Glutamine Synthesis and Interorgan Transport

Glutamine (Fig. 6.1) is the most abundant free amino acid in the bloodstream and in the body. It contributes about 50% of the free a-amino acid pool within the human body and is quantitatively the most important amino acid involved in inter-organ nitrogen transport (Lund and Williamson, 1985). Classically, glutamine is a non-essential amino acid. Indeed, it can be synthesized in many cells and tissues of the body. The immediate precursor of glutamine is glutamate and the enzyme responsible for glutamine synthesis is glutamine synthetase (Fig. 6.2). In turn, glutamate can be formed from 2-oxoglutarate by transamination. Thus, the transamination reaction serves to transfer amino groups from amino acids to gluta-mine via glutamate (Fig. 6.2). Although any amino acid can potentially participate in the transamination reaction with 2-oxoglutarate, it is considered that the branched-chain amino acids play an important role in amino-group donation. The ammonia for the glutamine synthetase reaction could be generated from any deamination reaction; however, it is likely that in muscle the glutamate dehydroge-nase and AMP deaminase reactions play important roles here.

Although many tissues can synthesize glutamine, only certain tissues are able to release significant amounts of it into the bloodstream. These include the lung, brain, skeletal muscle and perhaps adipose tissue. Because of its large mass, skeletal muscle is considered to be the most important glutamine producer in the body (see Elia and Lunn, 1997). In skeletal muscle, glutamine contributes approximately 60% of the total free amino acid pool and it has a concentration of approximately 20 mM (Bergstrom et al., 1974; Lund, 1981). It is estimated that skeletal muscle releases up to 9 g of glutamine day-1 (Elia and Lunn, 1997). This is a greater amount of glutamine than that typically provided by the diet (approximately 5 g day-1). It is estimated that about 60% of glutamine released by human skeletal muscle in healthy individuals comes from de novo synthesis, with the remaining 40% coming from protein breakdown (Hankard et al., 1995).

© CAB International 2002. Nutrition and Immune Function (eds P.C. Calder, C.J. Field and H.S. Gill)

COO-

Fig. 6.1. The structure of glutamine.

Energy -Oxo acid

Energy -Oxo acid

Glutamate

Amino acid 2-oxo-glutarate

Glutamate

Glutamine

Amino acid 2-oxo-glutarate

Deamination reactions

HsN+

Protein

Fig. 6.2. The pathway of glutamine biosynthesis. Enzymes are indicated as: 1, transaminase; 2, glutamine synthetase.

Once released from skeletal muscle, glutamine acts as an interorgan nitrogen transporter (Lund and Williamson, 1985; Newsholme et al., 1989; see Fig. 6.3). The plasma glutamine concentration in healthy adult humans is typically in the range 0.5-0.8 mM, with a mean concentration of approximately 0.65 mM. Important users of glutamine include the kidney (see Tizianello et al., 1982), liver (see Haussinger, 1989), small intestine (see Windmueller and Spaeth, 1974; Souba, 1991) and cells of the immune system (for reviews, see Calder, 1994, 1995a; Wilmore and Shabert, 1998; Calder and Yaqoob, 1999; Newsholme et al., 1999; Newsholme, 2001). Glutamine has a number of metabolic roles in these user organs (Table 6.1).

Glutamine Transport
Fig. 6.3. Inter-organ transport of glutamine.
Table 6.1. Metabolic roles of glutamine.

Organ

Metabolic role of glutamine

Liver

Glucose synthesis (C skeleton)

Amino acid synthesis

Urea synthesis

Glutathione synthesis (via glutamate)

Kidney

Glucose synthesis (C skeleton)

Energy (C skeleton)

Acid-base balance

Small intestine

Energy (C skeleton)

Immune system

Energy (C skeleton)

All tissues

Protein synthesis

Purine synthesis (RNA, DNA)

Pyrimidine synthesis (RNA, DNA)

In the liver, the carbon skeleton of glutamine is an important precursor for glucose synthesis, while glutamine itself can be used for the synthesis of other amino acids and proteins, with excess nitrogen disposed of via ureagenesis. Glutamine can also be used as the precursor for the glutamate portion of glutathione, which is synthesized primarily in the liver. In the kidney, glutamine participates in acid-base balance, donating its amido and amino nitrogens to join with protons to form ammonium ions, which are excreted in the urine. The remaining carbon skeleton can be used to generate energy or as a precursor for glucose synthesis (gluconeogenesis). Glutamine is the major energy source in the small intestine and is an important energy source for immune cells. Glutamine is a nitrogen donor for the synthesis of purines and pyrimidines.

Since these are the building blocks of RNA and DNA, this role of glutamine is likely to be a particularly important one in cells that have high rates of division and/or of protein secretion. These include cells of the immune system and cells of the small intestine, such as enterocytes.

The importance of glutamine to cell survival and proliferation in vitro was first reported by Ehrensvand et al. (1949) but was more fully described by Eagle et al. (1956). Glutamine needed to be present at ten- to 100-fold in excess of any other amino acid in cell culture and could not be replaced by glutamate or glucose. This work led to the development of the first tissue-culture medium, which contained essential growth factors, glucose, 19 essential and non-essential amino acids at approximately physiological concentrations and a high concentration of glutamine (2 mM).

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