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3 Department of Biochemistry, Memorial University of Newfoundland, St. John's, NL, Canada A1B 3X9 and 4 USDA Agricultural Research Service, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030
* To whom correspondence should be addressed. E-mail: rbertolo{at}mun.ca.
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ABSTRACT |
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 TOP ABSTRACT IntroductionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionLITERATURE CITED |
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It is instructive to evaluate the range of whole body flux rates of glutamine, proline, and related amino acids in adult humans. We have summarized reported data on whole body flux rates in humans and pigs measured using i.v. constant infusions of labeled amino acids (Table 1). Notably in adults, glutamine has a flux rate several-fold higher than glutamate, which is in turn higher than that for proline and arginine. It is also important to note that under anabolic or catabolic conditions, such as in rapidly growing neonates or catabolic burn patients, respective fluxes increase as expected. However, it is important to understand that these flux rates are measured using i.v. infusions of isotope with blood sampled as the central pool. Under these methodological conditions, only label that exchanges with the central plasma pool would be measured and interpreted as whole body flux. But it has been well established that this approximation of whole body flux severely underestimates the sum of intraorgan flux rates in the body, because not all metabolites readily exchange with the plasma pool. For example, it has been estimated that the hepatic arginine flux within the urea cycle is 
239 µmol·kg–1·h–1 (31), whereas the whole body flux is estimated at only 56–86 µmol·kg–1·h–1 (Table 1). Therefore, these i.v. flux estimates do not represent the true whole body metabolism of these amino acids and caution is warranted when extrapolating these data. Most importantly, i.v. infusion of isotope bypasses splanchnic metabolism (i.e. the gut and liver) and the disproportionately high metabolism by these tissues cannot be ignored in measurements of whole body flux rates.
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Role of proline and glutamine in arginine synthesis in the adult
Overall, both glutamine and proline have key roles as dietary precursors for arginine synthesis. Arginine is a semiindispensable amino acid involved primarily in urea synthesis but also key in nitric oxide, polyamine, and creatine syntheses. The roles of proline and glutamine in arginine metabolism change depending on stage of development. In fact, the changes in these metabolic pathways can be predicted by the relative enzyme activities in the various tissues involved.
Glutamine and glutamate can be converted to proline and the urea cycle amino acids via P5C, but this conversion occurs only in the gut, because P5C synthase activity is localized primarily to this tissue (41) (Figs. 1 and 2). The small intestine also has appreciable activities of P5C dehydrogenase (P5CDH) for proline synthesis as well as high activities of ornithine aminotransferase (OAT), carbamoyl phosphate synthetase I (CPS-I), and ornithine transcarbamoylase (OTC), which results in a net synthesis of citrulline (42). Because intestinal argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) activities are low, citrulline is released into the portal circulation and almost no arginine is synthesized in the gut. The intestine also has an appreciable level of arginase activity, which results in arginine to citrulline conversion while generating urea, a pathway once thought to occur only in the liver (43). Proline oxidase and OAT allow proline to also serve as an important dietary precursor for citrulline synthesis in the gut.
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Therefore, in the adult, proline, glutamine, and glutamate are effective dietary precursors for whole body arginine synthesis but only when converted to citrulline in the gut (40). Regulation occurs by releasing excess arginine to the portal circulation for catabolism by the liver. Indeed, in situations where high protein (i.e. high arginine) diets are fed, excess arginine downregulates CPS-I and OTC and is not converted to citrulline (48). The intact arginine is released to the portal vein for disposal by the liver. In contrast, low-protein (i.e. low-arginine) diets upregulate CPS-I and OTC and citrulline synthesis so more arginine can be synthesized in the kidney for whole body needs (43). Therefore, to provide more arginine to the adult, the dietary strategy should be based on feeding dietary precursors, not arginine. However, when the gut is bypassed, as in total parenteral nutrition feeding, then arginine (or citrulline) needs to be fed to meet arginine requirements.
