Nitric oxide pathway of arginine metabolism

No one molecule has attracted more attention in the last decade than nitric oxide (NO). This small molecule plays a pivotal role in a diverse range of functions, including vasodilatation, memory, peristalsis, penile erection, cytotoxicity and the control of various endocrine and exocrine secretions in the cardiovascular, reproductive, central nervous and immune systems (Nathan and Xie, 1994; MacMicking et al., 1997). NO is synthesized from arginine by nitric oxide synthase (NOS), with the formation of citrulline. There are three known forms of this enzyme: neuronal (nNOS) and endothelial cell (ecNOS) NO synthases, which are both constitutively expressed and calcium-activated, and an inducible form (iNOS), which is controlled at the transcriptional level and is of most interest in the setting of the immune system.

iNOS expression, and hence NO production, is induced in macrophages in response to a variety of stimuli, particularly the T-helper-1 cytokines interferon (IFN)-7 and tumour necrosis factor (TNF)-a and the Gram-negative bacterial wall component endotoxin (lipopolysaccharide (LPS)). Inhibition of

Protein synthesis

Arginine

Protein synthesis

Arginine

1 Nitric oxide synthase

2 Arginine decarboxylase

3 Argino-glycine amidinotransferase

4 Arginase

5 Ornithine aminotransferase

6 Ornithine decarboxylase

7 Ornithine transcarbamoylase

1 Nitric oxide synthase

2 Arginine decarboxylase

3 Argino-glycine amidinotransferase

4 Arginase

5 Ornithine aminotransferase

6 Ornithine decarboxylase

7 Ornithine transcarbamoylase

Fig. 5.2. A simplified outline of arginine metabolism, showing the major enzymes, intermediate molecules and end-points.

NO production increases the host susceptibility to viral, bacterial, fungal, protozoal and helminthic infections (MacMicking et al., 1997). In addition, the anti-tumour activity of stimulated mouse macrophages is absent in iNOS knockout mice (Stuehr and Nathan, 1989). The mechanisms of NO cytotoxi-city are complex, involving inhibition of DNA synthesis, mitochondrial inac-tivation, cell membrane lysis, cell cycle arrest, DNA strand break formation and induction of apoptosis (Burney et al., 1997). In addition, NO can react with superoxide to form peroxynitrite, a powerful oxidizing agent capable of inducing cell injury and death (Samar et al., 1997). Apart from its cytotoxic effects, NO is involved in regulating the expression of major histocompatibility complex (MHC) II expression in antigen-presenting cells, in modulating T-cell mitogenic responses and in the induction and suppression of many cytokines (Niedbala et al., 1999; Akaike and Maeda, 2000). However, the full extent of NO involvement in the functioning of the immune system has yet to be established.

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