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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:2760S-2764S, October 2004

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

Structure and Function of Arginases1,2

David E. Ash3

Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140

3To whom correspondence should be addressed. E-mail: deash{at}temple.edu.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
The arginases catalyze the divalent cation dependent hydrolysis of L-arginine to produce L-ornithine and urea. Although traditionally considered in terms of its role as the final enzyme of the urea cycle, the enzyme is found in a variety of nonhepatic tissues. These findings suggest that the enzyme may have other functions in addition to its role in nitrogen metabolism. High-resolution crystal structures have been determined for recombinant rat liver (type I) arginase and for recombinant human kidney (type II) arginase, their variants, and complexes with products and inhibitors. Each identical subunit of the trimeric enzyme contains an active site that lies at the bottom of a 15 Å deep cleft. The 2 essential Mn(II) ions are located at the bottom of this cleft, separated by ~3.3 Å and bridged by oxygens derived from 2 aspartic acid residues and a solvent-derived hydroxide. This metal bridging hydroxide is proposed to be the nucleophile that attacks the guanidinium carbon of substrate arginine. On the basis of this proposed mechanism, boronic acid inhibitors of the enzyme have been synthesized and characterized kinetically and structurally. These inhibitors display slow-onset inhibition at the pH optimum of the enzyme, and are found as tetrahedral species at the active site, as determined by X-ray diffraction. The potent inhibition of arginases I and II by these compounds has not only delineated key enzyme-substrate interactions, but has also led to a greater understanding of the role of arginase in nonhepatic tissues.

KEY WORDS: • arginase • manganese • protein structure • enzyme inhibitors • boronic acids

The arginases catalyze the divalent cation-dependent hydrolysis of L-arginine to form the nonprotein amino acid L-ornithine and urea (Fig. 1). In the liver, this reaction constitutes the final step in urea biogenesis. The flux through this reaction is considerable, as the average adult excretes ~10 kg of urea/y. The urea cycle arginase (arginase I or liver arginase) is cytosolic, and is the best characterized of the mammalian arginases. A second isozyme, arginase II or kidney arginase, is mitochondrial in location. The human type I and type II arginases are related by 58% sequence identity (1), and are immunologically distinct. The comparative properties of the 2 arginase isozymes are discussed in a number of recent reviews (2–4). Arginase activity has been detected in a number of nonhepatic tissues that lack a complete urea cycle; the reaction is thought to provide a source of ornithine, the biosynthetic precursor of proline and the polyamines. For example, in lactating mammary gland, arginase activity rises to about 25% that found in liver in order to supply the proline required for milk protein biosynthesis (5). Ornithine is also a biosynthetic precursor of the polyamines (6), and myometrial arginase activity increases ~25-fold during pregnancy to supply the rapidly growing fetus with polyamines to facilitate cell proliferation (7). The requirement of rapidly dividing tissues for enhanced polyamine biosynthesis is apparently met by increased arginase activity as found in gastric cancers (8–10) and in breast cancer (11). Recently, arginase activity has been detected in certain human colon cancer and human breast cancer cell lines (12,13).



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  		FIGURE 1 The arginase reaction.

 
Metal activation and kinetic properties

A common feature of all arginases thus far studied, whether of eukaryotic or prokaryotic origin, is a requirement of divalent cations for activity. Mn2+ is the physiologic activator, although the divalent cation requirement for some arginases has been reported to be satisfied by Co2+ and Ni2+ (14–16) and in some instances by Fe2+, VO2+, and Cd2+ (17,18). Mn(II) binding experiments in this laboratory have shown that fully Mn-activated arginase contains 2 Mn(II)/subunit and that these Mn2+ ions form electron paramagnetic resonance (EPR)4 spin-coupled binuclear centers (19). Detailed analyses of the temperature dependence of the Mn(II) EPR properties indicate an Mn(II)-Mn(II) separation of 3.36–3.57 Å in the native enzyme (20).

Similarly, most arginases have an alkaline pH optimum, with maximal velocities observed in the range of pH 9.0–9.5 (21). For the rat liver enzyme, plots of log Vmax versus pH provide a pK value of ~7.8–8.0 (22), while pK values of 7.8 and 7.9 have been reported for the human liver (23) and mouse liver (24) enzymes. These pK values are consistent with the pK expected for the ionization of a solvent molecule bridging the Mn(II)-Mn(II) center (25), and it is thought that the resultant metal bridging hydroxide is the catalytic nucleophile.