Role of proline and glutamine in arginine synthesis in the neonate
In contrast to the healthy adult, neonates of several species have been shown to require some dietary arginine, because de novo synthesis is not sufficient to meet whole body requirements (22,49–51). This requirement is particularly evident in light of the observation that mammary milk in several species (i.e. primates, ruminants, pig, rat, llama, and elephant) is abundant in glutamine, glutamate, and proline but low in arginine (52). In pigs, the arginine:lysine ratio is only 40% of that in the whole body, which infers that arginine synthesis is essential to meet growth requirements (53).
Recent studies have demonstrated that de novo arginine synthesis in the neonate does not follow the adult scheme of interorgan metabolism. Both in vitro and in vivo work has demonstrated that arginine is synthesized and released by the neonatal small intestine (22,23,54) (Fig. 3). Because of negligible P5C synthase activity in the neonatal gut, glutamate and glutamine are not effective precursors for arginine synthesis, leaving proline as the only key dietary precursor (42,51). This also has been demonstrated using in vivo kinetics in piglets, where limited amounts of label from glutamate and glutamine appear in either proline or arginine when i.g. infused (55). Indeed, the localization of OAT to the gut in the neonatal pig results in the proline to arginine interconversion being gut dependent (23). Furthermore, low P5CDH activity in the neonatal gut also translates to negligible conversion of proline to glutamate and glutamine (42), probably because so much glutamate and glutamine are available to the gut and their synthesis from proline is not necessary. Indeed, only 5% proline flux ends up in glutamate and glutamine across the gut in piglets (22). The net synthesis of arginine is facilitated by the higher activities of ASS and ASL and a near absence of arginase in the gut of the neonate, unlike the adult (42,53). In addition, the neonatal liver does not readily take up portal arginine, which allows arginine of gut origin to be available for whole body metabolism. Furthermore, the neonatal kidney has lower activities of ASS and ASL so the conversion of citrulline to arginine is not as important in preweaning neonates. These enzyme activity patterns in the suckling neonate seem to change to adult patterns sometime postweaning, at least in pigs (42).
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Splanchnic metabolism of glutamine and glutamate
A key determinant of whole body metabolism of glutamine, proline, and related amino acids is the extent of splanchnic tissue metabolism. As clearly demonstrated by recent research, the role of glutamine, glutamate, and proline as precursors for arginine synthesis is largely dictated by the different roles of the splanchnic organs and stage of development. However, it has become evident in recent years that splanchnic amino acid metabolism is dominated by the gastrointestinal tissues more so than the liver. Although gastrointestinal tissues represent only 4–6% of body mass, these tissues disproportionately account for 20–35% of whole body energy expenditure and protein turnover (56). The anatomical position of the splanchnic tissues also emphasizes that first-pass metabolism of amino acids needs to be considered, because it determines whole body systemic exposure to dietary doses of these amino acids. Not only do these tissues filter dietary excesses reaching the general circulation, they also preferentially utilize dietary amino acids, as opposed to arterial amino acids, for protein synthesis and conversions (12,36,57–59). So the fate of dietary excesses of proline, glutamine, and glutamate largely depends on splanchnic metabolism, especially first-pass metabolism by the gut.
Glutamine splanchnic extraction
Arguably, the most important amino acid associated with gut metabolism is glutamine. Its role as a fuel for small intestinal enterocytes has been investigated extensively since the seminal work of Windmueller and Spaeth (32–35) in rats. In adult humans, a substantial body of literature also has been generated by comparing glutamine kinetics during parenteral vs. oral stable isotopic tracer infusions. A series of human studies involving such infusions observed that much of the label disappears when infused orally compared with i.v. (3,5–7,60). Thus, the calculated whole body flux rates during oral infusion were consistently higher than those using parenteral infusion. These differences in whole body flux can be ascribed to first-pass splanchnic metabolism of the oral tracer, because all components of flux were identical, such as protein synthesis, breakdown, and dietary inputs.
