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PubMed1990

Molecular basis of argininemia. Identification of two discrete frame-shift deletions in the liver-type arginase gene.

Argininemia results from a deficiency of arginase (EC 3.5.3.1), the last enzyme of the urea cycle in the liver. We examined the molecular basis for argininemia by constructing a genomic library followed by cloning and DNA sequencing. Discrete mutations were found on two alleles from the patient, a product of a nonconsanguineous marriage. There was a four-base deletion at protein-coding region 262-265 or 263-266 in exon 3 that would lead to a reading-frame shift after amino acid residue 87 and make a new stop codon at residue 132. The other was a one-base deletion at 77 or 78 in exon 2 that would lead to a reading-frame shift after residue 26 and make a stop codon at residue 31. For confirmation, genomic DNAs from the patient and from her parents were amplified by the polymerase chain reaction method. The patient was shown to be a compound heterozygote, inheriting an allele with the four-base deletion from the father and the other allele with the one-base deletion from the mother. These data seem to be the first evidence of a case of argininemia caused by two different deletion mutations.

Amino Acid Metabolism, Inborn Errors↗
PubMed2007

Arginase 1 is expressed in myelocytes/metamyelocytes and localized in gelatinase granules of human neutrophils.

Arginase 1 (ARG1) metabolizes arginine, thus reducing the availability of arginine as a substrate for nitric oxide synthase (NOS). The decreased production of nitric oxide (NO) by NOS and the production of ornithine by ARG1 affect immune responses and tissue regeneration at sites of infection, respectively. We here demonstrate that ARG1 is synthesized in myelocytes/metamyelocytes and is stored in gelatinase granules. In accordance with this, activated neutrophils coreleased ARG1 and gelatinase to the extracellular environment on stimulation with phorbol-12-myristate 13-acetate (PMA), formyl-methionyl-leucyl-phenylalanine (fMLP), or tumor necrosis factor alpha (TNF-alpha). Overall, these findings define ARG1 as a genuine gelatinase granule protein and support a model in which activated neutrophils release ARG1 at sites of infection to modulate immune responses and promote tissue regeneration.

Arginase↗
PubMedDate not supplied

High-performance liquid chromatography method with radiochemical detection for measurement of nitric oxide synthase, arginase, and arginine decarboxylase activities.

Nitric oxide has been shown to be involved in numerous biological processes, and many studies have aimed to measure nitric oxide synthase (NOS) activity. Recently, it has been demonstrated that arginase and arginine decarboxylase (ADC), two enzymes that also employ arginine as a substrate, may regulate NOS activity. We aimed to develop a HPLC-based method to measure simultaneously the products of these three enzymes. Traditionally, the separation of amino acids and related compounds with HPLC has been carried out with precolumn derivatization and reverse phase chromatography. We describe here a simple and fast HPLC method with radiochemical detection to separate radiolabeled L-arginine, L-citrulline, L-ornithine, and agmatine. 3H-labeled L-arginine, L-citrulline, agmatine, and 14C-labeled L-citrulline were used as standards. These compounds were separated in the normal phase column (Allure Acidix 250 x 4.6 mm i.d.) under isocratic conditions in less than 20 min with good sensitivity. Using the current method, we have shown the formation of L-citrulline and L-ornithine in vitro using brain tissue homogenate of rats and that of agmatine by Escherichia coli ADC.

Agmatine↗
PubMed1976

The inhibition of arginase from the hepatopancreas of a terrestrial snail by amino acids.

The effects of L-amino acids on arginase from the hepatopancreas of the snail Ariophanta (=Cryptozona) ligulata were studied. This enzyme was inhibited by ornithine, valine, lysine, leucine, isoleucine, proline and threonine. The other amino acids were without any significant effect. Only ornithine was a non-competitive inhibitor, where as all the other inhibitory amino acids were competitive.

Amino Acids↗
PubMed1975

Growth inhibitory and arginase activities in liver and hepatoma extracts.

The growth-inhibitory activity against H.Ep. No 2 cells observed in phosphate buffer extracts of rat liver appears to be due to the enzyme, arginase. This conclusion is based on the findings that (1) extracts of hepatomas containing lower levels of the enzyme also contain less inhibitory activity; (2) partial purification of the inhibitory factor results in a similar purification of the enzyme; (3) molecular weights of the enzyme and of the inhibitory factor are similar; and (4) various treatments alter the enzyme and inhibitory activities similarly.

Animals↗
PubMed1993

Steroid hormones inhibit induction of spontaneous nitric oxide production in cultured hepatocytes without changes in arginase activity or urea production.

The spontaneous formation of nitrites was examined in the medium of cultured rat hepatocytes and taken as a measure of nitric oxide generation. The rate of nitrite formation increased after 8-12 hr in culture which was blocked by the addition of dexamethasone, actinomycin D, or cycloheximide. Various glucocorticoids, mineralocorticoids, and sex steroids also inhibited nitrite formation by varying degrees, without affecting arginase activity or urea production. The inhibition of nitric oxide formation appears, therefore, not to be due to changes in the availability of arginine. The results suggest that nitric-oxide synthase is induced in hepatocytes in culture and show that anti-inflammatory glucocorticoids are not the only steroids that inhibit nitric oxide formation.