Substrate specificity of the arginases depends on 1) the presence of an intact guanidinium group, 2) the proper length and hydrophobicity of the side chain, and 3) the stereochemistry and nature of substituents at C{alpha} (26). For example, D-arginine and guanidinobutyrate are not substrates for the enzyme, and alterations about C{alpha} (L-argininamide, L-argininic acid, and agmatine) result in 170–54,000-fold reductions in kcat/KM (26). Such exquisite substrate specificity suggests that a well-defined constellation of hydrogen bond donors must be present at the active site.

Structural properties of arginase

High resolution crystal structures are currently available for rat liver type I arginase (27), a truncated form of the recombinant human kidney type II arginase (28), and the arginase from the extreme thermophile Bacillus caldovelox (29). Additional structures are available for variants of the recombinant rat liver enzyme in complexes with products and a variety of inhibitors (30–34). Liver arginase is a 105 kDa homotrimer and each 35 kDa subunit contains a binuclear Mn(II) center that is critical for catalytic activity The overall fold of each subunit belongs to the {alpha}/ß family, consisting of a parallel, 8 stranded ß-sheet flanked on both sides by numerous {alpha}-helices. The binuclear Mn(II) center is located at the bottom of an ~15 Å-deep active site cleft (27). The Mn(II)-Mn(II) separation is 3.3 Å, a value that is consistent with that determined by EPR measurements (20). MnA, the more deeply situated metal ion, has square pyramidal coordination; His101 and As128 are terminal ligands and Asp124 (bidentate), Asp232 (monodentate) and hydroxide ions are bridging ligands (Fig. 2). MnB is coordinated with distorted octahedral geometry by terminal ligands His126 and Asp234 (bidentate), and bridging ligands Asp124 (bidentate), Asp232 (monodentate) and hydroxide ion. A hydrogen bond is donated by metal-bridging hydroxide to the noncoordinating oxygen of Asp128. Interestingly, residues analogous to Asp128 that coordinate a metal ion and hydrogen bond to a bridging hydroxide have been identified at the active sites of bimetallic hydrolases such as phosphotriesterase (35), dihydroorotase (36), isoaspartyl dipeptidase (37), aminopeptidase P (38), and prolidase (39). The polypeptide fold of human arginase II is topologically identical to the {alpha}/ß fold of rat arginase I and the hexameric arginase from Bacillus caldovelox (28). The structure of the binuclear Mn(II) cluster of human arginase II is nearly identical to that of rat arginase I, a finding that is not surprising considering that all metal ligands are conserved between the 2 sequences.



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  		FIGURE 2 Binuclear center of rat liver arginase I. Adapted from reference 27.

 
Catalytic mechanism

The arginase mechanism proposed by Kanyo and colleagues (27) is most consistent with available biochemical, enzymological, and structural data (Fig. 3). Key features of this mechanism include 1) a precatalytic binding side chain for arginine in which the side chain of Glu277 plays a role in substrate recognition, 2) attack of a nucleophilic metal-bridging hydroxide ion, 3) formation of a neutral tetrahedral intermediate that is stabilized by the binuclear Mn(II) center, and 4) a possible role for His141 as a proton shuttle in mediating proton transfer between the active site and bulk solvent. His141 resides about halfway out of the active site cleft, and it has been proposed that this residue is a proton shuttle, analogous to His64 of carbonic anhydrase II, which is known to facilitate proton transfer between zinc-bound water and bulk solvent in order to regenerate the catalytically active zinc-bound hydroxide (40). Additionally, His141 is extraordinarily reactive towards histidine modifying reagents such as diethylpyrocarbonate, and the modified enzyme has only about 10% residual activity (22).



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  		FIGURE 3 Proposed mechanism for the hydrolysis of arginine based on the crystal structure of liver arginase (27). The {alpha}-amino and {alpha}-carboxylate groups of the substrate are omitted for clarity.