We have summarized splanchnic glutamine extraction data in studies using isotope tracers (Table 3). In general, about two-thirds of glutamine delivered orally is extracted on first pass and does not reach the peripheral circulation. In adult human studies that measured the fate of this label, the vast majority of this extracted glutamine (77–93%) was oxidized. Recent studies, employing portal-drained viscera (PDV) tracer balance in adults undergoing abdominal surgery, have further demonstrated that the majority of this splanchnic extraction is due to intestinal extraction (36,40). These results are similar to PDV balance experiments conducted in young pigs (12) and in situ small intestinal experiments in adult rats (33,34) and support the observation that the net glutamine balance across the liver is essentially 0 (38–40). In animal studies, the nonoxidative products of glutamine extracted by the gut are alanine, proline, citrulline, ornithine, and arginine (12,33). It is notable that 15–33% of arterial glutamine is extracted by the PDV in adult humans (36), rats (33), and young pigs (12). Quantitatively, this translates into a substantial amount of glutamine metabolized, because the total flux of glutamine delivered to the gut by artery is several-fold higher than that typically fed (58) and of this arterially extracted glutamine, 57–70% is oxidized (12,32,34).
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800–1500 µmol/L) and returned to baseline values within 2 h, demonstrating the rapid removal of glutamine (62). Of the many studies on glutamine supplementation to date, no problems of toxicity have been observed (63). Whether or not these increased plasma concentrations of glutamate are of concern requires more information on glutamate splanchnic metabolism. Glutamate splanchnic extraction
Although glutamine is often considered the most important amino acid for the gut, the extraction and oxidation of glutamate by the intestine is more extensive than that for glutamine. Indeed, it has been proposed that glutamate may be the most important fuel for intestinal metabolism (56). The nearly complete extraction of glutamate by splanchnic tissues in adult humans, by the PDV in young pigs, and by the small intestine of adult rats (Table 4) supports the more important role of glutamate as a fuel for the gut. In addition, 81–86% of this extracted glutamate was oxidized in human subjects, which, when combined with the increased extraction rate, makes glutamate a more important oxidative fuel, at least on first pass. Interestingly, however, negligible amounts of arterial glutamate are extracted by the PDV. Thus, in the postabsorptive state, when the arterial supply of amino acids is the only source available, glutamine is the most important fuel source for the gut. In either the fed or postabsorptive state, glutamate or glutamine, respectively, is the preferred oxidative fuel by the gut over glucose (12,35).
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30 mg/kg body weight; indeed, only a slight increase in plasma glutamate was observed with a monosodium glutamate bolus of 150 mg/kg body weight. Infants are also able to metabolize similar amounts given in infant formula (66) and a recent report in premature infants showed that an oral glutamate dose of 3-fold the normal intake was completely extracted by first-pass splanchnic metabolism (67). A recent study in young pigs fed glutamate at a level 4 times the normal intake for 4 h showed that PDV glutamate utilization increased with increasing enteral glutamate such that the percent utilized did not change over the 4-fold range of intakes (15). However, with a 3-fold increase in dietary glutamate infusion, PDV extraction decreased from 97 to 88% and oxidation rates decreased from 49 to 33%; indeed, more glutamate was converted to glutamine and ornithine (but not citrulline, arginine, or proline) and arterial glutamate concentrations increased from 175 to 505 µmol/L. With respect to toxicity, even with 400% of normal intake and a 3-fold rise in arterial concentrations, glutamate concentrations in brain and hypothalamus did not change, supporting the nontoxicity of glutamate at high concentrations (65). In addition, a study by Chung and Baker (68) showed that increasing dietary glutamate from 1.0 to 9.8% of diet had no effects on growth or feed efficiency over 3 wk. It should be noted that these studies were conducted in young pigs (<10 kg) and developmental changes may play a role. However, interestingly, early studies in adult pigs demonstrated that glutamate, at dietary concentrations up to 14%, can replace dispensable amino acids effectively without detrimental effects, even during pregnancy (69,70).
