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Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
* To whom correspondence should be addressed. E-mail: smorris{at}pitt.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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Despite the existence of a considerable body of information about mammalian arginine metabolism, many very important questions still remain. Examples of major questions for which we do not have complete answers include the following: Where are the various arginine metabolic enzymes expressed? When are they expressed? What are their physiologic roles? How are they regulated? Although some information addressing each of these questions is provided here, this article draws attention to gaps in our knowledge and poses additional questions. Because arginine metabolism encompasses a vast range of topics, this article does not attempt to be comprehensive. Aspects of arginine metabolism not covered here have been reviewed elsewhere (4–15). Subsequent sections briefly discuss selected features of arginine metabolism and highlight additional questions for each topic.
Sources and availability of arginine
Free arginine within the body is derived from the diet, endogenous synthesis, and turnover of proteins. Although synthesis of arginine from citrulline can occur in many cell types (16–18), a major part of endogenous synthesis occurs via a collaboration between the epithelial cells of the small intestine and proximal tubule cells of the kidney (the "intestinal-renal axis" of arginine synthesis) (19–22). In healthy adults the level of endogenous synthesis is sufficiently great that arginine is not an essential dietary amino acid. However, in cases of catabolic stress (e.g., inflammation or infection) or conditions involving dysfunction of the kidneys or small intestine, levels of endogenous synthesis may not suffice to meet metabolic demands. Accordingly, arginine is classified as a semiessential or conditionally essential amino acid (8,23,24). Plasma levels of arginine in healthy adults are 
80–120 µmol/L. Therefore, how is arginine homeostasis maintained? Studies by Young and his associates indicated that it is accomplished by modulation of arginine catabolism rather than of arginine synthesis (25). If this is correct, what are the mechanisms by which arginine catabolism is regulated, and in which cells or organs does this regulation occur?
The roles and regulation of endogenous arginine synthesis by specific cell types have been extensively reviewed elsewhere (9,26,27), and so this topic will only be summarized here. Arginine synthesis from citrulline (Fig. 1) can occur to varying degrees in many different cell types, and expression of argininosuccinate synthetase (ASS) or argininosuccinate lyase (ASL) can be induced in response to many different stimuli. In many cases this induction occurs in parallel with up-regulation of inducible nitric oxide synthase (iNOS) such that some of the citrulline produced by NOS can be recycled to arginine in a pathway known as the Citrulline-NO Cycle. However, it is not known whether arginine synthesis is similarly induced under other conditions of high arginine demand, as in circumstances in which arginase becomes highly expressed.
In addition to dietary sources and endogenous synthesis, the availability of arginine for metabolic functions is also determined by activities of its transporters in the plasma and mitochondrial membranes. Transporters of arginine and other basic amino acids in the plasma membrane are well characterized (28–30), but information about arginine transporters in the mitochondrial membrane is still quite limited. Levels of plasma arginine transporters can change in response to arginine concentration or to specific stimuli (31–36). Failure to induce cationic amino acid transporter-2 (CAT-2) can limit arginine availability for induced NO synthesis to varying degrees, depending on cell type (37–39). Recently, CAT-2 deficiency in mice was shown to result in spontaneous baseline inflammation in lung, and the results suggested that CAT-2 regulates antiinflammatory processes in lung via its impact on NO production by alveolar macrophages, which in turn is required for suppression of the activation of dendritic cells (40). Because of their impact on intracellular availability of arginine, what are the roles of arginine transporters in cells expressing high activities of arginase or arginine:glycine amidinotransferase?
Information regarding mitochondrial transporters of arginine and ornithine is more limited than for the plasma membrane transporters. At least 2 such mitochondrial transporters—ORNT1 and ORNT2—are expressed in hepatocytes (41–43); they are important for urea cycle function as shown by the fact that a deficiency in ORNT1 in humans results in the hyperornithinemia-hyperammonenia-homocitrullinemia syndrome (41). Although ORNT1 and ORNT2 are expressed in cell types other than liver (41–43), a complete description of the identities and activities of the mitochondrial transporters of basic amino acids in other cell types is lacking. This is an important issue because such transport is important for determining availability of arginine for the mitochondrial isoform of arginase and for the metabolic fates of ornithine. For example, ornithine in mitochondria could be utilized preferentially by mitochondrial ornithine aminotransferase (OAT), whereas cytoplasmic ornithine could be utilized preferentially by ornithine decarboxylase (ODC) (Fig. 1), depending on how rapidly equilibration of ornithine occurs across the mitochondrial membrane and on the activities of ODC and OAT. Although we know that ORNT1 expression is inducible by cAMP and glucocorticoids in hepatocytes (44), is mitochondrial basic amino acid transport regulated in other cell types, and, if so, what is the impact of such regulation on arginine or ornithine metabolism?