 
Inhibition by N{omega}-hydroxy-L-arginine and boronic acids

The discovery of nitric oxide (NO) synthase, which catalyzes the oxidation of arginine to form NO and citrulline, has generated significant interest in the interplay between the NO synthase and arginase pathways. A number of tissues express both type I and type II arginases as well as nitric oxide synthase, and because these enzymes compete for a common substrate, L-arginine, the coexpression of these enzymes raises interesting questions concerning the regulation of arginine flux through the competing pathways (Fig. 4). N{omega}-hydroxy-L-arginine, an intermediate in the synthesis of NO, is a moderately potent competitive inhibitor of arginase with a Ki value in the range of 10–42 µmol/L (41–43), compared to the KM value of 1 mmol/L for arginine (26). Significant amounts of the N{omega}-hydroxy-L-arginine intermediate dissociate from the NOS active site to serve as an endogenous arginase inhibitor in both macrophages (43,44) and endothelial cells (45).



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  		FIGURE 4 The relationship between arginase activity and NO synthase activity. The synthesis of N{omega}-hydroxy-L-arginine by NO synthase requires O2 as a substrate.

 
The reciprocal nature of the regulation of NOS and arginase activity has only recently been appreciated and, in part, stems from the development of potent boronic acid-based inhibitors of type I and type II arginases (28,33,46,47). The boronic acids, 2(S)-amino-6-boronohexanoic acid (ABH) and S-(2-boronoethyl)-L-cysteine (BEC), were designed as potential mimics of the tetrahedral intermediate that is formed upon attack of the metal-bridging hydroxide on the guanidinium carbon of substrate arginine. The trigonal boronic acid could be converted to the tetrahedral boronate either by an analogous attack of the metal-bridging hydroxide at the active site or by direct binding of the tetrahedral species to the enzyme. Indeed, the boronic acids are potent inhibitors of both arginase I and arginase II (33,46–48); kinetic data are presented in Table 1 for inhibition of arginase II. The boronic acids are classic, competitive inhibitors at physiologic pH, with binding constants of ~0.3 µmol/L. The KM for arginine at this pH is 5 mmol/L, and hence the inhibitors bind with roughly 20,000-fold higher affinity than does substrate. At the pH optimum of 9.5, the boronic acids display slow-binding behavior as evidenced by nonlinear progress curves. Such curves are indicative of a rapid formation of a reversible enzyme-inhibitor complex, followed by a slow isomerization or conformational change to yield the final inhibitory complex. Analysis of these progress curves yields Ki values in the 10–30 nmol/L range, compared to a KM value of 0.3 mmol/L for arginine at this pH (48). Interestingly, a slight isozyme selectivity for inhibition of the arginases by the boronic acids is observed, with arginase II showing somewhat higher affinity for these compounds. This finding suggests that it may be possible to design isozyme selective inhibitors of the enzyme.


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  		TABLE 1 Potent competitive inhibitors of type II arginase1

 
Structures have been determined for complexes of arginase I and arginase II with the boronic acid inhibitors (28,33,47). In all complexes, the tetrahedral boronate is bound at the active site, with 1 of the boronate hydroxyl groups bridging the 2 Mn(II) ions, occupying the site normally populated by the bridging hydroxyl group in the free enzyme. Additionally, 1 of the boronate hydroxyl groups is now coordinated to the vacant coordination site on MnA. Although the binuclear Mn(II) cluster of human arginase II is nearly identical to that of rat liver arginase I in its complex with BEC, a number of notable differences are observed. First, the hydrogen bond between a boronate hydroxyl group and Glu277 is consistent with the proposal that Glu277 hydrogen bonds with the {eta}1-NH2 group of the substrate and stabilizes the tetrahedral transition state. Second, in the arginase II-BEC complex, Asp232 undergoes changes in MnB coordination to hydrogen bond with another boronate hydroxyl group. These results suggest that Asp232 could move to hydrogen bond with the {eta}2-NH2 group of substrate and tetrahedral intermediate.

Because the boronic acids ABH and BEC are not inhibitors of NO synthase, they have been used to probe the role of arginase in the regulation of NO-mediated smooth muscle relaxation in the gastrointestinal tract (46), as well as in penile (33,47) and clitoral (28) corpus cavernosum tissues. Both ABH and BEC enhance relaxation of these smooth muscle tissues in ex vivo organ bath experiments. Inhibitors of arginase activity thus enhance L-arginine concentrations for NO biosynthesis and NO-dependent smooth muscle relaxation. Recent studies have shown that type I and type II arginases are located extrahepatically [for a review, see (49)], and therefore both enzymes may be involved in the regulation of NO production in mammals. For example, type II arginase and NOS are induced early in lipopolysaccharide-induced mouse macrophages, while the type I isozyme is induced much later. It is believed that in this system the elevated type II arginase activity is involved in producing ornithine for the production of proline and the polyamines, necessary for wound healing, while expression of the type I isozyme prevents the overproduction of toxic NO (50,51). The development of isozyme selective inhibitors would be advantageous in delineating the precise biological roles of these enzymes in mammalian tissue.

