Arginine metabolic enzymes, nitric oxide and infection.

Nitric oxide (NO) is synthesized from arginine by NO synthase (NOS), and the availability of arginine is one of the rate-limiting factors in cellular NO production. Citrulline that is formed as a by-product of the NOS reaction can be recycled to arginine by successive actions of argininosuccinate synthetase (AS) and argininosuccinate lyase (AL), forming the citrulline-NO cycle. AS and sometimes AL have been shown to be coinduced with inducible NOS (iNOS) in various cell types including activated macrophages, microglia, vascular smooth muscle cells, glial cells, neuronal PC12 cells, retinal pigment epithelial cells, and pancreatic beta-cells. Coinduction of endothelial NOS (eNOS), AS, and AL are observed in human umbilical vein endothelial cells. In contrast, arginase can downregulate NO production by decreasing intracellular arginine concentrations. iNOS and arginase activities are regulated reciprocally in macrophages by cytokines, and this may guarantee the efficient production of NO. In contrast, iNOS and arginase isoforms (type I and/or II) are coinduced in immunostimulated macrophages, but not in PC12 cells and glial cells. These results indicate that NO production is modulated by the recycling and degradation of arginine. Arginase also plays an important role in regulation of polyamine and proline synthesis.