In addition to the known cellular and subcellular localization of arginine within specific physical compartments, evidence has recently been obtained for at least 2 kinetically distinct subcellular compartments/pools of arginine substrate for NOS in macrophage and endothelial cells (45,46). One pool can be depleted by exchange with extracellular lysine, but the other cannot. This phenomenon appears to be cell-type specific, as it was not observed for a bladder carcinoma cell line (46). What are the mechanisms that maintain these arginine pools and differentially restrict the availability of arginine to NOS enzymes, and is access differentially restricted also for other arginine metabolic enzymes?
Sensing arginine availability
Cells and organisms can indirectly "sense" changes in arginine availability via changes in activity of various metabolic pathways as described in subsequent sections. However, mechanism(s) by which changes in arginine concentration can be directly sensed by mammalian cells have not been elucidated. One possibility is that the cell senses changes in the ratio of charged:uncharged arginine tRNA molecules. Another possibility is that arginine is a ligand for receptor molecules that serve as sensors. As recent studies have reported that the G-protein-coupled receptor 6A (GPRC6A) is a receptor of L-
-amino acids, with a preference for the basic amino acids arginine, ornithine, and lysine (47,48), does GPRC6A indeed play a role in sensing changes in arginine levels?
Arginase and NO synthesis
Although the affinity of NOS enzymes for arginine is 1000-fold greater than is the affinity of the arginases, the Vmax of the arginases is 1000-fold greater than that of the NOS enzymes (5). In principle, the arginases should be able to effectively compete with the NOS enzymes for substrate and thus limit NO production. This has been confirmed experimentally in a number of studies in which inhibition of arginase activity or expression resulted in increased NO production (49–55). As a note of caution, it should be borne in mind that arginase activity may not always be high enough to limit NO synthesis (56). Moreover, the interplay between the arginases and NOS enzymes is not always a matter simply of substrate competition. NG-Hydroxy-L-arginine (NOHA), an intermediate in NO synthesis, is a potent inhibitor of the arginases (57,58) (as indicated in Fig. 1), and local concentrations of NOHA sufficient to inhibit arginase activity can accumulate under conditions of high rates of NO synthesis by iNOS, at least in cell culture (59). However, because the only data regarding inhibition of arginase by NOHA have been obtained in the test tube or under nonphysiologic conditions using cultured cells, it is important to ascertain whether this inhibition can occur also in vivo. If so, what are the circumstances and extent to which such inhibition occurs in vivo?
Finally, arginase can inhibit NO synthesis by inhibiting iNOS expression at the level of translation but not at the level of transcription (60,61). By mechanisms described in more detail below, translation of iNOS mRNA was more profoundly inhibited than was translation in general; overall protein synthesis was inhibited by only 50% at levels of arginase I expression that completely inhibited iNOS protein expression (61). Limiting arginine concentration in the medium mimicked the effect of elevated arginase expression, thus demonstrating that inhibition of iNOS expression results from restriction of arginine availability rather than from production of urea, ornithine, or some ornithine-derived compound (61). Questions remain: Does this phenomenon occur in vivo? Are these effects on iNOS expression cell-type specific? How is arginine insufficiency sensed by cells?
Arginase and polyamine synthesis
Arginase not only consumes arginine but also produces ornithine, which can serve as substrate for ODC, the initial enzyme in the polyamine biosynthetic pathway (Fig. 1). Review articles on polyamines often refer to ODC as the rate-limiting enzyme in polyamine synthesis but rarely consider whether the provision of ornithine is the rate-limiting step. To test the hypothesis that arginase activity might be a limiting factor for polyamine synthesis and also cell proliferation, primary cultures of rat VSM cells were stably transfected with an expression plasmid encoding rat arginase I (62). As a control for any effects of transfection, a parallel set of VSM cells was stably transfected with bacterial ß-galactosidase. The results showed that only a 3.5-fold increase in arginase activity (as indicated by urea synthesis in intact cells) resulted in a nearly 2-fold increase in cellular concentration of putrescine, spermidine, and spermine and also a significant increase in cell proliferation rate (Fig. 2). Similar findings were also obtained with stably transfected bovine endothelial cells, which showed that increased expression of either arginase I or arginase II resulted in increased polyamine synthesis and cell proliferation (63,64). These experiments provided "proof of principle" for the role of arginase as a regulatory factor in polyamine synthesis. Similar conclusions were reached in complementary studies that investigated the effects of arginase inhibitors: Inhibition of arginase activity in vascular smooth muscle (VSM) cells blocked TGFß-dependent increases in polyamine synthesis (65), and inhibition of arginase activity in tumor cell lines with elevated arginase activity resulted not only in reduced spermine content and decreased cell proliferation but also in induced apoptosis (66). Results of the latter study support the hypothesis that arginase may be an important factor in the metastatic potential of some tumors. The role of arginase activity as a limiting factor in polyamine synthesis was nicely demonstrated also in studies using cultured cerebellar neurons (67).