Concluding remarks

Despite the wealth of structural and biochemical information available, there remain a number of intriguing questions concerning the structure and function of the arginases. Although the enzyme can be activated by a number of metals in vitro, Mn(II) is the physiologically relevant metal ion. The molecular basis for the selection of this trace metal to serve as a cofactor in a hydrolytic reaction is unclear. Similarly, the role of His141 has remained enigmatic. This highly conserved residue is extraordinarily reactive towards chemical modification, yet its replacement by site-directed mutagenesis results in enzymes with considerable catalytic activity. Finally, and perhaps most important from the standpoint of understanding the biologic roles of the enzyme, can isozyme selective inhibitors be developed? The boronic acid-based inhibitors show modest selectivity for arginase II; however, the conservation of active site structures for arginase I and arginase II presents a significant challenge to the development of such isozyme selective inhibitors.


   ACKNOWLEDGMENTS
 
The author wishes to acknowledge the productive collaboration with the laboratory of David Christianson at the University of Pennsylvania that has resulted in the determination of arginase structures.


   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. Back

2 This work was supported by National Institutes of Health Grant GM 67788. Back

4 Abbreviations used: ABH, 2(S)-amino-6-boronohexanoic acid; BEC, S-(2-boronoethyl)-L-cysteine; EPR, electron paramagnetic resonance; NO, nitric oxide. Back


   LITERATURE CITED
TOP
 ABSTRACT
 LITERATURE CITED
 

1. Morris, S. M., Jr, Bhamidipati, D. & Kepka-Lenhart, D. (1997) Human type II arginase: sequence analysis and tissue-specific expression. Gene 193:157-161.[Medline]

2. Jenkinson, C. P., Grody, W. W. & Cederbaum, S. D. (1996) Comparative properties of arginases. Comp. Biochem. Physiol. 114B:107-132.

3. Iyer, R., Jenkinson, C. P., Vockley, J. G., Kern, R. M., Grody, W. W. & Cederbaum, S. (1998) The human arginases and arginase deficiency. J. Inher. Metab. Dis. 21(Suppl. 1):86-100.[Medline]

4. Perozich, J., Hempel, J. & Morris, S. M., Jr (1998) Roles of conserved residues in the arginase family. Biochim. Biophys. Acta 1382:23-37.[Medline]

5. Yip, M.C.M. & Knox, W. E. (1972) Function of arginase in lactating mammary gland. Biochem. J. 127:893-899.[Medline]

6. Tabor, C. W. & Tabor, H. (1984) Polyamines. Annu. Rev. Biochem. 53:749-790.[Medline]

7. Weiner, C. P., Knowles, R. G., Stegink, L. D., Dawson, J. & Moncada, S. (1996) Myometrial arginase activity increases with advancing pregnancy in the guinea pig. Am. J. Obstet. Gynecol. 174:779-782.[Medline]

8. Wu, C. W., Chi, C. W., Lin, E. C., Lui, W. Y., P’eng, F. K. & Wang, S. R. (1994) Serum arginase level in patients with gastric cancer. J. Clin. Gast. 18:84-85.

9. Wu, C. W., Chi, C. W., Ho, C. K., Chien, S. K., Liu, W. Y., P’eng, F. K. & Wang, S. R. (1994) Effect of arginase on splenic killer cell activity in patients with gastric cancer. Digest. Dis. Sci. 39:1107-1112.

10. Leu, S. Y. & Wang, S. R. (1992) Clinical significance of arginase in colorectal cancer. Cancer 70:733-736.[Medline]

11. Straus, B., Cepelak, I. & Festa, G. (1992) Arginase, a new marker of mammary carcinoma. Clin. Chim. Acta 210:5-12.[Medline]

12. Buga, G. M., Wei, L. H., Bauer, P. M., Fukuto, J. M. & Ignarro, L. J. (1998) NG-Hydroxy-L-arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms. Am. J. Physiol. 275:R1256-R1264.