Although it has been suggested that glutamine and glutamate are interchangeable as substrates for intestinal metabolism (71), it should be noted that more dietary glutamate is extracted on first pass, whereas on second pass, glutamine continues to be extracted from the arterial circulation, unlike glutamate. But arterial glutamate appears to be oxidized at a similar rate (i.e. 80%) as enteral glutamate, so it must be extracted by the liver or transaminated to glutamine for uptake by the gut (13). Despite these metabolic differences, either amino acid can support intestinal structure and function in the absence of the other (71,72). Such evidence, in addition to the abundance of glutaminase and the fact that pharmacological doses of glutamine leads to high plasma glutamate concentrations and vice versa, suggests that these amino acids interconvert readily and, in a dietary sense, are interchangeable. Although excess plasma glutamate is not appreciably taken up by the gut on second pass, circulating glutamate is readily utilized by the liver for gluconeogenesis (39). Furthermore, because of the extensive splanchnic extraction, almost all circulating glutamate and glutamine is synthesized de novo and the body can induce widely fluctuating arterial concentrations of either amino acid (64). This broad manipulation of concentrations under various physiological states would minimize the importance of diet-induced plasma concentrations of these amino acids.
Splanchnic metabolism of proline
There are very few published reports on splanchnic extraction of proline and, to our knowledge, there is no information in humans. Recent studies on intestinal metabolism of proline in young pigs provide the only evidence available. In young pigs (5–6 wk old, postweaning), the PDV mass extraction of proline has been estimated at 9% (fed hourly for 7 h) (63), 12% (fed bolus with cumulative balance over 8 h) (73), 38% (fed hourly for 6 h) (58), 57% (fed continuously via duodenum for 6 h) (74), and 57% (fed continuously via duodenum for 24 h) (75). Although these data are wide-ranging due to the types of feeding regimes, it appears that much less proline is extracted on first pass (i.e. 9–57%) compared with glutamine (108–129%, or some net synthesis by PDV) or glutamate (71–99%) in these same studies. In younger 10-d-old piglets (i.e. preweaning), proline concentrations in plasma did not change when identical diets were infused enterally, intraportally, or i.v. for 7 d, suggesting minimal extraction of proline by splanchnic organs (76). Indeed, in a series of isotope studies conducted in these piglets to investigate gut conversion of proline to arginine, proline extraction by the small intestine was determined by comparing fluxes from oral and intraportal infusions of labeled proline (22,23). Over a range of arginine intakes, small intestinal extraction was negligible during low and high arginine intakes and at most 14% during a moderate intake (Fig. 4). Indeed, even when arginine is deficient (i.e. 0.20 g·kg–1·d–1), extra proline is not extracted at a higher rate by the gut to synthesize arginine. Moreover, using intraportal and i.v. flux estimates, hepatic extraction of proline was also negligible (24).
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Although not directly addressing splanchnic extraction of proline, proline kinetic data provide insight into the potential for proline toxicity in adult humans. In a study by Jaksic et al. (16), proline was infused i.v. at rates of 20 or 40 µmol·kg–1·h–1 to reach steady-state plasma proline concentrations at 60 and 100 µmol/L above baseline, respectively. With an infusion of 20 µmol·kg–1·h–1, steady state in proline flux was achieved by increasing proline oxidation and decreasing endogenous synthesis of proline. With the 40 µmol·kg–1·h–1 infusion, a new steady state was achieved, but proline oxidation did not increase (i.e. oxidative capacity was maximized) and endogenous synthesis could not be decreased further. They suggested the extra proline must have been converted to other metabolites, but this was not directly measured. Although these i.v. infusions did not measure splanchnic metabolism, these data demonstrate that the whole body capacity to remove excess proline is rather limited, even in the adult human.
