Glutamine is the most abundant free amino acid in the body and is known to play a regulatory role in several cell specific processes including metabolism (e.g., oxidative fuel, gluconeogenic precursor, and lipogenic precursor), cell integrity (apoptosis, cell proliferation), protein synthesis, and degradation, contractile protein mass, redox potential, respiratory burst, insulin resistance, insulin secretion, and extracellular matrix (ECM) synthesis. Glutamine has been shown to regulate the expression of many genes related to metabolism, signal transduction, cell defense and repair, and to activate intracellular signaling pathways. Thus, the function of glutamine goes beyond that of a simple metabolic fuel or protein precursor as previously assumed. In this review, we have attempted to identify some of the common mechanisms underlying the regulation of glutamine dependent cellular functions.
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 glutamineutilizing cells are discussed in the context of glucose requirements and cell function.
Nuclear, mitochondrial, and plasma membrane events associated with apoptosis were investigated in rat neutrophils cultivated for 3, 24, and 48 h in the absence or presence of glutamine (0.5, 1.0, and 2.0 mM). Condensation of chromatin was reduced after 24 or 48 h of culture in the presence of glutamine compared with its absence as assessed by Hoechst 33342 staining. The level of Escherichia coli phagocytosis in the presence of glutamine was markedly increased compared with the level achieved by cells cultured in the absence of glutamine. Annexin V binding to externalized phosphatidylserine was reduced in the presence of glutamine. Sensitive fluorochrome rhodamine 123, as determined by fluorescence-activated cell sorting and confocal microscopy, was used to monitor loss of the mitochondrial transmembrane potential. In the absence of glutamine, neutrophils exhibited a marked reduction in the uptake of rhodamine 123. In the presence of 1.0 or 2.0 mM glutamine, the uptake of rhodamine was 20 or 38% higher, respectively. Similar effect was found in human neutrophils by measuring DNA fragmentation and mitochondrial transmembrane potential. Therefore, glutamine protects from events associated with triggering and executing apoptosis in both rat and human neutrophils.
The effect of glutamine on the activity of the NADPH oxidase complex from rat neutrophils was investigated. Superoxide anion (O(2)(-)) production was assessed: (1) by scintillation counting by using lucigenin, and (2) by reduction of cytochrome c over 10 min. The effects of glutamine and PMA on the expression of the NADPH oxidase components p22( phox ), gp91( phox ) and p47( phox ) were also determined. Glutamine at 1 and 2 mM increased O(2)(-) generation in the presence of PMA by 100% and 74% respectively, in neutrophils maintained previously for 3 h in medium deprived of this amino acid. DON (6-diazo-5-oxo-L-norleucine), an inhibitor of phosphate-dependent glutaminase and thus of glutamine metabolism, caused a significant decrease in O(2)(-) production by neutrophils stimulated with PMA both in the absence (44%) and in the presence (66%) of glutamine. PMA markedly increased the expression of gp91( phox ), p22( phox ) and p47( phox ) mRNAs. Glutamine (2 mM) increased the expression of these three proteins both in the absence and in the presence of PMA. We postulate that glutamine leads to O(2)(-) production in neutrophils, probably via the generation of ATP and regulation of the expression of components of NADPH oxidase.
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