13. Singh, R., Pervin, S., Karimi, A., Cederbaum, S. & Chaudhuri, G. (2000) Arginase activity in human breast cancer cell lines: N{omega}-hydroxy-L-arginine inhibits cell proliferation and induces apoptosis in MDA-MB-468 cells. Cancer Res. 60:3305-3312.[Abstract/Free Full Text]

14. Hellerman, L. & Perkins, M. E. (1935) Activation of enzymes. J. Biol. Chem. 112:175-194.[Free Full Text]

15. Mora, J., Tarrab, R., Martuscelli, J. & Soberon, G. (1965) Characteristics of arginase from ureotelic and non-ureotelic animals. Biochem. J. 96:588-594.[Medline]

16. Brown, G. W., Jr (1966) Studies in comparative biochemistry and evolution. I. Avian liver arginase. Arch. Biochem. Biophys. 114:184-194.[Medline]

17. Anderson, A. B. (1945) The activation of Jack-Bean arginase by cobalt, manganese, and iron. Biochem. J. 39:139-142.[Medline]

18. Edlbacher, S. & Baur, H. (1958) The nature of yeast and liver arginase. Hoppe-Seyler’s Z. Physiol. Chem. 254:275-284.

19. Reczkowski, R. S. & Ash, D. E. (1992) EPR evidence of binuclear Mn(II) centers in rat liver arginase. J. Am. Chem. Soc. 114:10992-10994.

20. Khangulov, S. V., Pessiki, P. J., Barynin, V. V., Ash, D. E. & Dismukes, G. C. (1995) Determination of the metal ion separation and energies of the three lowest electronic states of dimanganese (II,II) complexes and enzymes: catalase and liver arginase. Biochemistry 34:2015-2025.[Medline]

21. Roholt, O. A. & Greenberg, D. M. (1956) Liver Arginase. IV. Effect of pH on kinetics of manganese-activated enzyme. Arch. Biochem. Biophys. 62:454-470.[Medline]

22. Reczkowski, R. R. (1991) Characterization of the kinetic and catalytic mechanism of rat liver arginase. Ph.D. Thesis 1991 Temple University .

23. Kuhn, N. J., Ward, S., Piponski, M. & Young, T. M. (1995) Purification of human hepatic arginase and its manganese (II)-dependent and pH-dependent interconversion between active and inactive forms: a possible pH-sensing function of the enzyme on the ornithine cycle. Arch. Biochem. Biophys. 320:24-34.[Medline]

24. Kuhn, N. J., Talbot, J. & Ward, S. (1991) pH-Sensitive control of arginase by Mn(II) ions at submicromolar concentrations. Arch. Biochem. Biophys. 286:217-221.[Medline]

25. Sossong, T. M., Jr, Khangulov, S. V., Cavalli, R. C., Soprano, D. R., Dismukes, G. C. & Ash, D. E. (1997) Catalysis on dinuclear Mn(II) centers: hydrolytic and redox activities of rat liver arginase. J. Biol. Inorg. Chem. 2:433-443.

26. Reczkowski, R. S. & Ash, D. E. (1994) Rat liver arginase: kinetic mechanism, alternate substrates, and inhibitors. Arch. Biochem. Biophys. 312:31-37.[Medline]

27. Kanyo, Z. F., Scolnick, L. R., Ash, D. E. & Christianson, D. W. (1996) Structure of a unique binuclear manganese cluster in arginase. Nature 383:554-557.[Medline]

28. Cama, E., Colleluori, D. M., Emig, F. A., Shin, H., Kim, S. W., Kim, N. N., Traish, A. M., Ash, D. E. & Christianson, D. W. (2003) Human arginase II: crystal structure and physiological role in male and female sexual arousal. Biochemistry 42:8445-8451.[Medline]

29. Bewley, M. C., Jeffrey, P. D., Patchett, M. L., Kanyo, Z. F. & Baker, E. N. (1999) Crystal structures of Bacillus caldovelox arginase in complex with substrate and inhibitors reveal new insights into activation, inhibition and catalysis in the arginase superfamily. Structure Fold Des. 7:435-448.[Medline]

30. Cama, E., Emig, F. A., Ash, D. E. & Christianson, D. W. (2003) Structural and functional importance of first-shell metal ligands in the binuclear manganese cluster of arginase I. Biochemistry 42:7748-7758.[Medline]

