SEARCH · PubMed Health

Results for “ARGINASE”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 703 records · Page 39Linked to original sources

PubMed1988

Human liver-type arginase gene: structure of the gene and analysis of the promoter region.

The gene for human liver-type arginase (EC 3.5.3.1), a urea cycle enzyme, was cloned and the structure was determined. This gene is 11.5 kilobases long and is split into 8 exons. The cap site was determined by nuclease S1 mapping and primer extension. A "TATA box"-like sequence is located 28 bases upstream from the cap site, and a sequence similar to the binding sites of the transcription factor CTF/NF1, a "CAAT box"-binding protein, is located 72 bases upstream. In the 5' end region, sequences resembling the glucocorticoid responsive elements, the cAMP responsive elements, and the enhancer core sequences are present. The immediately 5' flanking region of the human gene up to position -105 is 84% identical with the corresponding segment of the rat gene. In this region of the human gene, one DNase I-protected area and several hypersensitive cleavage sites were detected by footprint analysis, using nuclear extracts from the rat liver. The protected area contains the sequence similar to the binding sites of CTF/NF1 and also overlaps with the sequence resembling the glucocorticoid responsive elements.

Amino Acid Sequence↗

PubMed2005

Arginase activity differs with allergen in the effector phase of ovalbumin- versus trimellitic anhydride-induced asthma.

Both trimellitic anhydride (TMA), a small molecular weight chemical, and ovalbumin (OVA), a reference protein allergen, cause asthma with eosinophilia. To test the hypothesis that different allergens elicit symptoms of asthma via different effector pathways, gene expression was compared in lungs of Balb/c mice sensitized with either TMA or OVA, followed by intratracheal challenge with TMA conjugated to mouse serum albumin (TMA-MSA) or OVA, respectively. Sensitized animals challenged with mouse serum albumin (MSA) alone were controls. Seventy-two hours after challenge, lung eosinophil peroxidase indicated that both allergens caused the same significant change in eosinophilia. Total RNA was isolated from lung lobes of 6-8 animals in each of four treatment groups and hybridized to Affymetrix U74Av2 GeneChips. False discovery rates (q-values) were calculated from an overall F test to identify candidate genes with differences in expression for the four groups. Using a q-value cutoff of 0.1, 853 probe sets had significantly different expression across the four treatment groups. Of these 853 probe sets, 376 genes had an Experimental/Control ratio of greater than 1.2 or less than 1/1.2 for either OVA- or TMA-treated animals, and 249 of the 376 genes were uniquely up- or down-regulated for OVA or TMA (i.e., differentially expressed with the allergen). qRT-PCR analysis of selected transcripts confirmed the gene expression analysis. Increases in both arginase transcript and enzyme activity were significantly greater in OVA-induced asthma compared to TMA-induced asthma. These data suggest that pathways of arginine metabolism and the importance of nitric oxide may differ in OVA- and TMA-induced asthma.

Allergens↗

PubMed1998

Paradoxical changes in organ blood flow after arginase infusion in the non-stressed rat.

Arginine (ARG) is the precursor of nitric oxide (NO), a potent vasodilator. Arginase (ASE) is released following hepatocellular damage, resulting in low plasma ARG levels. The effect of ASE infusion on hemodynamics was studied. Rats received a 20 min ASE or saline infusion, and systemic hemodynamics and organ blood flow were studied, at 30 and 270 min, using radiolabeled microspheres. Compared with control, ASE resulted (30 min) in 1) undetectable ARG levels; 2) higher mean arterial pressure and total peripheral resistance (both p < .05); 3) higher blood flow to the heart, kidneys, stomach, small intestine (all p < .05), and spleen (p < .001); and 4) lower vascular resistance in the heart, kidneys, stomach, and small intestine (all p < .05) and in the spleen (p < .005). At 270 min, ASE rats had similar organ blood flow and higher nitrate levels in urine and plasma (both p < .05) compared with control. We conclude that ASE reduces ARG levels with simultaneous increase in mean arterial pressure and total peripheral resistance. Higher nitrate production, suggesting higher NO formation in the presence of low ARG plasma levels, is paradoxical but could explain the higher blood flow in some organs. The increased total peripheral resistance during higher nitrate formation suggests regional differences in dependency of NO production on plasma ARG levels.

Animals↗

PubMed1987

The Noc region of Ti plasmid C58 codes for arginase and ornithine cyclodeaminase.

