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Supplement: Arginine Metabolism: Enzymology, Nutrition, and Clinical Significance

Ornithine -Ketoglutarate as a Potent Precursor of Arginine and Nitric Oxide: A New Job for an Old Friend^1,2

Biochemistry Laboratory, Hôtel-Dieu Hospital—AP-HP and Laboratory of Biological Nutrition EA 2498, School of Pharmacy, Paris 5 University

³To whom correspondence should be addressed. E-mail: luc.cynober{at}htd.ap-hop-paris.fr.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
Ornithine -ketoglutarate (OKG) is a salt formed of 2 molecules of ornithine and 1 -ketoglutarate. Its administration improves nutritional status in chronically malnourished (e.g., elderly) and acutely malnourished patients (especially burn and trauma patients). There is evidence that OKG activity is not the simple addition of the effects of ornithine (Orn) and -ketoglutarate (KG), because the presence of both moieties is required to induce the generation of key metabolites such as glutamine, proline, and arginine (Arg), whereas this does not occur when one or the other is given separately. This observation is related to the fact that the main feature of Orn at the whole-body level is to be metabolized through the Orn aminotransferase-dependent pathway, whereas the simultaneous administration of Orn and KG saturates this pathway, diverting Orn toward metabolism into Arg. For years, OKG activity has been associated with its ability to induce the secretion of anabolic hormones, such as insulin and growth hormone, and to increase glutamine and polyamine synthesis. Recent studies using chemical inhibitors of nitric oxide synthase (NOS) suggest that nitric oxide derived from Arg could be partly involved in OKG activity. The use of genetically modified animals (i.e., knockout for NOS expression) is required to confirm this hypothesis.

KEY WORDS: • ornithine -ketoglutarate • arginine • nitric oxide • burn injury

The claim that ornithine (Orn)⁴ is a precursor of arginine (Arg) and that ornithine -ketoglutarate–mediated actions could be linked to its ability to generate Arg is hardly an impressive statement, because any biochemistry textbook indicates that Orn generates Arg in 3 steps through the Krebs-Henseleit cycle. However, this complete pathway is almost entirely limited to the liver, and at the whole-body level, Orn is mainly driven through the ornithine aminotransferase (OAT, EC 2.6.1.13)–controlled pathway (see other contributions in this issue for further details and references). In addition, there is evidence that OAT naturally works mainly in the ornithine glutamate direction, because OAT-deficient patients (i.e., patients with gyrate atrophy) have high blood ornithine levels (1). The ability of ingested Orn to generate Arg is therefore very limited at the whole-body level. The situation is quite different when the -ketoglutarate salt of Orn (i.e., ornithine -ketoglutarate; OKG) is administered. The purpose of this review is to demonstrate that OKG is a precursor of Arg, and that the latter amino acid could be involved [through production of nitric oxide (NO^·)] in OKG-mediated effects.

Ornithine -ketoglutarate: an old friend

The concept of OKG was proposed in the 1960s by Robert Molimard with the aim of reducing hyperammonemia in end-stage liver failure [for rationale, see Cardenas et al. (2) and Cynober (3)] at a time when it was believed that ammonia was the determinant of hepatic encephalopathy. Indeed, this therapy was very successful in normalizing ammonia levels, but unfortunately had no effect on coma status. However, through a fortunate coincidence, OKG therapy improved the nutritional status of these patients [for details and references, see Cardenas et al. (2) and Cynober (3)]. It was therefore applied in various malnutrition situations, including burn injury (4) and postoperative stress (5).

Ornithine -ketoglutarate in chronic and acute malnutrition: it works!

Following the pioneering studies mentioned above, many studies confirmed that OKG administration regulates nutritional and immunological status and improves wound healing in chronically malnourished (e.g., elderly patients and infants receiving long-term parenteral nutrition) and acutely malnourished patients [e.g., burn, trauma, and postoperative patients; for reviews, see Blondé-Cynober et al. (6), Cardenas et al. (2), and Cynober (3,7)]. Numerous experimental studies confirm the beneficial effects of OKG therapy, with particular emphasis on immunological status, protein turnover, and gut structure and function [for reviews, see Cardenas et al. (2) and Cynober (3,7)]. Table 1 summarizes the effects of OKG in humans and in experimental animal models.

