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Title: Enteral arginase II provides ornithine for citrulline synthesis

item MARINI, JUAN - Children'S Nutrition Research Center (CNRC)
item KELLER, BETTINA - Baylor College Of Medicine
item DIDELIJA, INKS - Children'S Nutrition Research Center (CNRC)
item CASTILLO, LETICIA - Baylor College Of Medicine
item LEE, BRENDAN - Baylor College Of Medicine

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/25/2010
Publication Date: 1/1/2011
Citation: Marini, J.C., Keller, B., Didelija, I.C., Castillo, L., Lee, B. 2011. Enteral arginase II provides ornithine for citrulline synthesis. American Journal of Physiology - Endocrinology and Metabolism. 300:E188-E194.

Interpretive Summary: Arginine is an amino acid utilized for protein, creatine, polyamines and nitric oxide synthesis. The role of arginases in the catabolism and disposal of arginine is well established. In this communication we report that the product of arginase activity, ornithine, is utilized for the synthesis of citrulline. In turn, citrulline is the endogenous precursor for the synthesis of arginine thus establishing an apparent futile cycle. We have shown that the absence of arginase activity in arginase knock out mice reduces the amount of citrulline produced. Ornithine supplementation, in the other hand, was shown to increase the amount of citrulline produced. Because arginase inhibition is being evaluated as a pharmacological target in order to increase nitric oxide production, the role of arginase in citrulline synthesis has to be considered.

Technical Abstract: The synthesis of citrulline from arginine in the small intestine depends on the provision of ornithine. To test the hypothesis that arginase II plays a central role in the supply of ornithine for citrulline synthesis, the contribution of dietary arginine, glutamine, and proline was determined by utilizing multitracer stable isotope protocols in arginase II knockout (AII(-/-)) and wild-type (WT) mice. The lack of arginase II resulted in a lower citrulline rate of appearance (121 vs. 137 µmol/kg(-1)/h(-1)) due to a reduced availability of ornithine; ornithine supplementation was able to restore the rate of citrulline production in AII(-/-) to levels comparable with WT mice. There were significant differences in the utilization of dietary citrulline precursors. The contribution of dietary arginine to the synthesis of citrulline was reduced from 45 to 10 µmol/kg(-1)/h(-1) due to the lack of arginase II. No enteral utilization of arginine was observed in AII(-/-) mice (WT = 25 µmol/kg(-1)/h(-1)), and the contribution of dietary arginine through plasma ornithine was reduced in the transgenic mice (20 vs. 13 µmol/kg(-1)/h(-1)). Dietary glutamine and proline utilization were greater in AII(-/-) than in WT mice (20 vs. 13 and 1.4 vs. 3.7 µmol/kg(-1)/h(-1), respectively). Most of the contribution of glutamine and proline was enteral rather than through plasma ornithine. The arginase isoform present in the small intestinal mucosa has the role of providing ornithine for citrulline synthesis. The lack of arginase II results in a greater contribution of plasma ornithine and dietary glutamine and proline to the synthesis of citrulline.