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PubMed2004

Decreased arginine bioavailability and increased serum arginase activity in asthma.

Recent studies suggest that a nitric oxide (NO) deficiency and elevated arginase activity may play a role in the pathogenesis of asthma. Although much attention has been directed toward measurements of exhaled NO in asthma, no studies to date have evaluated levels of plasma arginase or arginine, the substrate for NO production, in patients with asthma. This study, therefore, measured amino acid levels, arginase activity, and nitric oxide metabolites in the blood of patients with asthma, as well as NO in exhaled breath. Although levels of virtually all amino acids were reduced, patients with asthma exhibited a striking reduction in plasma arginine levels compared with normal control subjects without asthma (45 +/- 22 vs. 94 +/- 29 microM, p < 0.0001), and serum arginase activity was elevated (1.6 +/- 0.8 vs. 0.5 +/- 0.3 micromol/ml/hour, asthma vs. control, p < 0.0001). High arginase activity in patients with asthma may contribute to low circulating arginine levels, thereby limiting arginine bioavailability and creating a NO deficiency that induces hyperreactive airways. Addressing the alterations in arginine metabolism may result in new strategies for treatment of asthma.

Adolescent↗

PubMed2003

Widespread expression of arginase I in mouse tissues. Biochemical and physiological implications.

Arginase I (AI), the fifth and final enzyme of the urea cycle, detoxifies ammonia as part of the urea cycle. In previous studies from others, AI was not found in extrahepatic tissues except in primate blood cells, and its roles outside the urea cycle have not been well recognized. In this study we undertook an extensive analysis of arginase expression in postnatal mouse tissues by in situ hybridization (ISH) and RT-PCR. We also compared arginase expression patterns with those of ornithine decarboxylase (ODC) and ornithine aminotransferase (OAT). We found that, outside of liver, AI was expressed in many tissues and cells such as the salivary gland, esophagus, stomach, pancreas, thymus, leukocytes, skin, preputial gland, uterus and sympathetic ganglia. The expression was much wider than that of arginase II, which was highly expressed only in the intestine and kidney. Several co-localization patterns of AI, ODC, and OAT have been found: (a) AI was co-localized with ODC alone in some tissues; (b) AI was co-localized with both OAT and ODC in a few tissues; (c) AI was not co-localized with OAT alone in any of the tissues examined; and (d) AI was not co-localized with either ODC or OAT in some tissues. In contrast, AII was not co-localized with either ODC or OAT alone in any of the tissues studied, and co-localization of AII with ODC and OAT was found only in the small intestine. The co-localization patterns of arginase, ODC, and OAT suggested that AI plays different roles in different tissues. The main roles of AI are regulation of arginine concentration by degrading arginine and production of ornithine for polyamine biosynthesis, but AI may not be the principal enzyme for regulating glutamate biosynthesis in tissues and cells.

Animals↗

PubMed2006

Suppression of T-cell functions by human granulocyte arginase.

Chronic inflammation is accompanied by impaired T-cell immunity. In the mouse, myeloid cell-associated arginase accounts for the suppression of immune reactivity in various models of tumor growth and chronic infections. Here we show that arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions. Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. This T-cell phenotype is due to arginase-mediated depletion of arginine in the T-cell environment, which leads to CD3zeta chain down-regulation but does not alter T-cell viability. Our study therefore demonstrates that human granulocytes possess a previously unanticipated immunosuppressive effector function. Human granulocyte arginase is a promising pharmacologic target to reverse unwanted immunosuppression.

Arginase↗

PubMed2004

Testosterone down-regulates ornithine aminotransferase gene and up-regulates arginase II and ornithine decarboxylase genes for polyamines synthesis in the murine kidney.

