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Research Project: Molecular, Cellular, and Regulatory Aspects of Nutrition During Development

Location: Children's Nutrition Research Center

Title: Plasma glutamine is a minor precursor for the synthesis of citrulline: A multispecies study

Author
item MARINI, JUAN - Children'S Nutrition Research Center (CNRC)
item AGARWAL, UMANG - Children'S Nutrition Research Center (CNRC)
item DIDELIJA, INKA - Children'S Nutrition Research Center (CNRC)
item AZAMIAN, MAHSHID - Baylor College Of Medicine
item STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)
item NAGAMANI, SANDESH - Baylor College Of Medicine

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/10/2017
Publication Date: 4/1/2017
Citation: Marini, J.C., Agarwal, U., Didelija, I.C., Azamian, M., Stoll, B., Nagamani, S.C. 2017. Plasma glutamine is a minor precursor for the synthesis of citrulline: A multispecies study. Journal of Nutrition. 147(4):549–555.

Interpretive Summary: The amino acid, glutamine, is considered by some researchers to be the precursor for the synthesis of the amino acid, citrulline. This has been shown using a tracer that follows a nitrogen atom of glutamine and its incorporation into citrulline. Here we have shown that when the whole carbon chain of glutamine is followed as it is converted into citrulline, plasma glutamine is a minor contributor to the synthesis of citrulline. We conducted this work in mice, rats, pigs and humans to show that this process is similar in all species studied. These results clarify the debate regarding the role of glutamine in the synthesis of citrulline.

Technical Abstract: Glutamine is considered the main precursor for citrulline synthesis in many species, including humans. The transfer of 15N from 2[15N]-glutamine to citrulline has been used as evidence for this precursor-product relationship. However, work in mice has shown that nitrogen and carbon tracers follow different moieties of glutamine and that glutamine contribution to the synthesis of citrulline is minor. It is unclear if this small contribution of glutamine is also true in other species. The objective of the present work was to determine the contribution of glutamine to citrulline production using nitrogen and carbon skeleton tracers in multiple species. Humans (n=4), pigs (n=5), rats (n=6), and mice (n=5), were infused with L-2[15N] and L-[2H5]-glutamine, and L-5,5-[2H2] citrulline. The contribution of glutamine to citrulline synthesis was calculated using different ions and fragments: glutamine M+1 to citrulline M+1, 2-[15N] glutamine to 2-[15N] citrulline and [2H5] glutamine to [2H5] citrulline. Species specific differences in glutamine and citrulline fluxes were found (P<0.001), with rats having the largest fluxes, followed by mice, pigs and humans. The contribution of glutamine to citrulline estimated using glutamine M+1 to citrulline M+1 ranged from 88% in humans to 46% in pigs. However, using 2-[15N] glutamine and 2-[15N] citrulline as precursor and product yielded values of 48% in humans and 28% in pigs. Furthermore, the use of [2H5] glutamine to [2H5] citrulline yielded lower values (P<0.001), resulting in a contribution of glutamine to the synthesis of citrulline of ~10% in humans and 3% in pigs. The recycling of the 15N glutamine label overestimates the contribution of glutamine to citrulline synthesis when compared to a tracer that follows the carbon skeleton of glutamine. Glutamine is a minor precursor for the synthesis of citrulline in humans, pigs, rats and mice.