Two forms of the arginase enzyme exist. While both forms catalyse the conversion of arginine to ornithine, they are encoded by separate gene sequences, are located in different subcellular compartments and are expressed to varying degrees in separate tissues. Type I arginase or hepatic arginase is constitutively expressed in hepatocytes. It is a cytosolic enzyme and is a central component of the urea cycle. While not constitutively present, its expression can be induced in macrophages by stimulation with T-helper-2 cytokines (especially by interleukins (IL)-4, -10 and -13) (Munder et al., 1999; Chang et al., 2000). Arginase II, on the other hand, is localized to the mitochondria and is found in high concentrations in kidney, brain and small intestine. Arginase II can also be induced in macrophages but by different stimuli, namely, LPS and dexam-ethasone (Corraliza et al., 1995). The expression of both forms of arginase in macrophages is reduced by T-helper-1 cytokines, such as IFN-7 (Munder et al., 1999).
Following conversion to ornithine, a number of pathways may be followed for further metabolism. What directs a cell to choose one pathway over another is not yet understood.
The reactions involved in the urea cycle are shown in Fig. 5.3 and occur primarily in the liver. The function of the urea cycle is to clear nitrogenous waste, by converting ammonia to urea for excretion by the kidneys. Nitrogen can enter the cycle either through conversion to carbamoyl phosphate and subsequent passage of the carbamoyl molecule to ornithine, forming citrulline, or via glutamate to aspartate, which enters the cycle by reacting with citrulline to form arginosuccinate. Arginosuccinate lysase converts arginosuccinate to arginine, and fumarate, and arginase catalyses the degradation of arginine to ornithine with the loss of one molecule of urea. The reactions involving carbamoyl phosphate and glutamate occur in the mitochondrion, whereas the remaining reactions take place in the cytosol.
Ornithine aminotransferase catalyses the transfer of one amine residue from a-keto-glutarate to ornithine, with the formation of pyrroline-5-carboxylate,
which can then be reduced to proline or pass, via glutamate semialdehyde, to glutamate. Proline and its derivative hydroxyproline (formed in situ by the action of ascorbic acid) constitute 25% of the collagen molecule and therefore play a vital role in wound healing and tissue repair. Glutamate can be used by the cell for energy production, by complete oxidation to CO2 through the citric acid cycle, or can be used for protein or amino acid synthesis.
The polyamines - putrescine, spermidine, spermine - are ubiquitous molecules found in all eukaryotic cells. They are synthesized from arginine via ornithine and ornithine decarboxylase, as shown in Fig. 5.2. The precise physiological role of polyamines has yet to be fully elucidated. It is known that they are required at low concentrations for cell viability and that levels increase during cell growth, differentiation and proliferation. They have been demonstrated to act through altering the three dimensional structure of tRNA thereby stimulating protein synthesis, through the phosphorylation of protein kinases, thereby accelerating intracellular signalling pathways, through modulation of transcription and mRNA turnover and through DNA editing. Inhibition of polyamine synthesis, using DL-alpha-difluoromethylor-nithine (DMFO) (a competitive inhibitor of ornithine decarboxylase), leads to a reduction in cell viability, cell-cycle arrest in S-phase and inhibition of cell differentiation.
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