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PubMed2001

Induction of arginases I and II in cornea during herpes simplex virus infection.

Induction of inducible nitric oxide synthase (iNOS) following corneal infection with herpes simplex virus type-1 (HSV-1) generates nitric oxide (NO), an important player in the defense against viral infection. Changes in arginine metabolism during infection are not limited to effects of iNOS but can also involve arginases, which can modulate NO synthesis and produce ornithine for the generation of polyamines and proline. The latter are important molecules involved in tissue damage and repair during inflammation. In this study we determined the responses of arginase I and II in a murine model of HSV-1-induced stromal keratitis (HSK). In the cornea iNOS and arginase II mRNA were co-induced as the initial inflammation developed at 2 days postinfection (p.i.). As stromal keratitis progressed (days 8-15 p.i.) arginase I mRNA was induced tenfold, in contrast to a moderate decrease in arginase II and a loss of iNOS expression. These results suggest that elevated expression of arginase I and II in the cornea at late stages of ocular HSV-1 infection may play a role in lesion expression in HSK.

Animals↗

PubMed2000

High plasma levels of arginine and liver arginase in Kupffer-cell-depleted rats after partial hepatectomy.

BACKGROUND/AIMS: The remnant liver after partial hepatectomy releases arginase into the plasma, which is a reliable indicator of hepatocellular damage. Little information is available on how this release affects arginine plasma levels. We hypothesized that Kupffer cells after partial hepatectomy may prevent further hepatocellular damage, contributing to lower arginase release. The aim of the study was to evaluate the role of Kupffer cells in plasma arginase activity and arginine plasma levels after partial hepatectomy. METHODS: Wag/Rij rats (n=72, 250-275 g) were randomly assigned to receive 1 ml liposome-encapsulated dichloromethylene-diphosphonate in order to eliminate Kupffer cells (DMDP, n=24), 1 ml liposome encapsulated-phosphate buffered saline (PBS, n=24) or 1 ml NaCl 0.9% (NaCl, n=24) intravenously. Forty-eight hours later, all rats had a two-third liver resection. Rats were killed at 0, 24, 48 and 96 h after partial hepatectomy. RESULTS: Arginase plasma activity was higher in the DMDP-treated group compared to NaCl and PBS (both p<0.01, p<0.05, p<0.01 and p<0.05 for 0, 24, 48 and 96 h after partial hepatectomy respectively). Arginine plasma levels increased, but were lower in the DMDP group compared to NaCl and PBS (both p<0.05, 24 h after hepatectomy). CONCLUSION: The study showed that Kupffer cell depletion results in a higher arginase release from the remnant liver after partial hepatectomy, indicating a hepatocellular protective function of Kupffer cells. Despite this arginase release, arginine plasma levels were increased after partial hepatectomy.

Amino Acids↗

PubMedDate not supplied

Arginase acts as an alternative pathway of L-arginine metabolism in experimental colon anastomosis.

L-Arginine is the substrate for the nitric oxide synthase (NOS) pathway that is essential for gastrointestinal wound healing. L-Arginine is also the substrate for the enzyme arginase which metabolizes L-arginine to ornithine and subsequently to proline and polyamines both known to interact in cell proliferation and collagen synthesis. Two distinct isoforms of arginase exist. The temporal expression of the L-arginine metabolism in experimental colon anastomosis was investigated. Male Lewis rats underwent laparotomy. A left-sided colotomy was performed and the colon reanastomosed using 6-0 prolene. Sham operation was performed in controls. On days 2, 5, 10, 14, and 28 after the surgery the anastomosis was excised. The tissue at the anastomosis (ANAST) as well as above and below the anastomosis (PDC) and from sham colon was harvested and analyzed for distinct arginase isoform I (AI) and arginase isoform II (AII) activity, protein and mRNA expression as well as immunohistochemistry. iNOS protein and mRNA expression were investigated in parallel. A mean of 3 to 4 separate rats were analyzed per time point. Statistical analysis was performed by student's t-test, significance was reached when P < 0.05. AI activity, protein, and mRNA expression were significantly upregulated at the anastomosis compared to sham controls and PDC colons at all time points. The maximum was achieved at days 10 to 14 after wounding, and decreased to baseline levels thereafter. Inflammatory cells stained positive for AI. AII protein was not detectable. However RT-PCR showed low baseline expression. iNOS expression was upregulated early but for a shorter time period after wounding and reverted quickly to undetectable levels. In anastomotic healing, AI upregulation suggests a prolonged metabolism of arginine via arginase to polyamines and proline to provide substrate for collagen synthesis and cell proliferation. The functional implication of this arginase pathway further needs to be elucidated.

