ABSTRACT

The functional significance of these GA isoforms is not fully known. However, the expression of one isoform known as GAC is controlled by acidity, which has important implications for the control of chronic metabolic acidosis.[4]

Metabolic Functions

The normal plasma concentration of glutamine is relatively high, whereas the plasma concentration of glutamate is quite low.[5,6] Cells also exhibit large capacities for the import of glutamine, much larger than that for glutamate.[7] Once inside the cell, glutamine is readily converted into glutamate by the action of amidotransferase and glutaminase enzymes. In fact, in most tissues (with the notable exception of muscle), the intracellular concentration of glutamine is much lower than that of glutamate.[6,8] Thus, glutamine represents the primary source of intracellular glutamate (for review see Ref.[9]). Glutamate is an important intracellular anion, playing a vital role in maintenance of cell osmolarity and, thus, cell volume.[10]

Glutamate formed from glutamine is itself indispensable for many cellular processes (for review, see Refs.[8,9]). For example, transamination reactions utilizing the amino nitrogen of glutamate convert certain keto acids to amino acids. In this way, glutamate is central to the cell’s amino acid economy. The anion also serves as a precursor for proline synthesis. It supports the synthesis of the tripeptide molecule glutathione, the cell’s major store of reducing equivalents.[11] Glutamate does this directly by serving as a substrate for glutathione synthesis, and indirectly by providing a means for the cell to import cysteine, another substrate for glutathione synthesis.[12] Glutamate is oxidatively deaminated by the enzyme glutamate dehydrogenase (GDH) to form a-ketoglutarate, with the concurrent reduction of NADþ (or NADPþ) to NADH (or NADPH). As a-ketoglutarate, the carbon

skeleton of glutamate enters the TCA cycle. In this way, glutamate carbons are utilized for anaplerosis (as carbon donor to replenish the tricarboxylic acid cycle) and are oxidized to CO2 making glutamine an important source of cellular energy.[13] Oxidation of glutamine carbons to CO2 and glutamine to pyruvate (a process referred to as ‘‘glutaminolysis’’ in analogy to glycolysis) produces reducing equivalents in the forms of NADH, NADPH, and FADH2. These reducing equivalents are utilized for ATP synthesis by oxidative phosphorylation, synthetic reactions, and cellular protection against oxidative stress (Fig. 2).[14]

PHYSIOLOGY

Cellular Functions

In 1955, Harry Eagle pioneered the growth of mammalian cells in culture. In the course of developing culture media for these cells, he tested the requirements for numerous salts, vitamins, minerals, carbohydrates, and amino acids.[15] The scientist discovered that glutamine was necessary to support the growth and viability of cell in culture, and at concentrations greater than that of any other amino acid.[16] Eagle and colleagues subsequently determined that both protein synthesis and nucleic acid synthesis were dependent on glutamine.[17] Now it is known that nearly all mammalian cell cultures benefit from the addition of glutamine to their media. Thus, cell culture media is almost always supplemented with concentrations of glutamine that are an order of magnitude greater than those of other amino acids. However, during all this time, the exact nature of this dependence on glutamine has not been clarified. Perhaps this is because the metabolic functions of glutamine and glutamate are so varied. Indeed, a supply of glutamine is needed to support numerous cellular processes.