Ornithine -ketoglutarate: more than the simple addition of Orn and KG

As mentioned in the introduction, Orn at the whole-body level does not contribute substantially to Arg synthesis. Results from studies using different approaches support this idea.

First, classical studies (8) measuring the effect of single amino acids on growth in rats indicate that Orn does not mimic Arg effects.

Second, in one study in rats, i.v. administration of ¹⁴C-ornithine produced trace amounts of ¹⁴C-arginine in the plasma but not in the kidney, liver, intestinal mucosa, or muscle (9). In another study using the same methodologies (10), ¹⁴C-ornithine was administered enterally. After 60 min, detectable amounts of ¹⁴C-arginine were found in the liver but not in the intestinal mucosa, kidney, or muscle. Whatever the route of administration of ¹⁴C-ornithine (9,10), the main metabolite produced was ¹⁴C-glutamate, confirming that the OAT-mediated pathway is the main Orn metabolic pathway at the whole-body level.

Third, when Orn hydrochloride was administered as a bolus to healthy subjects, there was a large increase in plasma glutamate (GLU; +65%, P < 0.001), peaking at 30–90 min; significant levels persisted until 150 min after Orn loading (11). It should be noted that administration of KG as a bolus produced similar GLU patterns. Conversely, Arg levels increased modestly (+20%, not significant) after Orn loading and decreased after KG loading (11).

Fourth, it is clear from demonstrations using stable isotopes (12) that the predominant direction of carbon flux in burn patients is from Orn to GLU, with little flux in the opposite direction.

Fifth, in healthy fasting subjects, the flux of Orn to citrulline represents 2.5 ± 0.5 µmol · kg^–1 · h^–1 compared to 6.5 ± 0.7 µmol · kg^–1 · h^–1 for Orn oxidation (presumably through GLU transamination followed by KG oxidation, the difference being even more important in fed subjects: 3.7 ± 0.8 vs. 14.4 ± 1.7 µmol · kg^–1 · h^–1, respectively) (13). Hence, it appears that at the whole body level, the Orn GLU pathway contributes up to 80–90% of the metabolism of Orn. This estimate fits very well with the fact that treating mice with gabaculine (an irreversible inhibitor of OAT) inhibits oxidation of Orn by 85% (14). In addition, conversion of Orn to citrulline represents only 6% of whole-body Orn flux in healthy subjects (15). However, it is worth noting that other calculations indicate that the contribution of oxidation to total Orn flux is 50% in healthy subjects and burn patients (16).

The earliest firm evidence that OKG metabolic behavior is different from that of its components comes from a study conducted with healthy subjects (11). On 3 separate occasions, subjects received 10 g OKG, 6.4 g Orn, or 3.6 g KG (i.e., the amounts of Orn and KG contained in 10 g OKG). Under these conditions, the peak plasma GLU level was lower after OKG loading than after KG or Orn loading alone, whereas Arg levels increased dramatically (+40%, P < 0.05), peaking at 30 to 90 min after OKG loading but not after Orn or KG loading (see above). Furthermore, there was a very significant relation between the increase in plasma Orn concentration and the plasma Arg concentration at 60 min after OKG loading (r = 0.89, P < 0.02). In fact, the same study showed that OKG stimulated insulin secretion, whereas Orn hydrochloride and Ca KG did not.

These data reinforce earlier pioneering work by Molimard et al. (17) indicating that perfusion of OKG but not of Orn hydrochloride or Na KG increases plasma Arg. Finally, in one rat model, OKG perfusion induced greater production of proline (Pro; a secondary product in the OAT-controlled pathway) than did Orn or KG perfusion (18).

It is not known why OKG is a potent precursor of Arg at the whole-body level whereas Orn hydrochloride is not. Our hypothesis, first published in 1993 (19) and still prevalent, is based on the fact that the sequence of reactions (Fig. 1) is fully reversible (reactions 1 and 4 depend on the transaminases, and reactions 2 and 3 are chemically driven and work at equilibrium). It is therefore likely that by increasing GLU formation, the administration of KG together with Orn displaces the equilibrium to the left, diverting Orn metabolism to Arg, Pro, and polyamine synthesis. The fact that OKG but not Orn increases Pro synthesis (11,18) suggests that either reaction 2 or reaction 3 acts as the site of interaction between Orn and KG.