Plant tumors induced by Agrobacterium tumefaciens synthesize a group of substances (opines) which can serve as sole source of carbon and nitrogen for the bacteria. We investigate Ti-plasmid-coded genes and enzymes involved in catabolism of the opine N2-(1,3-dicarboxypropyl)-L-arginine (nopaline) with a novel approach: expression and mapping of protein-coding regions in Escherichia coli minicells, followed by identification of enzyme functions in the heterologous E. coli background. The results show that a specific part of the nopaline catabolism (Noc) region of Ti plasmid C58 is packed with closely spaced protein-coding regions which can be expressed into polypeptides of distinct sizes in E. coli. We identify and map three enzyme activities: nopaline oxidase, arginase and ornithine cyclodeaminase, an unusual protein converting ornithine directly into proline. Nopaline oxidase requires two different Noc-gene-encoded proteins for function and the latter two enzymes are new discoveries in the Noc region. These three enzyme activities together constitute a catabolic pathway leading from nopaline through arginine and ornithine to proline.

Ammonia-Lyases↗

PubMed2005

Regulation of arginase II by interferon regulatory factor 3 and the involvement of polyamines in the antiviral response.

The innate antiviral response requires the induction of genes and proteins with activities that limit virus replication. Among these, the well-characterized interferon beta (IFNB) gene is regulated through the cooperation of AP-1, NF-kappaB and interferon regulatory factor 3 (IRF-3) transcription factors. Using a constitutively active form of IRF-3, IRF-3 5D, we showed previously that IRF-3 also regulates an IFN-independent antiviral response through the direct induction of IFN-stimulated genes. In this study, we report that the arginase II gene (ArgII) as well as ArgII protein concentrations and enzymatic activity are induced in IRF-3 5D-expressing and Sendai virus-infected Jurkat cells in an IFN-independent manner. ArgII is a critical enzyme in the polyamine-biosynthetic pathway. Of the natural polyamines, spermine possesses antiviral activity and mediates apoptosis at physiological concentrations. Measurement of intracellular polyamine content revealed that expression of IRF-3 5D induces polyamine production, but that Sendai virus and vesicular stomatitis virus infections do not. These results show for the first time that the ArgII gene is an early IRF-3-regulated gene, which participates in the IFN-independent antiviral response through polyamine production and induction of apoptosis.

Apoptosis↗

PubMed2006

Mutational analysis of substrate recognition by human arginase type I--agmatinase activity of the N130D variant.

Upon mutation of Asn130 to aspartate, the catalytic activity of human arginase I was reduced to approximately 17% of wild-type activity, the Km value for arginine was increased approximately 9-fold, and the kcat/Km value was reduced approximately 50-fold. The kinetic properties were much less affected by replacement of Asn130 with glutamine. In contrast with the wild-type and N130Q enzymes, the N130D variant was active not only on arginine but also on its decarboxylated derivative, agmatine. Moreover, it exhibited no preferential substrate specificity for arginine over agmatine (kcat/Km values of 2.48 x 10(3) M(-1) x s(-1) and 2.14 x 10(3) M(-1) x s(-1), respectively). After dialysis against EDTA and assay in the absence of added Mn2+, the N130D mutant enzyme was inactive, whereas about 50% full activity was expressed by the wild-type and N130Q variants. Mutations were not accompanied by changes in the tryptophan fluorescence properties, thermal stability or chromatographic behavior of the enzyme. An active site conformational change is proposed as an explanation for the altered substrate specificity and low catalytic efficiency of the N130D variant.

Amino Acid Substitution↗

PubMed1972

Identification of a canine adenovirus (infectious canine hepatitis virus) inhibitor in dog liver extracts as arginase.

Extracts of canine liver inhibited growth of infectious canine hepatitis (ICH) virus, a canine adenovirus. Purified extracts from mammalian, but not avian, liver tissue contained the inhibitor, and evidence is presented that the inhibitory factor is the enzyme arginase (arginine ureohydrolase). This study further emphasized the need for arginine in adenovirus growth and may explain some of the difficulties in isolating small amounts of ICH virus from suspensions of liver.

Adenoviruses, Canine↗

PubMed2000

A commercial preparation of catalase inhibits nitric oxide production by activated murine macrophages: role of arginase.

Catalase is widely used as a pharmacological probe to evaluate the role of hydrogen peroxide in antimicrobial activities of phagocytic cells. This report demonstrates that the ability of a commercial preparation of catalase to inhibit concomitantly macrophage antimycobacterial activity and production of reactive nitrogen intermediates can be attributed, at least in part, to the depletion of L-arginine by contaminating arginase. In experimental systems that employ pharmacological probes, the existence of nonspecific effects should be considered in data interpretation.