Anastomosis, Surgical↗

PubMed2001

Mechanistic and metabolic inferences from the binding of substrate analogues and products to arginase.

Arginase is a binuclear Mn(2+) metalloenzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. X-ray crystal structures of arginase complexed to substrate analogues N(omega)-hydroxy-L-arginine and N(omega)-hydroxy-nor-L-arginine, as well as the products L-ornithine and urea, complete a set of structural "snapshots" along the reaction coordinate of arginase catalysis when interpreted along with the X-ray crystal structure of the arginase-transition-state analogue complex described in Kim et al. [Kim, N. N., Cox, J. D., Baggio, R. F., Emig, F. A., Mistry, S., Harper, S. L., Speicher, D. W., Morris, Jr., S. M., Ash, D. E., Traish, A. M., and Christianson, D. W. (2001) Biochemistry 40, 2678-2688]. Taken together, these structures render important insight on the structural determinants of tight binding inhibitors. Furthermore, we demonstrate for the first time the structural mechanistic link between arginase and NO synthase through their respective complexes with N(omega)-hydroxy-L-arginine. That N(omega)-hydroxy-L-arginine is a catalytic intermediate for NO synthase and an inhibitor of arginase reflects the reciprocal metabolic relationship between these two critical enzymes of L-arginine catabolism.

Amino Acid Substitution↗

PubMed2001

Regulation of loblolly pine (Pinus taeda L.) arginase in developing seedling tissue during germination and post-germinative growth.

After seed germination, hydrolysis of storage proteins provides a nitrogen source for the developing seedling. In conifers the majority of these reserves are located in the living haploid megagametophyte tissue. In the developing loblolly pine (Pinus taeda L.) seedling an influx of free amino acids from the megagametophyte accompanies germination and early seedling growth. The major component of this amino acid pool is arginine, which is transported rapidly and efficiently to the seedling without prior conversion. This arginine accounts for nearly half of the total nitrogen entering the cotyledons and is likely a defining factor in early seedling nitrogen metabolism. In the seedling, the enzyme arginase is responsible for liberating nitrogen, in the form of ornithine and urea, from free arginine supplied by the megagametophyte. In this report we investigate how the seedling uses arginase to cope with the large arginine influx. As part of this work we have cloned an arginase cDNA from a loblolly pine expression library. Analysis of enzyme activity data, accumulation of arginase protein and mRNA abundance indicates that increased arginase activity after seed germination is due to de novo synthesis of the enzyme. Our results suggest that arginase is primarily regulated at the RNA level during loblolly pine seed germination and post-germinative growth.

Amino Acid Sequence↗

PubMed2000

Partial purification of a liver-derived tumor cell growth inhibitor that differentially inhibits poorly-liver metastasizing cell lines: identification as an active subunit of arginase.

Organ specific tumor metastasis is thought in part to require the ability of metastatic cells to respond to target-organ-associated growth factors or to avoid the effects of target organ associated growth inhibitors. We previously found that murine and rat liver-conditioned media inhibited the growth of the poorly-liver metastasizing murine RAW117-P large-cell lymphoma cells more than their highly liver-metastasizing RAW117-H10 counterparts. Using a six step chromatographic procedure, the major RAW117-P cell proliferation inhibitor from a rat liver extract was purified. The factor displayed a Mr of approximately 35,000 and an isoelectric point > 8.5. This material inhibited the growth of many cells at high concentration; however, in dose-response studies it displayed a higher IC50 for highly-liver metastatic murine RAW117-H10 lymphoma and human KM12SM colon carcinoma cells than for their poorly-liver metastatic counterparts. Attempts to identify the growth inhibitor led to the supplementation of tissue culture inhibitor assays with various components, including excess amino acids, and this was found to completely abrogate the factor's activity. Specifically, the addition of excess arginine resulted in the complete cellular recovery from inhibitor exposure. This tentatively identified the liver growth inhibitor as the enzyme arginase, a Mr approximately 10,000 multisubunit protein. A microtiter plate-based assay for arginase was developed and the purification repeated using human liver as a source of activity and the human KM12C colon carcinoma line as a target. The growth inhibitory and arginase activities were found to co-purify, identifying the factor as arginase. Highly-metastatic cells displayed no ability to preferentially inactivate or inhibit the activity of arginase, but they did they display slightly greater amounts of intracellular arginine. The liver is a major site of arginase localization as the enzyme is required for the functioning of the urea cycle. The results indicate that certain liver-colonizing tumor cells can escape, to a degree, the proliferation-damping effects of arginine depletion.

