The Journal of Nutrition
Commentary
Channeling of Citrulline for the Renal
Synthesis of Guanidino Acetate
Juan C Marini
USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics Baylor College of Medicine, Houston, TX 77030, USA
Although protein synthesis dominates the requirements for
dietary amino acids, the need for amino acids to meet demand
for synthesis of other compounds is not negligible. This
is especially true of production of creatine, which requires
substantial amounts of arginine and methionine. Synthesis of
guanidino acetate (GAA), the precursor for creatine, constitutes
the main pathway for the obligatory irreversible loss of arginine
consuming an equivalent to ∼20% of the dietary intake (1). In
turn, methylation of GAA to make creatine can represent up to
75% of all methylation reactions imposing a heavy burden on
methionine and 1-carbon metabolism (2).
The unique role of the kidney as the source for GAA, a
reaction catalyzed by l-arginine: glycine amidinotransferase
(AGAT), has been questioned since high AGAT activity was first
identified in the pancreas of dogs (3) and extra-renal sources for
GAA production were shown in nephrectomized rats (4). In this
issue of The Journal of Nutrition, Dinesh et al. (5) studied the
role of kidney, pancreas, and gut on the synthesis of GAA in a
neonatal pig model. They also investigated the effect of acute
supplementation with different precursors on the GAA output
by these organs. The rapid accretion of protein by the neonatal
piglets and their high demand for arginine and methionine,
make the piglet the ideal model to study supplementation with
various creatine precursors.
Dinesh et al. demonstrated that up to ∼90% of the GAA
produced can originate in the kidney (5). Despite the high
in vitro specific AGAT activity reported previously (1, 3), the
contribution of the pancreas to whole body GAA synthesis was
modest although not negligible. The determination of enzyme
activity in vitro provides optimized conditions (precursor and
cofactor concentrations, pH, no end product inhibition, etc.),
which can be very different in an intact cell (6). For these reasons
the direct measurements made by Dinesh et al. (5) provide
a better estimate of the actual production and contribution
of each organ. Not surprisingly, arginine supplementation
increased GAA production by both the kidney and pancreas;
citrulline supplementation, however, was even more effective at
increasing renal GAA output, but had no effect on pancreatic
production. Because of extensive arginine extraction during first
pass metabolism, oral citrulline supplementation is considered
No funding was received for this work.
Author disclosures: The author reports no conflicts of interest. JCM is a member
of the editorial board of The Journal of Nutrition.
Address correspondence to JCM (e-mail: marini@bcm.edu).
Abbreviations used: AGAT, L-arginine: glycine amidinotransferase; ASL, argini-
nosuccinate lyase; ASS, argininosuccinate synthase; GAA, guanidino acetate
Copyright  C The Author(s) 2019.
Manuscript received October 30, 2019. Revision accepted November 25, 2019.
First published online December 23, 2019; doi: https://doi.org/10.1093/jn/nxz310.
See corresponding article on page 443.
Downloaded from https://academic.oup.com/jn/article-abstract/150/3/423/5685400 by guest on 14 June 2020
more effective at increasing arginine availability than arginine
supplementation itself (7). Dinesh et al. (5) provided arginine
parenterally (circumventing first pass extraction) and plasma
arginine concentrations were similar in the arginine and
citrulline supplemented groups, and these results seem to
suggest that citrulline is more effective at providing arginine
at the site of GAA synthesis than arginine itself. These new
data by Dinesh et al. (5) are an addition to the mounting
body of evidence suggesting that citrulline is more effective at
providing intracellular arginine and fueling different processes
that require this amino acid (8–10). The ubiquitous presence of
argininosuccinate synthase and lyase (ASS and ASL), enzymes
responsible for the conversion of citrulline into arginine, is able
to catalyze the conversion of citrulline into arginine in many
(if not all) cell types. We have shown in mice (11, 12) and
pigs (Marini, unpublished) that this pathway is able to provide
sufficient intracellular arginine to sustain most cell processes
despite total plasma arginine depletion (<1 μmol/L).
In addition to providing intracellular arginine, the high
renal expression of ASS and ASL is responsible for most of
the de novo circulating arginine (13). In this process known as
the “intestinal-renal” axis for arginine synthesis, the citrulline
produced in the gut is converted into arginine by the kidney. The
existence of this axis in newborns has been questioned because
during the neonatal period the expression of ASS and ASL is
lower than later in life (14). Recently, we have shown that the
“intestinal-renal” axis is present and functional in neonatal pigs
(15), which is supported by the present observations of Dinesh
et al. (5). They also demonstrated that not only can citrulline
be used by the neonatal kidney for arginine synthesis, but also
that the neonatal kidney has excess capacity to use exogenous
citrulline (16).
In conclusion, the study by Dinesh et al. (5) confirms the
central role in GAA production, furthers the concept that
citrulline supplementation is a more effective way to increase
arginine availability than arginine itself, and confirms the ability
of the neonatal kidney to use citrulline.
Acknowledgments
The sole author was responsible for all aspects of this
manuscript.
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