View larger version (7K): [in this window] [in a new window]   FIGURE 1 The common metabolic pathway between ornithine and -ketoglutarate. Reactions 1 to 4 are fully reversible (1 and 4 depend on transaminases; 2 and 3 are chemically driven). Enzymes involved in the reactions are discussed in other articles in this issue.

Mechanisms of action previously proposed for OKG

Orn and KG are central to intermediary metabolism, and as such OKG is a potential precursor of several potential modulating agents. Hence, polyamines (24), branched-chain keto acids (25) and glutamine (Gln) (23,26) have all been suggested as being involved in OKG mechanisms of action, and they probably are, because OKG seems to have different mechanisms depending on the underlying pathology (3), or even different overlapping mechanisms in a given situation (discussed later).

OKG also acts a potent stimulator of the secretion of anabolic hormones such as insulin, growth hormone, and IGF-1/Sm-C, and this effect has been implicated in OKG anabolic activity in infants receiving long-term total parenteral nutrition (27) and trauma patients (28).

Until recent times (i.e., when NO was discovered), Arg generation was not really considered as a mechanism of OKG, and even recently (26) only a limited role was attributed to Arg and NO^· in OKG mechanisms.

Ornithine -ketoglutarate as an Arg and NO precursor: the new job

Nutritionists ignored what the pharmacologists were doing for far too long. It is to the credit of Jorge Albina and co-workers that they pointed out the role of NO^· in Arg-mediated effects on wound healing [see Mahoney and Albina (29) for a recent review]. It was then recognized that OKG action could be at least partly mediated through Arg, followed by NO^· generation.

In addition to the data presented above, several studies indicate that OKG increases Arg pools or counteracts the stress-induced decrease in Arg tissue pools, for example, in muscle in rats with tumors (30) or after surgical removal of a tumor (31), or after burn injury (32,33); or in the intestine in rats treated with LPS (34) or subjected to burn injury (32). In postoperative patients, parenteral OKG (0.35 g · kg^–1 · d^–1 for 3 d) counteracts the stress-induced decrease in muscle Arg concentration (35). It is interesting to note that perfused Na KG does not have this effect in the same model (36).

The intestine may play a major role in the ability of OKG to generate Arg, because OKG does not increase Arg pools in plasma or muscle after massive intestinal resection (i.e., 80%) in rats (37).

Again, after reading the discussion sections of most of these papers (including those from our own group), we must remark that it is surprising that this feature of Arg was never specifically discussed until fairly recently.

Because OKG perfusion (28 mg/min for 150 min) does not modify leg exchange of Arg in healthy subjects, it is likely that muscle Arg is derived from Orn taken up by the muscle (Orn flux: 48 ± 6 vs. –1 ± 1 µmol/min during infusion and basal level, respectively; P < 0.001) (38).

Original data suggesting that Arg is involved in OKG-mediated effects are rather indirect: in OKG-treated rats with burn injuries, there was a correlation between muscle Arg content and thymus weight (32). More consistent are data from Robinson et al. (30): rats with tumors were fed OKG, Gln, or Arg for 14 d. Splenocytes and macrophages were then studied in vitro. Nitrite production in mitogen-activated splenocytes increased in rats fed an OKG-enriched diet but not in those fed a Gln- or Arg-enriched diet. Similarly, nitrite production in stimulated macrophages was higher in cells of rats treated with OKG compared with control and Arg treatment groups. These results are difficult to explain because the cells were incubated in a medium that did not contain OKG. It may be suggested that in vivo OKG treatment modifies the NO synthase (NOS):Arg balance by inhibiting arginase (39), and therefore later favoring the flux of Arg from the culture medium through NOS action. Indeed, recent studies (40) strongly support the idea that the arginase:NOS balance is a key regulatory step in immune cell metabolism and function.