Animals↗

PubMed1973

Purification and properties of arginase of rat kidney.

l-Arginase from rat kidney was partially purified and some properties were compared with those of l-arginase of rat liver. The kidney enzyme was firmly bound to the mitochondrial fraction and after solubilization required arginine or an unknown factor in tissue extracts for stabilization after dialysis. The two enzymes differed also in stability with respect to acetone treatment, heating or freezing. In further contrast with liver arginase, arginase from kidney was not adsorbed to CM-cellulose at pH7.5 and its activity was not increased by incubation with Mn(2+). Other differences were seen in relative specificities for substrates, ratio of hydrolysis rates with high and low concentrations of arginine and effects of certain inhibitors. Antisera prepared to pure liver arginase did not cross-react with partially purified kidney arginase.

Acetone↗

PubMed2005

Crystal structure of human arginase I at 1.29-A resolution and exploration of inhibition in the immune response.

Human arginase I is a potential target for therapeutic intervention in diseases linked to compromised l-arginine homeostasis. Here, we report high-affinity binding of the reaction coordinate analogue inhibitors 2(S)-amino-6-boronohexanoic acid (ABH, Kd = 5 nM) and S-(2-boronoethyl)-l-cysteine (BEC, Kd = 270 nM) to human arginase I, and we report x-ray crystal structures of the respective enzyme-inhibitor complexes at 1.29- and 1.94-A resolution determined from crystals twinned by hemihedry. The ultrahigh-resolution structure of the human arginase I-ABH complex yields an unprecedented view of the binuclear manganese cluster and illuminates the structural basis for nanomolar affinity: bidentate inner-sphere boronate-manganese coordination interactions and fully saturated hydrogen bond networks with inhibitor alpha-amino and alpha-carboxylate groups. These interactions are therefore implicated in the stabilization of the transition state for l-arginine hydrolysis. Electron density maps also reveal that active-site residue H141 is protonated as the imidazolium cation. The location of H141 is such that it could function as a general acid to protonate the leaving amino group of l-ornithine during catalysis, and this is a revised mechanistic proposal for arginase. This work serves as a foundation for studying the structural and chemical biology of arginase I in the immune response, and we demonstrate the inhibition of arginase activity by ABH in human and murine myeloid cells.

Aminocaproates↗

PubMed2006

Modulating role of estradiol on arginase II expression in hyperlipidemic rabbits as an atheroprotective mechanism.

We evaluated the effects of a 0.5% cholesterol-enriched diet (HCD) on nitric-oxide synthase (NOS) and arginase expression and the modulating role of 17beta-estradiol (E(2)) on this phenomenon. Thirty oopherectomized rabbits were divided into three groups and treated for 15 weeks. Group I received normal chow; group II, HCD; and group III, HCD plus E(2) pellets. Animals in group II showed an increase in plasma lipids, and they demonstrated atheromatous lesions as well as expression of arginase I and II accompanied by a significant number of BrdU-positive cells in endothelial cells and intimal muscle cells, suggestive of an increase in cellular proliferation. There was significant expression of inducible NOS and increased staining of nitrotyrosine-positive areas. These were not observed in group I animals. In both groups, E(2) levels were low. In group III animals, E(2) supplementation led to a decrease in atheromatous lesions and BrdU-positive cells and reduced expression of both inducible NOS and arginase I and II accompanied by a decrease in nitrotyrosine staining. E(2) levels were increased. Our results suggest that E(2) was responsible for these effects, despite the animals being hyperlipidemic, similar to those in group II. Because arginase is responsible for cell proliferation by converting l-arginine to polyamines, our results indicate that expression of arginase may play an important role in cellular proliferation in atherosclerosis, and inhibition of arginase expression by E(2) may be another potential mechanism in attenuating atherogenesis.

