Glutamine Metabolism by Cells of the Immune System

The possible fates of glutamine carbon are shown in Fig. 6.4. One possible rate-determining step in the pathway of glutamine utilization is that catalysed by the enzyme phosphate-dependent glutaminase (hereafter referred to as glutaminase), which is found within mitochondria. The activity of glutaminase is high in all lym-phoid organs examined, including lymph nodes, spleen, thymus, Peyer's patches and bone marrow (Ardawi and Newsholme, 1985), and in lymphocytes (Ardawi, 1988a; Keast and Newsholme, 1990), macrophages (Newsholme et al., 1986), and

Fig. 6.4. The pathway of glutamine utilization. Enzymes are indicated as: 1, glutaminase; 2, transaminase, 3; enzymes of part of the citric acid cycle; 4, malate dehydrogenase; 5, malic enzyme; 6, phosphoenolpyruvate carboxykinase; 7, pyruvate kinase; 8, lactate dehydrogenase. PEP phosphoenolpyruvate.

Glutamine

Glutamine

Malic Enzyme

Fig. 6.4. The pathway of glutamine utilization. Enzymes are indicated as: 1, glutaminase; 2, transaminase, 3; enzymes of part of the citric acid cycle; 4, malate dehydrogenase; 5, malic enzyme; 6, phosphoenolpyruvate carboxykinase; 7, pyruvate kinase; 8, lactate dehydrogenase. PEP phosphoenolpyruvate.

neutrophils (Curi et a/., 1997). Glutaminase activity increases in the popliteal lymph node in response to an immunological challenge (Ardawi and Newsholme, 1982). Consistent with the high activity of glutaminase, glutamine is utilized at a high rate by cultured lymphocytes (Ardawi and Newsholme, 1983; Brand, 1985; Ardawi, 1988a; Brand et a/., 1989; O'Rourke and Rider, 1989), macrophages (Newsholme et a/., 1987; Newsholme and Newsholme, 1989; Spolarics et a/., 1991) and neutrophils (Curi et a/., 1997; see Table 6.2). Mitogenic stimulation of lymphocytes increases both glutaminase activity (Brand, 1985) and the rate of glutamine utilization (Ardawi and Newsholme, 1983; Brand, 1985; Ardawi, 1988a; Brand et a/., 1989; O'Rourke and Rider, 1989). Glutamine utilization by macrophages was increased by bacillus Calmette-Guerin (BCG) activation in vivo or by bacterial lipopolysaccharide (LPS) stimulation in vitro (Murphy and Newsholme, 1998). The major products of glutamine utilization by cultured lymphocytes and macrophages are glutamate, aspartate, lactate and ammonia, although alanine and pyruvate are also produced and some glutamine (approx. 25%) is completely oxidized (Ardawi and Newsholme, 1983; Brand, 1985; Newsholme et a/., 1987; Ardawi, 1988a; Brand et a/, 1989; Newsholme and Newsholme, 1989; O'Rourke and Rider, 1989). Macrophages are known to have a large oxidative capacity and their rate of O2 consumption (515 nmol h-1 mg-1 protein) is similar to those of sheep heart (696 nmol h-1 mg-1 protein) and rat liver (520 nmol h-1 mg-1 protein) in vitro (Newsholme, 1987). Newsholme (1987) calculated ATP generation rates for isolated, incubated macrophages, taking into account oxygen utilized by the NADPH oxidase of these cells. The ATP generation rate in the presence of both glucose and glutamine was 930 nmol h-1 mg-1 protein, based on known pathways of metabolism. Glucose contributed 62% and glutamine 38% of the energy requirement of the cell. Since the ATP concentration of the macrophage is approximately 7 nmol mg-1 protein (Newsholme et a/., 1987), the total ATP concentration of the cell must have been turned over at least twice per minute. It has been calculated that glutamine can contribute up to 35% of the energy requirement of other immune cells in culture (Spolarics et a/., 1991).

Table 6.2. Rates of utilization of glucose or glutamine and of production of various metabolites by isolated mouse macrophages, rat lymphocytes or rat neutrophils. Rates of formation of 14CO2 are from 14C-labelled glucose or glutamine. (Data are from Ardawi and Newsholme, 1983; Newsholme et al., 1987; Curi et al., 1997.)

Rate of utilization Rate of production

(nmol It1 mg-1 cell (nmol It1 mg-1 cell protein) protein)

Table 6.2. Rates of utilization of glucose or glutamine and of production of various metabolites by isolated mouse macrophages, rat lymphocytes or rat neutrophils. Rates of formation of 14CO2 are from 14C-labelled glucose or glutamine. (Data are from Ardawi and Newsholme, 1983; Newsholme et al., 1987; Curi et al., 1997.)

Rate of utilization Rate of production

(nmol It1 mg-1 cell (nmol It1 mg-1 cell protein) protein)

Cell type

Addition

Glucose

Glutamine

Lactate

Glutamate

Aspartate

14co2

Macrophage

Glucose

355

-

632

-

-

11

Glutamine

-

186

33

137

25

9

Lymphocyte

Glucose

42

-

91

-

-

1.5

Glutamine

-

223

9

132

59

6.1

Neutrophil

Glucose

460

-

550

-

-

2.4

Glutamine

-

770

320

250

68

6.5

0 0

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