Regulation of nitric oxide production by arginine metabolic enzymes

Biochem Biophys Res Commun. 2000 Sep 7;275(3):715-9. doi: 10.1006/bbrc.2000.3169.


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, which 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, vascular smooth muscle cells, glial cells, neuronal PC12 cells, and pancreatic beta-cells. Cationic amino acid transporter (CAT)-2 is induced in activated macrophages but not in PC12 cells. On the other hand, 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 II) are coinduced in lipopolysaccharide (LPS)-activated macrophages. These results indicate that NO production is modulated by the uptake, recycling, and degradation of arginine.

Publication types

  • Review

MeSH terms

  • Amino Acid Transport Systems, Basic
  • Animals
  • Arginase / metabolism*
  • Arginine / metabolism*
  • Carrier Proteins / metabolism
  • Citrulline / metabolism
  • Enzyme Inhibitors / therapeutic use
  • Humans
  • Membrane Proteins / metabolism
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II


  • Amino Acid Transport Systems, Basic
  • Carrier Proteins
  • Enzyme Inhibitors
  • Membrane Proteins
  • Citrulline
  • Nitric Oxide
  • Arginine
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Arginase