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Arginase and proline synthesis
Because ornithine produced by arginase also can serve as a precursor for synthesis of proline (Fig. 1), which can support production of proline-rich proteins such as collagen, there has been interest in the role of arginase in wound healing, tissue remodeling, or fibrosis (68–75). Therefore, the role of the arginases in proline synthesis was evaluated in bovine endothelial cells that had been stably transfected with arginase I or II; increased expression of either arginase enhanced conversion of arginine to proline (Fig. 3) (63). Durante et al. (65) presented evidence that arginase was involved in synthesis of proline and collagen in vascular smooth muscle cells stimulated with TGFß. Another group demonstrated that induction of endogenous arginase expression in primary macrophages also stimulated production of proline from arginine, confirming that the results with cultured endothelial cells were not merely an artifact of cell transfection (76). Because proline can also be derived from glutamate (Fig. 1), it would be useful to determine in what cell types and under what circumstances proline synthesis is indeed dependent on catabolism of arginine. It is important to note that conversion of arginine to proline requires expression of OAT, whereas conversion of glutamate to proline does not (5,77,78). The presence of OAT activity in endothelial cells (79) is consistent with the above-cited observations of arginine conversion to proline in this cell type. The observation that arginine can be converted to proline in any cell is indirect evidence for the presence of OAT, which is expressed in a variety of organs (78).
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Most studies of the effects of the arginases on arginine metabolism have evaluated the consequences of altered arginase expression on synthesis of NO, polyamines, or proline. However, recent studies of patients with sickle cell disease have revealed a new paradigm for pathological effects of the arginases, namely, changes in localization of arginase (80). This could be termed the "real estate" model of disease, as the arginase effects are dependent on "location, location, location." Briefly, in sickle cell patients, circulating arginine levels are about half those of healthy nonsickle-cell individuals, and plasma arginine:ornithine ratios are reduced, consistent with increased arginine catabolism (Fig. 4). These apparent changes in arginine metabolism are highly significant, as sickle cell patients with the greatest decreases in plasma arginine:ornithine ratios are most likely to have severe pulmonary hypertension and also are at greater risk of death (80). The decreases in arginine:ornithine ratio suggested increased arginine catabolism and were found to correlate with increased arginase activity in plasma. The increased plasma arginase activity (which we have determined by ELISA to result exclusively from type I arginase) correlates with increased cell-free hemoglobin in plasma. Because type I arginase is expressed and active in human erythrocytes (81–84), these observations indicate that increases in plasma arginase result from hemolysis and that decreases in circulating arginine levels are caused primarily—if not entirely—by mislocalization of arginase rather than by changes in arginase expression. [These observations do not rule out the possibility that some increases in arginase expression and arginine catabolism also may occur within specific tissue compartments in sickle cell patients. Indeed, arginase activity in platelets of sickle cell patients is higher than that in healthy controls (85).] Overall, the reduced plasma levels of arginine, together with increased plasma levels of cell-free hemoglobin (which acts as a trap for NO) (86), result in NO insufficiency, consistent with the increased incidence of pulmonary hypertension in sickle cell patients. As a practical matter, the presence of arginase in human red blood cells or plasma can result in inaccurate determinations of urea or arginine in plasma if blood samples are not appropriately processed and stored, particularly in cases where hemolysis occurs (87–89).
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Recently, arginase I has been found in granules of human neutrophils and thus can be released into extracellular space following activation or death of neutrophils (94–96). Arginase expression in these cells is apparently species-specific because there is high arginase expression in resting human leukocytes but little or no arginase activity in resting murine leukocytes (95). These findings raise new questions: What are the roles of neutrophil-derived extracellular arginase in modulating arginine metabolism, e.g., at localized sites of inflammation or wound healing? How is the normally cytoplasmic arginase I packaged into a secretory granule?