A further study on dexamethasone treatment in rats (41) demonstrated that LPS-stimulated macrophages from rats treated with OKG in vivo stimulate NO^· production in vitro (1.77 ± 0.64 vs. 0.29 ± 0.28 µmol/10⁶ cells in treatment and control groups, respectively; P < 0.05). Treatment with S-methylthiourea (SMT), a specific inhibitor of NOS II, abolished OKG-induced NO^· production. Recently, Moinard et al. (42) conducted similar experiments in polymorphonuclear (PMN) cells of dexamethasone-treated rats. Treatment with OKG increased both the production of reactive oxygen species (evaluated by chemiluminescence, ferricytochrome C reduction, and flow cytometry) and chemotaxis. Treatment with SMT in addition to OKG abolished the effect of the OKG on respiratory burst and PMN migration. An intriguing finding was that Arg treatment affected chemotaxis less than did OKG treatment, suggesting differences in intracellular channeling. This point deserves further study.

Finally, Schneid et al. (43) recently addressed the involvement of the NOS pathway in OKG-mediated effects on insulin secretion. Pancreatic islets were isolated from Wistar rats and incubated in the presence of OKG. OKG stimulated insulin secretion in a dose-dependent manner, and this effect was inhibited when cells were incubated in the presence of L-nitroarginine-methylester (L-NAME), again suggesting the involvement of NO^· in OKG-mediated activity.

In a further study (44), i.v. OKG (25 mg/kg) was administered with or without glucose (0.8 g/kg). OKG alone increased plasma insulin, and OKG with glucose increased glucose-induced insulin secretion. This latter effect was also demonstrated in vitro. In any case (i.e., in vivo or in vitro), L-NAME abolished the effects of OKG but did not affect basal insulin secretion or glucose-mediated insulin secretion.

However, reports by Moinard et al. (41,42) and Schneid et al. (43,44), could not credit NO^· as the sole mediator responsible for OKG action (Table 3).

There is now firm evidence that OKG is a potent Arg precursor (which is not shown with Orn hydrochloride), and that some of these effects are mediated, at least in part, through NO^· synthesis. These latter results were obtained using chemical inhibitors such as SMT and L-NAME. Whether these molecules are truly specific inhibitors of NOS remains subject to discussion. Studies using genetically manipulated animal models should reinforce the results presented above. For example, Barbul’s group (45), using inducible NOS knockout mice, elegantly demonstrated that Arg effects on wound healing are mediated by NO^· production. Of major interest, the same group (46), using the same model, showed that the effects of Orn hydrochloride are not mediated through NO^· production. This finding does not conflict with our results and hypothesis.

Clearly, our old friend OKG is enrolled for further work in its new job.

	ACKNOWLEDGMENTS

 
The author is indebted to S. Ngon for her excellent secretarial assistance. A number of co-workers have shared the OKG adventure over the past 20 y and must be thanked for their involvement in this unpredictable field of research: C. Coudray-Lucas, J. P. De Bandt, J. Le Boucher, T. Le Bricon, C. Moinard, P. Pernet, C. Schneid, and M. Vaubourdolle, among others.

	FOOTNOTES

 
¹ Prepared for the conference "Symposium on Arginine" held April 5–6, 2004 in Bermuda. The conference was sponsored in part by an educational grant from Ajinomoto USA, Inc. Conference proceedings are published as a supplement to The Journal of Nutrition. Guest Editors for the supplement were Sidney M. Morris, Jr., Joseph Loscalzo, Dennis Bier, and Wiley W. Souba.

² The studies described here were substantially supported by grants from Chiesi SA (formerly Lab. J. Logeais).

⁴ Abbreviations used: Arg, arginine; KG, -ketoglutarate; GLU, glutamate; Gln, glutamine; L-NAME, L-nitroarginine-methylester; NO, nitric oxide; NOS, nitric oxide synthase; OAT, ornithine aminotransferase; OKG, ornithine -ketoglutarate; Orn, ornithine; PMN, polymorphonuclear; Pro, proline; SMT, S-methylthiourea.

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TOP ABSTRACT LITERATURE CITED

 

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