Arginine and Ornithine Are the Main Precursors for Citrulline Synthesis in Mice3

Abstract

Recent isotopic tracer studies in mice, piglets, and humans have produced conflicting results as to the main carbon skeleton precursor for citrulline and arginine synthesis. This may be due in part to the different tracers infused and models used to interpret the stable isotope data. Furthermore, previous studies usually investigated a single precursor, which prevented the direct comparison among multiple precursors. To further elucidate the contribution of different precursors to citrulline synthesis, all possible enteral and plasma precursors of citrulline were studied in a mouse model during the postabsorptive and postprandial period using multitracer protocols. In addition, three different models were used to interpret the stable isotope data. The utilization of the classic precursor-product equation, developed for i.v. infused tracers but also used to include i.g. tracers, grossly overestimated the contribution of enteral precursors. Regardless of the model employed, dietary and plasma arginine were the main precursors for citrulline synthesis during feeding and plasma arginine during feed deprivation. The contribution of arginine was directly at the site of citrulline synthesis and through plasma ornithine. The predominant role of arginine and ornithine seen in this study supports the observations in mice, piglets, and humans suggesting that ornithine amino transferase is a pivotal enzyme in this pathway.

De novo synthesis is the main source of ornithine for citrulline production in neonatal pigs

“…Plasma amino acid isotopic enrichments were determined as their dansyl derivatives by LC-MS/MS (20) utilizing a TSQ Quantum Ultra System (Thermo Finnigan, San Jose, CA). The parent-daughter ion transitions monitored have been described elsewhere (18).…”

“…1). We have shown in adult mice that, in fact, arginine and plasma ornithine are the main precursors for citrulline synthesis (18,(21)(22)(23), indicating that the preformed pathway predominates in adulthood. The present experiments were conducted to test the hypothesis that the de novo pathway for ornithine synthesis is the predominant source of ornithine for citrulline synthesis during the neonatal period.…”

“…Feeding vs. fasting, luminal vs. arterial precursors together with species differences are just a few of the physiological factors that may affect the utilization of different precursors for citrulline synthesis. Other factors that add to the differences found by the different research groups are the choice of tracer to determine precursor-product relationships (21) and model employed to interpret the isotopic data (18).…”

Dietary Arginine Requirements for Growth Are Dependent on the Rate of Citrulline Production in Mice

“…Phenylalanine and tyrosine tracers were also used to determine whole-body protein turnover. Methods and calculations have been described in detail elsewhere (18,19). The plasma concentrations of arginine and citrulline were determined by isotopic dilution with use of an LC-MS/MS (TSQ Vantage; Thermo Scientific).…”

L-Arginine and L-Citrulline in Sports Nutrition and Health

“…Enterocytes are actually the only cell type containing the necessary enzymes required for this conversion, making the small intestine an integral part in the endogenous synthesis of Cit. Cit can also be synthesized from Arg and ornithine, with plasma glutamine and Arg serving as the main precursors during food deprivation [57]. Cit is used in several metabolic pathways throughout the body, the most notable of which being Arg synthesis and the urea cycle.…”