The enzymes ornithine aminotransferase (OAT) and ornithine decarboxylase (ODC) share L-ornithine as a common substrate and arginase II produces this amino acid. In the murine kidney, testosterone induced ODC gene expression and polyamine production, but it is unknown how OAT gene is expressed under androgen treatment. These experiments were designed to study the influence of testosterone on the renal expression of OAT gene. Pharmacological and physiological doses of testosterone were injected into female and castrated male mice. Total RNA and soluble proteins extracted from whole kidneys were analyzed by Northern and Western blots, respectively. The results clearly indicate that pharmacological doses of testosterone simultaneously down-regulated the level of OAT protein and up-regulated the expression of arginase II and ODC genes. Variations of the levels of OAT protein and arginase II mRNA and protein were strongly correlated with testosteronemia. Orchidectomy increased the renal level of OAT protein and decreased that of ODC and arginase II. These effects were reversed by injecting a physiological dose of testosterone into castrated male mice. In conclusion, OAT and ODC genes are inversely regulated by testosterone in the mouse kidney. Consequently, in kidneys of testosterone-treated mice, L-arginine-derived ornithine produced by arginase II might be preferentially used by ODC for putrescine production rather than by OAT. This metabolic fate of L-ornithine was facilitated by decreasing OAT gene expression. In contrast, in female and castrated male mice devoided of testosterone, OAT gene is highly expressed and L-ornithine is converted into L-glutamate.

Androgens↗

PubMed1994

Immunological identity of the two different molecular mass constitutive subunits of liver arginase.

A detailed understanding of the regulatory mechanisms of arginase in the cell will depend on the clarification of the origin of the two different molecular mass subunits and on the arrangements of them to constitute the native enzyme. Here, we show the immunological recognition of the 39.5 and 37.0 kDa subunits of arginase by antibodies against both subunits. We also find that the subunit stoichiometry (39.5 kDa: 37.0 kDa) present in purified arginase preparations as well as in fresh isolated microsomes and cytoplasm corresponds to 3:1, indicating high prevalence of a constant arrangement of the constitutive subunits of arginase. These findings represent evidence for a limited posttranscriptional or posttranslational modification of only a fraction of the synthesized arginase in liver.

Animals↗

PubMed1985

Human salivary arginase and its deficiency in argininaemia.

Arginase from normal human mixed saliva was characterized. The enzyme was completely activated after a preincubation of 20 min at 55 degrees C and a Mn2+ final concentration of 5 mmol/l. The pH optimum was 9.6-9.8, and the Km for L-arginine was 4.2 +/- 0.7 mmol/l. In normal saliva only one form was found, which was chromatographically identical with the cationic form of arginase in liver and blood cells. Salivary arginase was completely precipitated by rabbit antiserum against human liver arginase. Arginase activity was not detectable in the saliva of patients suffering from argininaemia. Enzyme activities in the saliva of the heterozygous parents and the unaffected daughter were 0.08, 0.07 and 0.12 U/mg protein, respectively, whereas the activities in the saliva of 60 healthy adults and 8 children were 0.17 +/- 0.11 and 0.16 +/- 0.06 U/mg protein, respectively.

Adolescent↗

PubMed2006

Arginase 1 regulation of nitric oxide production is key to survival of trophic factor-deprived motor neurons.

When deprived of trophic factors, the majority of cultured motor neurons undergo nitric oxide-dependent apoptosis. However, for reasons that have remained unclear, 30-50% of the motor neurons survive for several days without trophic factors. Here we hypothesize that the resistance of this motor neuron subpopulation to trophic factor deprivation can be attributed to diminished nitric oxide production resulting from the activity of the arginine-degrading enzyme arginase. When incubated with nor-N(G)-hydroxy-nor-L-arginine (NOHA), the normally resistant trophic factor-deprived motor neurons showed a drop in survival rates, whereas trophic factor-treated neurons did not. NOHA-induced motor neuron death was inhibited by blocking nitric oxide synthesis and the scavenging of superoxide and peroxynitrite, suggesting that peroxynitrite mediates NOHA toxicity. When we transfected arginase 1 into motor neurons to see whether it alone could abrogate trophic factor deprivation-induced death, we found that its forced expression did indeed do so. The protection afforded by arginase 1 expression is reversed when cells are incubated with NOHA or with low concentrations of nitric oxide. These results reveal that arginase acts as a central regulator of trophic factor-deprived motor neuron survival by suppressing nitric oxide production and the consequent peroxynitrite toxicity. They also suggest that the resistance of motor neuron subpopulations to trophic factor deprivation may result from increased arginase activity.

