The Arginine Metabolic Pathways: Nitric Oxide Synthase and Arginase

Two important metabolic pathways use the amino acid arginine as the precursor: the enzyme nitric oxide synthase, which converts arginine to nitric oxide, and citrulline and the enzyme arginase, which converts arginine to ornithine and urea. The latter is part of a pathway for detoxifying ammonia. Ornithine is also part of a proliferative pathway that is involved in cell division and tissue regeneration. Arginase II is the form of arginase that is thought to be involved in the synthesis of polyamines, which control cell proliferation and collagen production. It is most highly expressed in the prostate and kidney.1

There has been considerable recent publication of papers on nitric oxide synthase because of the importance of nitric oxide in functions such as (importantly) vasodilation (endothelial function). Scientists have found that an inadequate supply of arginine or too little of the cofactor tetrahydrobiopterin (which one paper reports may be mimicked by folic acid2) results in an “uncoupling” of nitric oxide synthase from the production of nitric oxide, producing superoxide anion instead. Not only is there a reduction in the production of nitric oxide when nitric oxide synthase is uncoupled, but oxidative stress is greatly increased.

Now, another major mechanism of decreased production of nitric oxide has been reported: an increase in the arginase pathway for the use of arginine. Recent studies have reported increases in arginase in conditions including reperfusion injury,3asthma,4,5 psoriasis,6 arthritis,7 and human breast cancer.8 (Since arginase II is highly expressed in the prostate, it would be interesting to see whether there is increased expression in prostate cancer.) The increased arginase decreases arginine availability to be converted to nitric oxide, as well as increasing ornithine that can be converted into polyamines, procellular proliferation factors.6 In psoriasis, for example, there is hyperproliferation of keratinocytes. In the arthritis paper,7 it was reported that arginase II could be induced ex vivo (outside the body) by inflammatory factors such as PGE2 and LPS (lipopolysaccharide, from bacteria). Ornithine, produced by arginase, is necessary for the production of collagen, which occurs in rheumatoid arthritis.7

Arginase in the brain

Not only is arginine in the brain vital for the manufacture of nitric oxide, it is also used in brain protein synthesis and is the substrate for the production of urea (detoxification of ammonia), creatine, agmatine, glutamic acid, ornithine, proline, and polyamines.9 In a new study,9 caffeine was shown, in Wistar rats given “small doses” of caffeine in their drinking water (2 g/l over the first 3 days to 4 g/l over the last 7 days—however, mice drink far less water in proportion to food than humans do), to decrease arginase activity. The results indicated that caffeine’s inhibitory effect on arginase left more arginine available for use by the nitric oxide synthase pathway.

As the authors9 explained, caffeine is an inhibitor of adenosine receptors, decreasing adenosine bound to its receptors and increasing free adenosine. Adenosine, adenine, inosine, and uric acid are competitive inhibitors of arginase.9 Valine, leucine, isoleucine, and ornithine are also reported to have inhibitory effects on arginase activity.

Caffeine and compounds related to caffeine, such as theophylline and theobromine, increase cellular levels of cyclic AMP that are hypothesized9 to possibly be, at least in part, a reason for caffeine’s depression of arginase activity. We wonder, too, whether the prescription drug pentoxifylline, a prescription methylxanthine drug used in the treatment of poor circulation in the extremities (especially legs), might reduce arginase activity (thus increasing arginine’s availability to be converted to nitric oxide), which (if true) might account for some of the drug’s beneficial effects.

  1. Vercelli. Arginase: marker, effector, or candidate gene for asthma? J Clin Invest111(12):1815-17 (2003).
  2. Hyndman et al. Interaction of 5-methyltetrahydrofolate and tetrahydrobiopterin on endothelial function. Am J Physiol Heart Circ Physiol 282:H2167-72 (2002).
  3. Hein et al. Ischemia-reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J2003;17(15):2328-30.
  4. Meurs et al. Arginase and asthma: novel insights into nitric oxide homeostasis and airway hyperresponsiveness. Trends Pharmacol Sci 24(9):450-5 (2003).
  5. Zimmermann et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Invest 111(12):1863-74 (2003).
  6. Bruch-Gerharz et al. Arginase I overexpression in psoriasis. Am J Pathol162(1):203-11 (2003).
  7. Corraliza and Moncada. Increased expression of arginase II in patients with different forms of arthritis. Implications of the regulation of nitric oxide. J Rheumatol 29:2261-5 (2002).
  8. Porembska et al. Arginase in patients with breast cancer. Clin Chim Acta328:105-11 (2003).
  9. Nikolic et al. Effect of caffeine on metabolism of L-arginine in the brain. Molec Cell Biochem 244:125-8 (2003).