31. Lavulo, L. T., Sossong, T. M., Jr, Brigham-Burke, M. R., Doyle, M. L., Cox, J. D., Christianson, D. W. & Ash, D. E. (2001) Subunit-subunit interactions in trimeric arginase. Generation of active monomers by mutation of a single amino acid. J. Biol. Chem. 276:14242-14248.[Abstract/Free Full Text]

32. Cox, J. D., Cama, E., Colleluori, D. M., Pethe, S., Boucher, J. L., Mansuy, D., Ash, D. E. & Christianson, D. W. (2001) Mechanistic and metabolic inferences from the binding of substrate analogues and products to arginase. Biochemistry 40:2689-2701.[Medline]

33. Kim, N. N., Cox, J. D., Baggio, R. F., Emig, F. A., Mistry, S. K., Harper, S. L., Speicher, D. W., Morris, S. M., Jr, Ash, D. E., Traish, A. & Christianson, D. W. (2001) Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase as a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum. Biochemistry 40:2678-2688.[Medline]

34. Scolnick, L. R., Kanyo, Z. F., Cavalli, R. C., Ash, D. E. & Christianson, D. W. (1997) Altering the binuclear manganese cluster of arginase diminishes thermostability and catalytic function. Biochemistry 36:10558-10565.[Medline]

35. Benning, M. M., Shim, H., Raushel, F. M. & Holden, H. M. (2001) High resolution X-ray structures of different metal-substituted forms of phosphotriesterase from Pseudomonas diminuta. Biochemistry 40:2712-2722.[Medline]

36. Thoden, J. B., Phillips, G. N., Jr, Neal, T. M., Raushel, F. M. & Holden, H. M. (2001) Molecular structure of dihydroorotase: A paradigm for catalysis through the use of a binuclear metal center. Biochemistry 40:6989-6997.[Medline]

37. Thoden, J. B., Marti-Arbona, R., Raushel, F. M. & Holden, H. M. (2003) High-resolution X-ray structure of isoaspartyl dipeptidase from Escherichia coli. Biochemistry 42:4874-4882.[Medline]

38. Wilce, M.C.J., Bond, C. S., Dixon, N. E., Freeman, H. C., Guss, J. M., Lilley, P. E. & Wilce, J. A. (1998) Structure and mechanism of a proline-specific aminopeptidase from Escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 95:3472-3477.[Abstract/Free Full Text]

39. Maher, M. M., Ghosh, M., Grunden, A. M., Menon, A. L., Adams, M.W.W., Freeman, H. C. & Guss, J. M. (2004) Structure of the prolidase from Pyrococcus furiosus. Biochemistry 43:2771-2783.[Medline]

40. Tu, C., Silverman, D. N., Forsman, C., Jonsson, B.-H. & Lindskog, S. (1989) Role of histidine 64 in the catalytic mechanism of human carbonic anhydrase II studied with a site-specific mutant. Biochemistry 28:7913-7918.[Medline]

41. Daghigh, F., Fukuto, J. M. & Ash, D. E. (1994) Inhibition of rat liver arginase by an intermediate in NO biosynthesis, NG-hydroxy-L-arginine: Implications for the regulation of nitric oxide biosynthesis by arginase. Biochem. Biophys. Res. Commun. 202:174-180.[Medline]

42. Boucher, J.-L., Custot, J., Vadon, S., Delaforge, M., Lepoivre, M., Tenu, J.-P., Yapo, A. & Mansuy, D. (1994) N-Omega-hydroxyl-L-arginine, an intermediate in the L-arginine to nitric oxide pathway, is a strong inhibitor of liver and macrophage arginase. Biochem. Biophys. Res. Commun. 203:1614-1621.[Medline]

43. Hecker, M., Nematollahi, H., Hey, C., Busse, R. & Racke, K. (1995) Inhibition of arginase by NG-hydroxy-L-arginine in alveolar macrophages: Implications for the utilization of L-arginine for nitric oxide synthesis. FEBS Lett. 359:251-254.[Medline]

44. Chenais, B., Yapo, A., Lepoivre, M. & Tenu, J.-P. (1993) N{omega}-Hydroxy-L-arginine, a reaction intermediate of nitric oxide biosynthesis, induces cytostasis in human and murine tumor cells. Biochem. Biophys. Res. Commun. 196:1558-1565.[Medline]

45. Buga, G. M., Singh, R., Pervin, S., Rogers, N. E., Schmitz, D. A., Jenkinson, C. P., Cederbaum, S. D. & Ignarro, L. J. (1996) Arginase activity in endothelial cells: Inhibition by NG-hydroxy-L-arginine during high-output NO production. Am. J. Physiol. 271:H1988-H1997.