Animals↗

PubMed1992

Molecular genetic study of human arginase deficiency.

We have explored the molecular pathology in 28 individuals homozygous or heterozygous for liver arginase deficiency (hyperargininemia) by a combination of Southern analysis, western blotting, DNA sequencing, and PCR. This cohort represents the majority of arginase-deficient individuals worldwide. Only 2 of 15 homozygous patients on whom red blood cells were available had antigenically cross-reacting material as ascertained by western blot analysis using anti-liver arginase antibody. Southern blots of patient genomic DNAs, cut with a variety of restriction enzymes and probed with a near-full-length (1,450-bp) human liver arginase cDNA clone, detected no gross gene deletions. Loss of a TaqI cleavage site was identified in three individuals: in a homozygous state in a Saudi Arabian patient at one site, at a different site in homozygosity in a German patient, and in heterozygosity in a patient from Australia. The changes in the latter two were localized to exon 8, through amplification of this region by PCR and electrophoretic analysis of the amplified fragment after treatment with TaqI; the precise base changes (Arg291X and Thr290Ser) were confirmed by sequencing. It is interesting that the latter nucleotide variant (Thr290Ser) was found to lie adjacent to the TaqI site rather than within it, though whether such a conservative amino acid substitution represents a true pathologic mutation remains to be determined. We conclude that arginase deficiency, though rare, is a heterogeneous disorder at the genotypic level, generally encompassing a variety of point mutations rather than substantial structural gene deletions.

Amino Acid Sequence↗

PubMed1990

Lymphocyte arginase activity in leprosy--a preliminary report.

Arginase activity was estimated in serum and lymphocytes of 22 healthy controls and 50 untreated leprosy patients across the spectrum. The patients included 21 lepromatous/borderline lepromatous (LL/BL); 20 borderline borderline/borderline tuberculoid (BB/BT) and 9 tuberculoid (TT) cases. Mean serum arginase levels were 1.51 +/- 0.43, 1.41 +/- 0.43, 1.24 +/- 0.43 and 1.10 +/- 0.026 mu moles/min/ml in LL/BL, BB/BT and TT patients and healthy controls respectively. The lymphocyte arginase activity showed a similar increasing trend from TT to LL/BL. The mean lymphocyte arginase levels were 0.87 +/- 0.31 mu moles/min/10(6) cells in healthy controls and 1.81 +/- 0.40, 2.54 +/- 0.60 and 5.48 +/- 0.56 mu moles/min/10(6) cells in TT, BB/BT and LL/BL patients respectively. The increasing trend specially in lymphocyte arginase levels across the spectrum of leprosy correlated with the degree of impairment in the protective cell mediated immune response and also the extent of disease. The role of these pathophysiological alterations in relation to defect in immune response calls for investigation.

Arginase↗

PubMed1989

Measurement of erythrocyte arginase activity and the effect of lead on the activity in vitro.

Measurement of arginase activity made by varying the arginine concentration and the reaction time clarified that the amount of urea formed by arginase peaked at the substrate concentration of 150 mmol/l, and increased linearly by 20 minutes. By using discs punched out from a dried blood filter paper prepared from identical human blood sample, the amount of formed urea showed linear increase up to 160 U/g.Hb. The coefficients of variation in ten measurements were 6.1% for the mean activity of 46.2 U/g.Hb and 2.1% for 152.1 U/g.Hb. No decreases in arginase activity were observed when two different dried blood filter papers were left for one week at room temperature. Intact erythrocytes were treated with various concentrations of lead from 0 to 5 mumols/l and their arginase activities were measured. The activity did not elevate linearly with the rise of lead concentration, but an almost diphasic elevation was observed. The arginase activity of erythrocytes treated with 5 mumols/l of lead was higher than that for untreated ones by 32%.

