both in vivo and in vitro. I have attempted to answer this question in this article. Additionally, knowledge of the rate of utilization and the pathway of metabolism of glutamine by cells of the immune system raises some intriguing questions concerning therapeutic manipulation of utilization of this amino acid such that the proliferative, phagocytic and secretory capacities of cells of the defense system may be beneficially altered. Evidence to support the hypothesis that glutamine is beneficially immunomodulatory in animal models of infection and trauma, as well as trauma in humans, is provided.
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            Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages.

            Maximum activities of some key enzymes of metabolism were studied in elicited (inflammatory) macrophages of the mouse and lymph-node lymphocytes of the rat. The activity of hexokinase in the macrophage is very high, as high as that in any other major tissue of the body, and higher than that of phosphorylase or 6-phosphofructokinase, suggesting that glucose is a more important fuel than glycogen and that the pentose phosphate pathway is also important in these cells. The latter suggestion is supported by the high activities of both glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. However, the rate of glucose utilization by 'resting' macrophages incubated in vitro is less than the 10% of the activity of 6-phosphofructokinase: this suggests that the rate of glycolysis is increased dramatically during phagocytosis or increased secretory activity. The macrophages possess higher activities of citrate synthase and oxoglutarate dehydrogenase than do lymphocytes, suggesting that the tricarboxylic acid cycle may be important in energy generation in these cells. The activity of 3-oxoacid CoA-transferase is higher in the macrophage, but that of 3-hydroxybutyrate dehydrogenase is very much lower than those in the lymphocytes. The activity of carnitine palmitoyltransferase is higher in macrophages, suggesting that fatty acids as well as acetoacetate could provide acetyl-CoA as substrate for the tricarboxylic acid cycle. No detectable rate of acetoacetate or 3-hydroxybutyrate utilization was observed during incubation of resting macrophages, but that of oleate was 1.0 nmol/h per mg of protein or about 2.2% of the activity of palmitoyltransferase. The activity of glutaminase is about 4-fold higher in macrophages than in lymphocytes, which suggests that the rate of glutamine utilization could be very high. The rate of utilization of glutamine by resting incubated macrophages was similar to that reported for rat lymphocytes, but was considerably lower than the activity of glutaminase.
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              Nitrogen metabolism in liver: structural and functional organization and physiological relevance.

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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                bjmbr
                Brazilian Journal of Medical and Biological Research
                Braz J Med Biol Res
                Associação Brasileira de Divulgação Científica (Ribeirão Preto )
                1414-431X
                February 2003
                : 36
                : 2
                : 153-163
                Affiliations
                [1 ] University College of Dublin Ireland
                [2 ] Universidade de São Paulo Brasil
                [3 ] Universidade Metodista de Piracicaba e Unicastelo Brasil
                [4 ] Uniformed Services University of Health Sciences USA
                [5 ] Universidade Estadual de Maringá Brazil
                Article
                S0100-879X2003000200002
                10.1590/S0100-879X2003000200002
                12563517
                d86a8e0f-a0ba-4763-a856-c3bd75fce88c

                http://creativecommons.org/licenses/by/4.0/

                History
                Product

                SciELO Brazil

                Self URI (journal page): http://www.scielo.br/scielo.php?script=sci_serial&pid=0100-879X&lng=en
                Categories
                BIOLOGY
                MEDICINE, RESEARCH & EXPERIMENTAL

                Medicine,General life sciences
                Glutamine,Glutamate,Glucose,Metabolism,Cell function
                Medicine, General life sciences
                Glutamine, Glutamate, Glucose, Metabolism, Cell function

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