Animals↗
PubMed2003

IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice.

We previously demonstrated that a specialized subset of immature myeloid cells migrate to lymphoid organs as a result of tumor growth or immune stress, where they suppress B and T cell responses to Ags. Although NO was required for suppression of mitogen activation of T cells by myeloid suppressor cells (MSC), it was not required for suppression of allogenic responses. In this study, we describe a novel mechanism used by MSC to block T cell proliferation and CTL generation in response to alloantigen, which is mediated by the enzyme arginase 1 (Arg1). We show that Arg1 increases superoxide production in myeloid cells through a pathway that likely utilizes the reductase domain of inducible NO synthase (iNOS), and that superoxide is required for Arg1-dependent suppression of T cell function. Arg1 is induced by IL-4 in freshly isolated MSC or cloned MSC lines, and is therefore up-regulated by activated Th2, but not Th1, cells. In contrast, iNOS is induced by IFN-gamma and Th1 cells. Because Arg1 and iNOS share L-arginine as a common substrate, our results indicate that L-arginine metabolism in myeloid cells is a potential target for selective intervention in reversing myeloid-induced dysfunction in tumor-bearing hosts.

Animals↗
PubMed1976

Separation of arginase isoenzymes from human tissues by agar gel electrophoresis.

Arginase (EC 3.5.3.1) from human liver. kidney, mammary gland, and erythrocytes, was separated by agar-gel electrophoresis using barbital buffer pH 8.6. Three isoenzymes were separated. Two of these, A2 and A3, occur in liver and erythrocytes. The same two isoenzymes were found in the kidney, but in reversed proportions. In addition to the A3 isoenzyme, the mammary gland contains a fast anodically moving A1 isoenzyme. The three isoenzymes differ in their degree of sensitivity to ornithine.

Arginase↗
PubMed1999

Structure of the arginase coding gene and its transcript in Aspergillus nidulans.

The arginase structural gene (agaA) from Aspergillus nidulans has been cloned and characterised. Depending on the growth conditions of the mycelium, transcripts of this gene have different 5'ends. These differences could result either from the presence of multiple transcription initiation sites or from differential processing of mRNA. The agaA mRNA has a long 5'UTR with a potentially complex secondary structure. Putative arginine binding aptamers were found in this UTR suggesting interesting possibilities for regulation of the agaA expression.

5' Untranslated Regions↗
PubMed2001

[Inhibitors of arginase in the L-arginine metabolic pathway as a new class of antihypertensive drugs: effect of carbamide on lipid oxidative metabolism and on vessel tonus during arterial hypertension].

Have studied action of chronic urea--an arginase inhibitor--introduction (40 mg/kg, 28 days) on blood pressure, endothelium-dependent reactions of aorta smooth muscle cells (SMC) and nonenzymatic (contents of diene conjugates and H2O2) and enzymatic (contents of free arachidonic acid and vasoconstrictic eicosanoids LTC4 and TXA2) oxidizing lipid metabolism of heart, aorta, plasma and erythrocytes of spontaneously hypertensive rats. Have shown, that urea down regulate blood pressure without any normalization of endothelium-dependent reactions of SMC of aorta and down regulate both enzymatic and nonenzymatic oxidizing lipid metabolism. Down regulation of two alternative (by cyclooxygenase and by lipoxygenase) enzymatic pathways of free arachidonic acid oxidizing metabolism by urea can be one of mechanisms of its antihypertensive action. The possibility of urea use at hypertension and various pathophysiological conditions are discussed.

Animals↗
PubMed2002

Nitric oxide synthase, arginase and cyclooxygenase are involved in muscarinic receptor activation in different murine mammary adenocarcinoma cell lines.

Investigations on the influence of the parasympathetic nervous system via muscarinic signaling in tumor progression have produced contradictory evidence. We investigated the expression of muscarinic acetylcholine receptors (mAchR) and their intracellular transduction pathways, in two murine mammary adenocarcinoma cell lines, LM3 and LM2 in comparison with the normal murine mammary epithelial cell line: NMuMG. Saturation binding assays with the tritiated muscarinic antagonist quinuclidinyl benzilate ([3H]-QNB) indicate that LM3 cells express higher amounts of mAchR than LM2 cells. Muscarinic receptor activation with carbachol (CARB) enhanced basal production of citrulline to a greater extent in LM3 cells than in LM2 cells. The nitric oxide synthase (NOS) inhibitor, NGmono-methyl-L-arginine (L-NMMA), blunted this effect only in LM3 cells while in LM2 cells the action of CARB was blocked by Nomega hydroxy-L-arginine (L-OH-Arg), which is known to inhibit the arginase pathway. Atropine blocks the action of CARB in both cell lines. Additionally, mAchR activation stimulates prostaglandin E2 (PGE2) synthesis only in LM2 cells. NMuMG cells show detectable basal amounts of nitric oxide and PGE2, but they did not respond to CARB. Binding experiments confirm the absence of mAchR in these cells. The findings indicate that mAchR expression in tumor cells, and its control on arginine metabolism, via NOS/arginase, and on PGE2 synthesis by COX activation, could be a switch on mechanism that might lead mammary cells from normal to malignant phenotype. Moreover, mAchR coupling to distinct effectors might be associated with differences in aggressiveness of tumor cells.