Arginase↗

PubMed1989

Tissue-specific differential modulation of arginase and ornithine aminotransferase by hydrocortisone during various developmental stages of the rat.

The activities and regulatory patterns of arginase and ornithine aminotransferase (OAT) of the liver (a mitotic tissue) and kidney cortex (a post-mitotic tissue) of immature, adult, and senescent male rats were studied. The activities of the liver enzymes were highest in the immature rat and decreased gradually with age. However, in the kidney cortex, the activity of arginase was highest and decreased significantly thereafter while that of OAT shows no significant change throughout the life span of the rat. Further, the activity of kidney cortex arginase was approximately 1/20th of that of the liver enzyme. Adrenalectomy and hydrocortisone treatments altered the activity of arginase in both tissues and that of OAT in the liver only. However, the kidney cortex OAT was not responsive towards these treatments. Actinomycin D inhibited the hydrocortisone-mediated induction of arginase of both the liver and kidney cortex and that of the liver OAT.

Adrenalectomy↗

PubMed1986

Regulation of arginine metabolism in Saccharomyces cerevisiae. Association of arginase and ornithine transcarbamoylase.

Association of arginase and ornithine transcarbamoylase (OTCase) has been proposed to play an essential role in the regulation of arginine metabolism in Saccharomyces cerevisiae (Wiame, J.-M. (1971) Curr. Top. Cell. Reg. 4, 1-39). In this report multienzyme complex formation is directly demonstrated in the presence of the active-site ligands for OTCase and arginase. Using equilibrium sedimentation, a dissociation constant for complex formation was determined to be 2.3 X 10(-8) M in the presence of ornithine and agmatine, active-site ligands for OTCase and arginase, respectively. A molecular stoichiometry in the complex of one molecule of OTCase to one molecule of arginase was verified using transmission electron microscopy. The dimensions of the complex were determined by negative staining and rotary and unidirectional shadowing techniques to be 102 A wide by 81 A high. These dimensions are quantitively consistent with dimensions of the individual enzymes (Duong, L. T., Eisenstein, E., Green, S. M., Ornberg, R. L., and Hensley, P. (1986) J. Biol. Chem. 261, 12807-12813). The enzymatic activity of OTCase is virtually completely inhibited when associated with arginase, reflecting the dramatic modulation of enzyme activity as a consequence of the acquisition of quaternary structure in this multienzyme complex.

Arginase↗

PubMedDate not supplied

[Comparative study of the action of O-phenanthroline metal complexes and a number of other compounds on the activity of brain arginase isoforms].

Two isoforms of arginase were isolated from rat brain tissue: isoform I-adsorbed on CM-Sephadex and isoform II-unadsorbed on the sorbent. In samples with arginine as a substrate Km values for isoforms I and II constituted 1.7 X 10(-3) M and 3.8 X 10(-3) M, respectively. EDTA and o-phenanthroline inhibited these both brain arginase isoforms. As shown in experiments with o-phenanthroline metal complex affecting the brain arginase activity some copper complexes were able to inhibit most effectively the activity of the isoform II. Activity of both these isoforms was inhibited also by dithiothreitol, proline and acetaldehyde. Complexes of o-phenanthroline with Co2+ and Fe2+ inhibited only slightly the activity of the isoform II and did not affect the isoform I. These data showed that brain arginase isoforms were markedly distinct in their properties from the ureotelic liver tissue arginase.

Animals↗

PubMed1978

Liver arginase activity and plasma urea-nitrogen in steers fed diets containing different levels of protein.

