Mechanisms governing the expression of the enzymes of glutamine metabolism- Glutaminase and glutamine synthetase

Whether on the scale of a single cell, organ or organism, glutamine homeost asis is to a large extent determined by the activities of glutaminase (GA, EC 3.5.1.2) and glutamine synthetase (GS, EC 6.3.1.2), the two enzymes that are the focus of this report. GA and GS each provide examples of regulatio n of gene expression at many different levels. In the case of GA, two diffe rent genes (hepatic- and kidney-type GA) encode isoforms of this enzyme. Th e expression of hepatic GA mRNA is increased during starvation, diabetes an d high protein diet through a mechanism involving increased gene transcript ion. In contrast, the expression of kidney GA mRNA is increased post-transc riptionally by a mechanism that increases mRNA stability during acidosis. W e found recently that several isoforms of rat and human kidney-type GA are formed by tissue-specific alternative RNA splicing. Although the implicatio ns of this post-transcriptional processing mechanism for GA activity are no t yet clear, it allows for the expression of different GA isoforms in diffe rent tissues and may limit the expression of GA activity in muscle tissues by diverting primary RNA transcripts to a spliceform that produces a nonfun ctional translation product. The expression of GS enzyme is also regulated by both transcriptional and post-transcriptional mechanisms. For example, t he GS gene is transcriptionally activated by glucocorticoid hormones in a t issue-specific fashion. This hormonal response allows GS mRNA levels to inc rease in selected organs during catabolic states. However, the ultimate lev el of GS enzyme expression is further governed by a post-transcriptional me chanism regulating GS protein stability. In a unique form of product feedba ck, GS protein turnover is increased by glutamine. This mechanism appears t o provide a means to index the production of glutamine to its intracellular concentration and, therefore, to its systemic demand. Herein, we also prov ide experimental evidence that GS protein turnover is dependent upon the ac tivity of the 26S proteosome.