Arginine metabolism

ODC = ornithine decarboxylase OAT = ornithine aminotransferase

FIGURE 6.1 Arginine metabolism.

ODC = ornithine decarboxylase OAT = ornithine aminotransferase

FIGURE 6.1 Arginine metabolism.

In such situations, arginine becomes indispensable for optimal growth and maintenance of positive nitrogen balance.

The major synthesis pathway involves the intestinal-renal axis in which the small intestine releases citrulline into the blood circulation and is then extracted by the kidney for conversion into arginine. It is released into the bloodstream for uptake by tissues for protein synthesis. The hepatic arginine pathway contributes the lowest arginine amount, because the liver does not express large amounts of the cationic transporter for the basic amino acid arginine. Therefore, most of the portal venous arginine and citrulline enters the systemic circulation and serves as substrate for extrahepatic tissues. The intestinal absorption of arginine occurs via a transport system shared with lysine, ornithine, and cysteine. Arginine, ornithine, and lysine also share a common uptake and transport system in the brain, leukocytes, erythrocytes, fibroblasts, and leukocytes.2

Arginine catabolism occurs in a wound via two separate enzymatic pathways — nitric oxide synthase isoforms and the two arginase isoforms. Arginine plays a key role within the urea cycle, the major pathway for ammonia detoxification (Figure 6.1). There are two distinct isoenzymes of mammalian arginase, which are encoded by separate genes. Type I arginase, a cytosolic enzyme, is highly expressed in liver as a component of the urea cycle and is also present in wound-derived fibroblasts. Type II arginase is a mitochondrial enzyme expressed at lower levels in the kidney, brain, small intestine, mammary gland, and macrophages. Any condition that increases demand for ammonia detoxification is likely to increase arginine requirements. Inherited defects in the hepatic type I arginase are partially compensated for by elevated expression of type II arginase in the kidney, resulting in a less severe clinical disorder.

Arginine has been shown to be the unique substrate for the production of the highly reactive radical nitric oxide (NO) molecule. This important pathway has been shown to be present in many tissues and cells, including endothelium, brain, inflammatory cells (lymphocytes, macrophages, neutrophils, mast cells), platelets, and hepa-tocytes. NO is pharmacologically and chemically identical to endothelial-derived relaxant factor (EDRF), a biological effector molecule. In addition to its role in vasodilation, NO is a putative neurotransmitter and cytotoxic effector molecule. NO is formed by the oxidation of one of the two identical terminal guanidino groups of L-arginine by the enzyme NO synthase (NOS), a dioxygenase, of which there are at least two identified isoforms. Both isoforms of NOS have been identified as flavoproteins, each containing flavine adenine dinucleotide and flavine adenine mononucleotide, and both are inhibited by diphenyleneiodonium, a flavoprotein inhibitor. Neuronal NOS and endothelial NOS, collectively referred to as cytosolic NOS (cNOS), are expressed constitutively and are activated by Ca2+/calmodulin. Inducible NOS is calcium dependent and is expressed in response to inflammatory cytokines and endotoxins, including interleukin-1, tumor necrosis factor-a, y-interferon, and lipopolysaccharide.

There are strong regulatory mechanisms between the different metabolic pathways. L-hydroxyarginine and nitrite, the intermediate end products, respectively, of the NO pathway, are both strong arginase inhibitors. Furthermore, urea, an end product of arginase activity, inhibits NO formation. Each pathway is stimulated by a well-defined set of cytokines that then downregulates the alternate pathway (e.g., transforming growth factor [TGF]-P stimulates arginase but inhibits inducible nitric oxide synthetase [iNOS]).34

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