Seventeen Charolais-Hereford crossbred steers averaging 220.0 kg in weight initially were randomly allotted to three treatments and fed diets containing (A) 9%, (B) 11%, or (C) 13% protein ad libitum in individual pens for 238 days. Liver samples were taken by aspiration biopsy on days 47 (sampling I) and 238 (sampling II) for arginase assay. Blood samples were taken by jugular puncture at these same times for plasma urea-nitrogen analysis. Mean hepatic arginase activities (mumole urea/mg protein/hr) of steers fed the three diets at sampling I were: (A) 224.8, (B) 327.8 and (C) 333.3. The activities of B and C were significantly (P less than .05) higher than A. Plasma urea-N levels at this same time averaged: (A) 4.44, (B) 8.55 and (C) 12.22 mg/100 ml, and were significantly different (P less than .01) from each other. Arginase activities at sampling II were: (A) 240.6, (B) 305.2 and (C) 353.0. A differed significantly (P less than .05) from C. Plasma urea-N at this time averaged: (A) 8.69, (B) 10.72 and (C) 15.00 mg/100 ml, and C was significantly (P less than 5.0) higher than A and B. These data suggest that in the bovine hepatic arginase activity levels increase with increases in dietary protein and that similar patterns in activity are maintained after feeding for an extended period of time. The increased arginase activity was accompanied by increased plasma urea-nitrogen.

Animal Nutritional Physiological Phenomena↗

PubMed1980

Stimulation of peritoneal cell arginase by bacterial lipopolysaccharides.

The conditions under which bacterial endotoxins stimulate arginase production in mouse peritoneal macrophages have been defined. Both lipid-A and lipid-A-associated protein are potent activators. Fetal calf serum and normal mouse serum enhance macrophage arginase levels in the presence and absence of lipopolysaccharide (LPS). LPS in the amount of 10(-1) microgram/ml represents a maximal stimulus for macrophage arginase production and release. Thioglycollate-elicited peritoneal cells have increased arginase activity, compared with resident cells. This activity can be stimulated further by the addition of LPS. Arginase levels may alter the outcome of in vitro immunologic processes by depleting arginine and may also serve as a useful indicator of the state of activation of macrophages.

Animals↗

PubMed1981

[Cerebral and hepatic arginase and polyamines in the mechanisms of the protective effect of arginine in hyperoxia].

The effect of protective concentrations of arginine on the arginase activity and the content of rat brain and liver spermidine and spermine was studied under hyperoxia (6 atmospheres). Intraperitoneal injection of arginine to intact animals increases the arginase activity and the brain content of spermidine and spermine by 15, 19 and 25%, respectively. The liver arginase activity rises by 55%, while the level of the polyamines remains almost unchanged. Arginine injection before hyperoxic exposure prevents the significant lowering of the arginase activity and polyamine content seen in the unprotected animals. The relationship between the arginase activity and the polyamine level in the brain and liver is discussed with emphasis on arginine efficacy as protective agent in hyperoxia.

Animals↗

PubMed1994

Purification of arginase from Aspergillus nidulans.

Arginase (EC 3.5.3.1) of Aspergillus nidulans, the enzyme which enables the fungus to use arginine as the sole nitrogen source was purified to homogeneity. Molecular mass of the purified arginase subunit is 40 kDa and is similar to that reported for the Neurospora crassa (38.3 kDa) and Saccharomyces cerevisiae (39 kDa) enzymes. The native molecular mass of arginase is 125 kDa. The subunit/native molecular mass ratio suggests a trimeric form of the protein. The arginase protein was cleaved and partially sequenced. Two out of the six polypeptides sequenced show a high degree of homology to conserved domains in arginases from other species.

Amino Acid Sequence↗

PubMed1977

[Urea concentration and arginase activity in the organs of rats during acclimatization to cold].

Arginase activity in the brain and liver and the urine contents in the brain, liver, and blood of rats on the 1st, 3rd, 30th, and 45th days of the cold acclimation (+2--+4 degrees C), were studied. The arginase activity was also studied in the brain, liver, and kidneys of adrenalectomized rats. During the acclimation, the arginase activity decreases by 1.5--2 times in the brain and increases 202.5-fold in the liver. The urine contents in the tissues raised dur to arginase activation in the liver. The brain activity of adrenalectomized animals does not differ from the control, while decreasing in the liver and kidneys by 33% and 60% respectively. We suppose that the difference between responses of the brain and liver arginases to cold is based on their different regulation by the adrenal hormones.

Acclimatization↗