Arginine availability and gene expression
Changes in arginine availability—usually decreases in arginine concentration as a result of changes in arginase activity—can selectively alter the expression of specific genes [reviewed by Morris (14)]. This is not a new discovery: repression of ASS and ASL expression by arginine in cultured cells was demonstrated 40 y ago (97,98). The effect of arginine on ASS expression is at the level of transcription, but details of the molecular mechanisms involved have not been elucidated (99). More recent studies have shown that arginine limitation results in decreased expression of iNOS (60,61) and the 
-chain of the T-cell receptor (TCR) (100,101), but it results in increased expression of CAT-1 (31,102–104). The mechanisms involved are not identical for each of these genes and also may exhibit some cell-type specificity. For example, arginine-dependent changes in expression occur via reduced translational efficiency of iNOS mRNA (60,61), decreased stability of iNOS protein (60), decreased half-life of the mRNA encoding the TCR -chain (100), and by increases both in translational efficiency of CAT-1 mRNA (104) and in transcription of the CAT-1 gene (102). Interestingly, phosphorylation of eIF2, which plays a direct role in regulating translational efficiency of iNOS mRNA (Fig. 5), also indirectly plays a role in regulating transcription of the CAT-1 gene (35) via its effects on efficiency of translation initiation. Reduced plasma arginine levels correlate with reduced expression of the TCR -chain in patients with renal cell carcinoma (105) and in patients with pulmonary tuberculosis (106), consistent with results of studies using cell culture models. Because of the likely significant impact on cell function, high priority should be given to addressing the following questions: What are the identities of other genes whose expression is altered by changes in arginine availability, and what are the mechanisms and extent to which such changes occur in vivo?
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Agmatine, the decarboxylation product of arginine, is produced by arginine decarboxylase and can be metabolized by agmatinase to produce putrescine and urea (107,108). Although various effects of agmatine, mostly pharmacologic, have been known for many years (107,109–112), very little is known about the metabolism and physiologic role(s) of endogenous agmatine in mammals. How much of the agmatine present in mammalian tissues is derived from the diet, from endogenous synthesis, or produced by commensal organisms within the gastrointestinal tract?
Cloned cDNAs for mammalian agmatinases were isolated only a few years ago, and some initial studies on agmatinase expression have been reported (113–115). To date, however, there is very little information regarding the enzymologic properties of mammalian agmatinases (116), and there are no enzymologic studies of purified agmatinase from any mammalian species. Surprisingly, analysis of the predicted amino acid sequence of murine agmatinase reveals that 4 of the 6 amino acid residues involved in binding of the manganese cofactor that are virtually invariant in other eukaryotic agmatinases as well as in other members of the arginase superfamily (117) are not conserved in murine agmatinase, indicating that it should be enzymatically inactive (118). If this is indeed the case, then what is the metabolic fate(s) of agmatine in mice?
Although agmatine synthesis occurs in mammalian tissues (119–122), there is controversy regarding the identification of a mammalian arginine decarboxylase. A putative cDNA encoding arginine decarboxylase has been reported (123), but other groups have failed to confirm that this cDNA actually encodes arginine decarboxylase (124,125). In fact, one group concluded that the putative arginine decarboxylase is actually an ornithine decarboxylase antizyme (125). From the discussion in this section, it is clear that many questions remain. For example, are there alternate routes for the synthesis and degradation of agmatine in mammalian cells? In what cell types does agmatine synthesis or degradation occur, how are they regulated, and are expression and regulation of these processes species-specific?
It is hoped that this brief article will stimulate interest and research on arginine metabolism. It also should be apparent from the preceding discussions that no single approach will be sufficient to completely elucidate the roles and regulation of arginine metabolism. As described above, arginine insufficiency in sickle cell disease was revealed by reductions in plasma arginine (a "metabolomics" approach), and the likely basis for this was indicated by the increased levels of cell-free arginase in plasma (a "proteomics" approach). In contrast, a "genomics" approach was used to initially identify the rapid and dramatic increase in arginase expression in acute asthma (126). To fully understand arginine metabolism in these and other cases, however, integration of information obtained by multiple approaches will be necessary.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Author disclosures: The ICAAS paid the author's travel expenses to attend the meeting.
3 Supported in part by grants GM57384 and GM64509 from the NIH.
4 Abbreviations used: ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; CAT, cationic amino acid transporter; GPRC, G-protein-coupled receptor; iNOS, inducible NOS; NO, nitric oxide; NOHA, NG-hydroxy-L-arginine; NOS, NO synthase; ODC, ornithine decarboxylase; TCR, T-cell receptor; VSM, vascular smooth muscle.
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1-pyrroline-5-carboxylate; PRMT, protein-arginine methyltransferase. The metabolite P5C is in chemical equilibrium with L-glutamate-
-semialdehyde (not shown) via a spontaneous nonenzymatic reaction. Reproduced from Morris (
