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ABSTRACT

The amino acid L-glutamine is an important substrate in intermediary metabolism as carrier of nitrogen and carbon moieties. Its homeostasis is controlled primarily by two enzymes, glutaminase (glutamine amidohydrolase) and glutamine synthetase (glutamate-ammonia ligase). This chapter provides an overview of the molecular and protein heterogeneity of these two enzymes and their physiological roles. Murine glutaminase deficiency and glutamine synthetase deficiency, both in Drosophila and in two patients, also are summarized. In humans, glutamine synthetase deficiency (MIM 138290, 610015) is associated with severe brain malformations, including underdeveloped gyri and intracranial cysts, as well as with respiratory failure and early death. Both patients were of Turkish descent and manifested a substitution of cysteine for arginine in exon 6 of the glutamine synthetase gene (locus 1q31). In addition, potential pathomechanisms of secondary glutamine synthetase deficiencies (e.g., ammonia-induced neurotoxicity and hepatic encephalopathy) also are discussed.

INTRODUCTION

In humans, the amino acid L-glutamine serves fundamental roles as an important substrate and carrier of nitrogen and carbon moieties. Glutamine is a substrate for protein synthesis, functions in acid-base balance in the kidney, is a substrate for ureogenesis in the liver, and is involved in hepatic and renal gluconeogenesis. Glutamine is also an oxidative fuel for intestinal and immune cells, an anabolic precursor for skeletal muscle, functions in interorgan nitrogen transport and ammonia detoxification, serves as precursor for neurotransmitter synthesis, and is a building block for nucleotide and nucleic acid synthesis as well as glutathione production (Bak et al.,3; Häussinger20; Hertz,22; Kovacevic and McGivan,25; Melis et al.,35; Newsholme et al.,38; Nurjhan et al.,39, Watford et al.,56). These roles underscore a pivotal role for glutamine in basic cellular processes such as cell signaling, proliferation, and apoptosis (Fumarola et al.,12; Huang and Graves,23; Rhoads et al.,42).

The functional properties and cellular distribution of glutamine necessitate high-affinity transporters. Glutamine is the favored substrate for the sodium-coupled neutral amino acid transporters (SNATs; SLC 38 family), which resemble the transporters classically designated as System A and System N (Mackenzie and Erickson,30).

Glutamine is the most prevalent amino acid in human plasma, and glutamine homeostasis is strictly controlled by several mechanisms. Regulation of the glutamine pool consists of control of glutamine utilization and production within cells and extracellularly. Although transport into and out of cells plays an important role in homeostasis of the glutamine pool, the balance between glutamine formation and catabolism relies primarily on the activity of two enzymes (Krebs,24; Labow et al.,27):

  • Glutaminase (L-glutamine amidohydrolase; GLase, GLS, or GA, EC 3.5.1.2). For GLase, two isoforms exist, GLase 1 (kidney or brain isoform, phosphate-activated GLase; chromosomal location 2q32-q34; GenBank AB020645; MIM 138280) and GLase 2 (liver isoform, phosphate-dependent GLase; chromosomal location 12q13; GenBank NM013267; MIM 606365).

GLASE ...

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