46. Baggio, R., Emig, F. A., Christianson, D. W., Ash, D. E., Chakder, S. & Ratan, S. (1990) Biochemical and functional profile of a newly developed potent and isozyme-selective arginase inhibitor. J. Pharmacol. Exp. Ther. 290:1409-1416.

47. Cox, J. D., Kim, N. N., Traish, A. M. & Christianson, D. W. (1999) Arginase-boronic acid complex highlights a physiological role in erectile function. Nat. Struct. Biol. 6:1043-1047.[Medline]

48. Colleluori, D. M. & Ash, D. E. (2001) Classical and slow-binding inhibitors of human type II arginase. Biochemistry 40:9356-9362.[Medline]

49. Mori, M & Gotoh, M. (2000) Regulation of nitric oxide production by arginine metabolic enzymes. Biochem. Bipohys. Res. Commun. 275:715-719.

50. Salimuddin, , Nagasaki, A., Gotoh, T., Isobe, H. & Moti, M. (1999) Regulation of the genes for arginase isoforms and related enzymes in mouse macrophages by lipopolysaccharide. Am. J. Physiol. 277:E110-E117.

51. Louis, C. A., Reichner, J. S., Henry, W. L., Mastrofrancesco, B., Gotoh, T., Mori, M. & Albina, J. E. (1998) Distinct arginase isoforms expressed in primary and transformed macrophages: Regulation by oxygen tension. Am. J. Physiol. 274:R775-R782.




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K. Kitowska, D. Zakrzewicz, M. Konigshoff, I. Chrobak, F. Grimminger, W. Seeger, P. Bulau, and O. Eickelberg
Functional role and species-specific contribution of arginases in pulmonary fibrosis
Am J Physiol Lung Cell Mol Physiol, January 1, 2008; 294(1): L34 - L45.
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 Circ. Res.Home page
L. Santhanam, H. K. Lim, H. K. Lim, V. Miriel, T. Brown, M. Patel, S. Balanson, S. Ryoo, M. Anderson, K. Irani, et al.
Inducible NO Synthase Dependent S-Nitrosylation and Activation of Arginase1 Contribute to Age-Related Endothelial Dysfunction
Circ. Res., September 28, 2007; 101(7): 692 - 702.
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 Am. J. Respir. Cell Mol. Bio.Home page
K. Ckless, A. van der Vliet, and Y. Janssen-Heininger
Arginase Modulates NF-{kappa}B Activity via a Nitric Oxide-Dependent Mechanism
Am. J. Respir. Cell Mol. Biol., June 1, 2007; 36(6): 645 - 653.
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 BloodHome page
P. C. Rodriguez, D. G. Quiceno, and A. C. Ochoa
L-arginine availability regulates T-lymphocyte cell-cycle progression
Blood, February 15, 2007; 109(4): 1568 - 1573.
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 Antimicrob. Agents Chemother.Home page
F. Yu, K. Zaleta-Rivera, X. Zhu, J. Huffman, J. C. Millet, S. D. Harris, G. Yuen, X.-C. Li, and L. Du
Structure and Biosynthesis of Heat-Stable Antifungal Factor (HSAF), a Broad-Spectrum Antimycotic with a Novel Mode of Action
Antimicrob. Agents Chemother., January 1, 2007; 51(1): 64 - 72.
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I. Nissim, B. Luhovyy, O. Horyn, Y. Daikhin, I. Nissim, and M. Yudkoff
The Role of Mitochondrially Bound Arginase in the Regulation of Urea Synthesis: STUDIES WITH [U-15N4]ARGININE, ISOLATED MITOCHONDRIA, AND PERFUSED RAT LIVER
J. Biol. Chem., May 6, 2005; 280(18): 17715 - 17724.
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 J. Nutr.Home page
S. M. Morris Jr
Enzymes of Arginine Metabolism
J. Nutr., October 1, 2004; 134(10): 2743S - 2747S.
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