Animals↗

PubMed2006

Melatonin reduces nitric oxide via increasing arginase in rhabdomyolysis-induced acute renal failure in rats.

Melatonin, the chief secretory product of the pineal gland, is a direct free radical scavenger. In addition to a direct scavenging effect on nitric oxide (NO), its inhibitory effect on nitric oxide synthase (NOS) activity has been also reported. L-arginine is the substrate for both NOS and arginase. It has been suggested that there is a competition between arginase and NOS and that they control each other's level. NO plays a crucial role in the pathogenesis of myoglobinuric acute renal failure (ARF). In this study, the authors aimed to investigate the effect of melatonin on arginase activity, ornithine, and NO levels on the myoglobinuric ARF formed by intramuscular (i.m.) injection of hypertonic glycerol. Forty rats were randomly divided into four groups. Rats in SHAM were given saline, and those in groups ARF, ARF-M5, and ARF-M10 were injected with glycerol (10 mL/kg) i.m. Concomitant and 24 hours after glycerol injection for the ARF-M5 and ARF-M10 groups, melatonin--5 mg/kg and 10 mg/kg, respectively--was administrated intraperitoneally. Forty-eight hours after the glycerol injection, kidneys of the rats were taken under anesthesia. Arginase activity, ornithine, and NO levels in the kidney tissue were determined. Melatonin had an increasing effect on kidney tissue arginase activities and ornithine levels while decreasing NO concentration. It is possible that besides the direct scavenging effect, the stimulatory effect of melatonin on arginase activity may result in an inhibition of NOS activity and, finally, a decrease in the kidney NO level.

Acute Kidney Injury↗

PubMed2004

How could aortic arginase activity enhancement be involved in DOCA-salt hypertension?

This study was to examine whether the increase in aortic arginase activity observed in DOCA-salt hypertensive rats is involved in the mechanism of physiological hypertension by participating to vessel hypertrophy and/or to the impairment of endothelium-dependent relaxation to acethylcholine. We measured polyamine content and relaxation-response to acethylcholine in aortic rings isolated from control and DOCA-salt treated Sprague-Dawley rats after in vitro modification of arginase activity. Polyamine content was significantly increased in aorta from DOCA-salt hypertensive rats compared with controls. In the normotensive rats, the addition of L-valine (an inhibitor of arginase) decreased the relaxation response to acethylcholine whereas the addition of arginase increased the relaxation dependent response. On the contrary, in DOCA-salt hypertensive rats, the addition of L-valine or of arginase did not change the endothelium dependent relaxation. The results obtained suggest that the increase in aortic arginase activity in DOCA-salt hypertension could contribute to vascular hypertrophy but not to the impairment of endothelium-dependent relaxation.

Acetylcholine↗

PubMed1958

The arginase and rhodanese activities of certain cell strains after long cultivation in vitro.

The activities of the enzymes arginase and rhodanese were examined in homogenates of 13 mouse cell strains and 2 human cell strains after long cultivation of the cells in vitro. Three strains of mouse liver origin showed both high arginase and rhodanese activities in keeping with activities of the tissue of origin. Two strains of cells of human epithelial origin, HeLa and epidermis, were found to have high rhodanese activity but low arginase activity, the skin being almost devoid of it. Seven mouse fibroblast strains or substrains had moderate rhodanese activity and all except one of the strains had low arginase activity. Two of the fibroblast strains tested, NCTC 1745 and NCTC 2050, were derived from a single cell of a tumor appearing after injection of the high tumor producing strain NCTC 1742 into a mouse. The strain 1745 had 20 times and the strain 2050 had 400 times the arginase activity of the parent strain of cells. The findings imply a considerable biochemical variation in the three strains. Three mouse mammary carcinoma clones were devoid of arginase activity, but had considerable rhodanese activity.

