Glutamine is the most abundant free amino acid in the body, and has its primary source in skeletal muscle, from where it is released into the bloodstream and transported to a variety of tissues (Young and Ajami, 2001; Newsholme et al., 2003a,b). Intracellular glutamine concentration varies between 2 and 20 mM (depending on cell type) whereas its extracellular concentration averages 0.7 mM (Newsholme et al., 2003b). Glutamine plays an essential role, promoting and maintaining function of various organs and cells such as kidney (Conjard et al., 2002), intestine (Lima et al., 1992; Ramos Lima et al., 2002), liver (de Souza et al., 2001), heart (Khogali et al., 2002), neurons (Mates et al., 2002), lymphocytes (Curi et al., 1986, 1999), macrophages (Newsholme et al., 1986), neutrophils (Garcia et al., 1999; Pithon-Curi et al., 2002a, 2003b; Pithon-Curi et al., 2003), pancreatic β-cells (Skelly et al., 1998), and white adipocytes (Curi et al., 1987; Kowalchuk et al., 1988). At the most basic level, glutamine serves as important fuel in these cells and tissues. A high rate of glutamine uptake is characteristic of rapidly dividing cells such as enterocytes, fibroblasts, and lymphocytes (Wiren et al., 1998; Curi et al., 1999) where glutamine is an important precursor of peptides and proteins, as well as of amino sugars, purines, and pyrimidines, thus participating in the synthesis of nucleotides and nucleic acids (Szondy and Newsholme, 1989; Szondy and Newsholme, 1990; Boza et al., 2000). Glutamine metabolism additionally provides precursors for the synthesis of key molecules, such as glutathione (GSH) (Higashigushi et al., 1993; Roth et al., 2002). Flaring et al. (2003) showed that glutamine supplementation attenuates glutathione depletion in human skeletal muscle following surgical trauma. Recently, Brennan et al. (2003) have demonstrated that glutamine metabolism in the pancreatic β-cells are related to optimal glutathione production via the gamma-glutamyl cycle and hence influences insulin secretion. Unpublished work by some of the authors of this review has recently demonstrated that the effect of glutamine on gene expression in the pancreatic β-cell was specific and approximately 1% of 10,000 genes assessed by micro-array techniques were altered on addition of glutamine. As changes in gene expression will impact on cell function then a change in glutamine concentration in vivo will alter many clinical parameters. For example, plasma glutamine concentration decreased by up to 50% in patients with HIV, severe burns, sepsis or post-surgery (Lacey and Wilmore, 1990; Smith and Wilmore, 1990), which was correlated with patient outcome. In cultures of neutrophils recovered from burnt and post-operative patients, addition of glutamine augmented the in vitro bacterial killing activity (Furukawa et al., 1997) and was also important to the production of reactive oxygen species (Garcia et al., 1999; Pithon-Curi et al., 2002a).
Thus the importance of glutamine for cell function, first recognized by Prof. Hans Krebs (reviewed in Brosnan, 2001), is now firmly established. However, Kreb's early assumptions that glutamine provided a source of respiratory fuel and nitrogen for biosynthetic reactions has been replaced by a realization that this amino acid plays diverse regulatory roles in the relevant target cells. The mechanisms underlying these diverse actions of glutamine are only now becoming clear and are discussed in the present review.