Adenocarcinoma↗
PubMed1975

Arginase activity of human erythrocyte ghosts in uremia.

Arginase activity of erythrocyte membrane fragments has been determined in normal subjects and in two groups of uremic patients: 1) those having a blood urea concentration of 100 mgm/100 ml or higher and with an elevated erythrocyte sodium concentration and 2) patients with a blood urea concentration of 100 mgm/100 ml and higher and a normal erythrocyte sodium concentration. No statistically significant difference was detected between the normal subjects and the uremic patients. It is concluded, therefore, that the effect of uremia on the magnesium dependant, Na and K activated adenosine triphosphatase of erythrocyte membranes is not applicable to all enzymes of the erythrocyte.

Arginase↗
PubMed1991

Glutamic acid-induced shoot differentiation in tobacco callus tissues and changes in nicotine content and in activities of aminotransferases, ornithine transcarbamylase, and arginase.

Floral bud calluses of Nicotiana tabacum L. var. Anand-2 produced multiple shoots on Murashige and Skoog's (MS) medium supplemented with 2 mg/l indole-3-acetic acid (IAA), 0.4 mg/l kinetin (Kn), and L-glutamic acid (2.5 mM). However cultures of calluses on MS medium containing only the IAA and Kn did not differentiate shoots. Specific activities of phenylalanine aminotransferase, tyrosine aminotransferase, and ornithine aminotransferase were over 7-, 5- and 5-fold higher, respectively, in the glutamic acid-treated calluses than in the nonshoot-forming ones on the day of shoot emergence. Activities of ornithine transcarbamylase and arginase decreased after the onset of the differentiation process. Implications of the enzyme activities in the differentiation process and in nicotine biogenesis are discussed.

Arginase↗
PubMedDate not supplied

[Activity of liver and brain arginase during hypothermia].

The content of urea and activity of arginase in the brain and liver have been determined in squirrels falling into hibernation and in rats with an artificial decrease of the body temperature. It is shown that the intensity of urea synthesis under hypothermia (20, 10 degrees C) in the studied organs of animals falling into hibernation remains at high level in contrast to animals without such adaptation.

Animals↗
PubMed1975

Purification and some properties of arginase from human lung.

Arginase from human lung has been isolated and purified about 100-fold. During the purification procedure the enzyme was stabilized by Mn2+. The molecular weight determined by Sephadex G-150 gel filtration was found to be 120 000. The enzyme is highly specific towards L-arginine. Incubation of the enzyme with EDTA for 60 min at pH 7.5 and 37 degrees C results in dissociation into inactive subunits of mol. wt. 30 000. On addition of Mn2+ ion to the inactivated enzyme, the subunits reassociate into the native form of the enzyme of mol. wt. 120 000, and the activity is restored.

Adult↗
PubMed1987

Purification, modification, physico-chemical and pharmacokinetic characterization of arginase, an enzyme of potential use in therapy.

Beef liver arginase, an enzyme potentially useful in the therapy of arginine dependent tumors or of familial hyperargininemia, was purified to homogeneity by a procedure involving a key step of hydrophobic affinity chromatography. The enzyme was extensively modified by the covalent linking of monomethoxypolyethyleneglycol molecules according to a procedure recently proposed by the Authors (Veronese et al., Appl. Biochem. Biotecnol. 11, 869, 1985) without any significant loss of activity. The derivative enzyme presents more convenient properties for a therapeutic use, as compared to the native enzyme, such an increased structural stability, a decreased digestion by proteolytic enzymes and an expanded clearance time in rats.

Animals↗
PubMed1987

Human arginase isozymes.

Studies in experimental animals and humans demonstrate the existence of two arginase isozymes. One, designated AI (or A1), has a high pI, is located in the cytosol, is most abundant in liver, and is thought to be primarily responsible for ammonia detoxification as urea. The gene coding for this isozyme is mutated in human hyperargininemia. A second isozyme, designated AII (or A4), has a neutral pI, is located in the mitochondrial matrix, and is thought to be involved primarily in the production of ornithine as a precursor of proline and glutamate. It appears to be expressed in most but not all tissues and in more nearly equal amounts. The two isozymes are immunologically distinct and are coded for by two separate genes. The great similarity in all measured kinetic and some physicochemical properties implies a high degree of structural similarity at the active site, but the lack of immunological cross-reactivity and DNA cross-hybridization implies substantial compositional differences in other parts of the enzyme molecules.

Animals↗