Amidohydrolases↗

PubMed2002

Expression and regulation of the gene for arginase I in mouse salivary glands: requirement of CCAAT/enhancer-binding protein alpha for the expression in the parotid gland.

Arginase in salivary glands is potentially involved in the synthesis of proline, glutamate, and polyamines that play specific physiological roles in the glands, and also in depletion of arginine in the oral cavity to protect teeth from microorganisms. We detected protein and mRNA for the type I isoform of arginase in mouse salivary glands. Enzymes of the arginine-biosynthetic pathway were also detected. Immunohistochemical analysis revealed that arginase I was enriched in the striated duct, and was also present in the acinus, demilune and granulated duct. Mice with targeted disruption of the gene for C/EBPalpha, which is a transcription factor essential for expression of the arginase I gene in the liver, showed dramatically reduced immunoreactivity for arginase I in the parotid gland but not in the submandibular and sublingual glands. Therefore, C/EBPalpha is specifically required for expression of the arginase I gene in the parotid gland.

Animals↗

PubMed2004

Involvement of increased arginase activity in impaired cavernous relaxation with aging in the rabbit.

PURPOSE: Arginase shares L-arginine as a common substrate with nitric oxide (NO) synthase (NOS). We examined whether increased arginase activity is involved in impaired cavernous relaxation with aging in the rabbit. MATERIALS AND METHODS: Young adult (3 to 5 months old) and aged (36 to 48 months old) rabbits were used for the current experiments. Cavernous tissues obtained from the 2 groups were processed for isometric tension experiments, cyclic guanosine monophosphate determination, measurements of NOS and arginase activities, endogenous methylarginines and L-arginine. RESULTS: Carbachol (CCh) produced an endothelium dependent and NO mediated relaxation that was significantly impaired in aged cavernous specimens without change in sodium nitroprusside induced relaxation. Stimulated cyclic guanosine monophosphate production with CCh was significantly decreased in aged cavernous specimens. Ca dependent NOS was predominant in rabbit cavernous specimens. Ca dependent and independent NOS activities remained unchanged in the 2 groups. The tissue contents of N-monomethyl-L-arginine and asymmetric N,N-dimethyl-L-arginine as endogenous NOS inhibitors, symmetrical N,N'-dimethyl-L-arginine and L-arginine as a substrate of NOS were decreased in aged cavernous specimens. Arginase activity was significantly higher in aged cavernous specimens. Impaired CCh induced relaxation in aged cavernous specimens was normalized in the presence of N-hydroxy-L-arginine as an arginase inhibitor or by the supplementation of excess L-arginine. CONCLUSIONS: These results strongly suggest that impaired endothelium dependent and NO mediated cavernous relaxation with aging is due to decreased NO production, which would result from increased arginase activity and probably from decreased L-arginine content.

Aging↗

PubMed2005

Modulation of erythrocyte arginase activity in sickle cell disease patients during hydroxyurea therapy.

An elevated erythrocyte arginase activity with a corresponding decrease in nitric oxide (NO) level has been implicated in the pathophysiology of sickle cell disease (SCD). Recent studies have shown that hydroxyurea (HU) increases the production of NO, which increases the soluble guanylate cyclase activity and fetal haemoglobin (HbF) synthesis. To study the effects of HU on the arginase and nitric oxide synthase (NOS) activities in SCD patients, we compared levels of arginase activity and NO metabolites in red blood cells and plasma, respectively, from 23 patients with SCD (HbSS) receiving HU therapy, with those of 12 SCD patients not receiving HU treatment. Patients on HU therapy showed significantly lower arginase activity than that of HbSS patients not on HU therapy (1.36+/-0.2 U/10(8) cells vs. 3.31+/-0.29 U/10(8) cells). NOS activity was higher in patients on HU therapy than in untreated patients (0.72+/-0.4 nmol/ml/min vs. 0.35+/-0.15 nmol/ml/min, P<0.05). Among the HU-treated patients, the decreased level of arginase activity correlated (r=0.71) with HbF level as well as the mean corpuscular haemoglobin content. These data suggest that one of the beneficial effects of HU in vivo may involve the regulation of arginase activity and a concomitant induction of NOS activity, which may lead to an increased production of NO. The outcome of this study may lead to the development of improved NO-based treatments for SCD.