The converse is also true; when proline is removed from the diet, proline synthesis capacity is also limited. Ball et al. (50) demonstrated that proline may be an indispensable amino acid in piglets. Subsequent studies also demonstrated that when piglets were infused with proline-free diets either parenterally or enterally, plasma proline concentrations decreased to 16–18% of baseline regardless of whether splanchnic metabolism was maintained (51). So in neonatal piglets, proline synthesis capacity is limited and a dietary source appears necessary to at least maintain plasma concentrations. However, proline is considered dispensable in the adult human. Therefore, data from Jaksic et al. and Hiramatsu et al. (17,18) were rather surprising by demonstrating that in humans on proline-free diets, plasma proline concentrations decreased by 22–29% after 1 wk (17) and by 60–65% after 4 wk (18). Despite this extended adaptation to the lack of dietary proline, the adult human still cannot seem to synthesize sufficient proline to maintain plasma concentrations.
Summary
Glutamine, glutamate, and proline are very important dietary precursors in adult mammals for de novo arginine synthesis. Net citrulline production occurs in the gut from all 3 precursors and the citrulline released largely escapes hepatic metabolism and is converted to arginine in the kidney. There are key developmental differences in arginine synthesis such that in the neonate, glutamine and glutamate are not effective dietary precursors and only proline can be converted to arginine, but only in the gut on first pass. Thus, splanchnic metabolism and stage of development are key factors that affect the whole body metabolism of glutamine, glutamate, and proline.
The majority (i.e. 50–75%) of dietary glutamine and almost all of dietary glutamate (i.e. 90–98%) are extracted on first pass by splanchnic tissues and most of this metabolism occurs in the small intestine. In addition, the vast majority (i.e. 60–90%) of this extracted glutamine and glutamate is oxidized as a fuel by the small intestine. Notably, although less glutamine than glutamate is extracted on first pass, a substantial arterial extraction of glutamine (i.e. 15–30%) by the small intestine occurs, especially during the postabsorptive state. Unlike glutamine, negligible amounts of arterial glutamate appear to be extracted, but glutamate can be readily utilized by the liver for gluconeogenesis or transaminated to glutamine for use by the gut. Less is known about proline extraction by splanchnic tissues, but limited data in young pigs suggest very little proline is extracted and therefore may present considerable toxicity potential compared with glutamate and glutamine. The oxidative and synthetic capacities for proline metabolism seem limited, even in adult humans.
The net result is that the plasma concentration of glutamine and glutamate is not a sensitive indicator of dietary load and de novo synthesis can increase plasma concentrations dramatically for nondietary reasons. However, the plasma proline concentration is sensitive to dietary inputs given the body's limited capacity to synthesize or oxidize proline. The lower extraction rate and oxidative limitations may lead to a higher toxicity potential for proline, which may be associated with neurological problems (77). Our survey of the existing evidence clearly warrants further study of the extent of splanchnic proline metabolism in adult humans.
In the context of establishing the safe upper limits for dietary amino acid intake, especially those like glutamine or glutamate, it is important to consider the extent of first-pass splanchnic metabolism. In circumstances where splanchnic tissue metabolism is bypassed, such as total parenteral nutrition, the safe upper limit may be considerably lower than when fed orally. The application of tracer kinetics approaches to address safe upper limits of amino acid intakes needs to include oral delivery of isotope to accommodate the massive splanchnic metabolism, which is often the most substantial component of whole body metabolism.
Other articles in this supplement include references (78–88).
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FOOTNOTES |
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2 Author disclosures: R. F. Bertolo, ICAAS paid travel expenses to attend the meeting; D. G. Burrin, no conflicts of interest.
5 Abbreviations used: ASL, argininosuccinate lyase; ASS, argininosuccinate synthase; CPS-I, carbamoyl phosphate synthetase; OAT, ornithine aminotransferase; OTC, ornithine transcarbamylase; P5C, pyrroline-5-carboxylate; P5CDH, pyrroline-5-carboxylate dehydrogenase; PDV, portal-drained viscera.
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LITERATURE CITED |
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TOPABSTRACTIntroductionLITERATURE CITED |
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