Adolescent↗

PubMed1992

Arginine catabolism in the phototrophic bacterium Rhodobacter capsulatus E1F1. Purification and properties of arginase.

The phototrophic bacterium Rhodobacter capsulatus E1F1 grew with L-arginine or L-homoarginine as nitrogen source under light/anaerobiosis. However, when L-arginine was used as the only source of both carbon and nitrogen, the bacterium exhibited weak growth levels and the excess of nitrogen was excreted to the medium as ammonia. By contrast, L-ornithine was used under phototrophic conditions as either nitrogen or carbon source. Other compounds of the arginine catabolic pathways, such as putrescine or proline, also supported phototrophic growth of this bacterium. Under heterotrophic/dark conditions, R. capsulatus always showed a low growth rate with those nitrogen compounds. Cells growing on media containing L-arginine, L-homoarginine or L-ornithine induced an Mn(2+)-dependent arginase activity regardless of the presence of ammonium ions and other readily utilizable nitrogen sources. Arginase activity was strongly inhibited by Zn2+, Cu2+, borate, L-cysteine, L-ornithine and gamma-guanidinobutyrate. Mercurials also inactivated arginase, the activity being partially restored by the presence of thiols. Arginase was purified to electrophoretic homogeneity and found to consist of four identical subunits of 31 kDa. The molecular parameters and kinetic constants of arginase from R. capsulatus E1F1 resembled those previously described for the Saccharomyces cerevisiae enzyme rather than those of bacterial arginases.

Arginase↗

PubMed1996

CCAAT/enhancer-binding protein beta (C/EBP beta) binds and activates while hepatocyte nuclear factor-4 (HNF-4) does not bind but represses the liver-type arginase promoter.

In an attempt to elucidate the mechanism governing liver-specific transcription of the arginase gene, we previously detected two protein-binding sites designated footprint areas A and B at positions around--90 and --55 bp, respectively, relative to the transcription start site of the rat arginase gene. Based on the finding that area A was bound by a liver-selective factor(s) related to CCAAT/enhancer-binding protein (C/EBP), we performed cotransfection assay and showed that C/EBP family members and a related factor, albumin D-element-binding protein (DBP) stimulate transcription from the arginase promoter. In addition to area A, a recombinant C/EBP beta protein bound to area B, which appeared to be primarily responsible for activation by C/EBPs. We unexpectedly found that the arginase promoter activity stimulated by C/EBPs and DBP was repressed by another liver-enriched transcription factor, hepatocyte nuclear factor-4 (HNF-4). Analysis of chimeras formed between the arginase promoter and the herpes simplex virus thymidine kinase promoter allowed us to delimit the negative HNF-4-responsive element into the region overlapping with footprint area B. However, no apparent binding of HNF-4 was observed in this negative element. We speculate that HNF-4 is involved in fine regulation of the arginase gene in the liver or shutdown of the gene in nonhepatic tissues without direct binding to the promoter region.

Animals↗

PubMed1978

Oxygen and nitrate in utilization by Bacillus licheniformis of the arginase and arginine deiminase routes of arginine catabolism and other factors affecting their syntheses.

Bacillus licheniformis has two pathways of arginine catabolism. In well-aerated cultures, the arginase route is present, and levels of catabolic ornithine carbamoyltransferase were low. An arginase pathway-deficient mutant, BL196, failed to grow on arginine as a nitrogen source under these conditions. In anaerobiosis, the wild type contained very low levels of arginase and ornithine transaminase. BL196 grew normally on glucose plus arginine in anaerobiosis and, like the wild type, had appreciable levels of catabolic transferase. Nitrate, like oxygen, repressed ornithine carbamoyltransferase and stimulated arginase synthesis. In aerobic cultures, arginase was repressed by glutamine in the presence of glucose, but not when the carbon-energy source was poor. In anaerobic cultures, ammonia repressed catabolic ornithine carbamoyltransferase, but glutamate and glutamine stimulated its synthesis. A second mutant, derived from BL196, retained the low arginase and ornithine transaminase levels of BL196 but produced high levels of deiminase pathway enzymes in the presence of oxygen.

Ammonia↗