Animals↗

PubMed1992

Nitrogen catabolite repression of arginase (CAR1) expression in Saccharomyces cerevisiae is derived from regulated inducer exclusion.

Expression of the Saccharomyces cerevisiae arginase (CAR1) gene is regulated by induction and nitrogen catabolite repression (NCR). Arginine was demonstrated to be the native inducer. CAR1 sensitivity to NCR has long been accepted to be accomplished through a negative control mechanism, and cis-acting sites for it have been hypothesized. In search of this negatively acting site, we discovered that CAR1 sensitivity to NCR derives from regulated inducer (arginine) exclusion. The route of catabolic entry of arginine into the cell, the general amino acid permease (GAP1), is sensitive to NCR. However, CAR1 expression in the presence of sufficient intracellular arginine is NCR insensitive.

Arginase↗

PubMed1992

Tripartite structure of the Saccharomyces cerevisiae arginase (CAR1) gene inducer-responsive upstream activation sequence.

Arginase (CAR1) gene expression in Saccharomyces cerevisiae is induced by arginine. The 5' regulatory region of CAR1 contains four separable regulatory elements--two inducer-independent upstream activation sequences (UASs) (UASC1 and UASC2), an inducer-dependent UAS (UASI), and an upstream repression sequence (URS1) which negatively regulates CAR1 and many other yeast genes. Here we demonstrate that three homologous DNA sequences originally reported to be present in the inducer-responsive UASI are in fact three exchangeable elements (UASI-A, UASI-B, and UASI-C). Although two of these elements, either the same or different ones, are required for transcriptional activation to occur, all three are required for maximal levels of induction. The elements operate in all orientations relative to one another and to the TATA sequence. All three UASI elements bind protein(s); protein binding does not require arginine or overproduction of any of the putative arginine pathway regulatory proteins. The UASI-protein complex was also observed even when extracts were derived from arg80/argRI or arg81/argRII deletion mutants. Similar sequences situated upstream of ARG5,6 and ARG3 and reported to negatively regulate their expression are able to functionally substitute for the CAR1 UASI elements and mediate reporter gene expression.

Arginase↗

PubMed1993

Participation of RAP1 protein in expression of the Saccharomyces cerevisiae arginase (CAR1) gene.

Regulated expression of the inducible arginase (CAR1) gene of Saccharomyces cerevisiae has been shown to require three upstream activation sequences (UASs) and an upstream repression sequence, URS1. Two of the UAS elements, UASC1 and UASC2, operate in an inducer-independent manner, while the third, UASI, is inducer dependent. UASC1 and UASC2 were previously shown to contain ABF-1 binding sites that were required for normal transcription. In this work, we demonstrate that UASC1 and UASC2 also contain two and three sites, respectively, that are able to bind RAP1 protein. RAP1 binding to these sites, however, is significantly weaker than that to sites in TEF2 and HMRE. The effects of mutating the sites individually or in combination suggest that at least three of them, two in UASC1 and one in UASC2, probably participate in CAR1 expression.

Arginase↗

PubMed1990

Multiple positive and negative cis-acting elements mediate induced arginase (CAR1) gene expression in Saccharomyces cerevisiae.

Expression of the arginase (CAR1) gene in Saccharomyces cerevisiae is induced by arginine or its analog homoarginine. Induction has been previously shown to require a negatively acting upstream repression sequence, which maintains expression of the gene at a low level in the absence of inducer. The objective of this work was to identify the cis-acting elements responsible for CAR1 transcriptional activation and response to inducer. We identified three upstream activation sequences (UASs) that support transcriptional activation in a heterologous expression vector. Two of these UAS elements function in the absence of inducer, whereas the third functions only when inducer is present. One of the inducer-independent UAS elements exhibits significant homology to the Sp1 factor-binding sites identified in simian virus 40 and various mammalian genes.

Arginase↗

PubMed1996

Combinatorial regulation of the Saccharomyces cerevisiae CAR1 (arginase) promoter in response to multiple environmental signals.

CAR1 (arginase) gene expression responds to multiple environmental signals; expression is induced in response to the intracellular accumulation of arginine and repressed when readily transported and catabolized nitrogen sources are available in the environment. Up to 14 cis-acting sites and 9 trans-acting factors have been implicated in regulated CAR1 transcription. In all but one case, the sites are redundant. To test whether these sites actually participate in CAR1 expression, each class of sites was inactivated by substitution mutations that retained the native spacing of the CAR1 cis-acting elements. Three types of sites function independently of the nitrogen source: two clusters of Abflp- and Rap1p-binding sites, and a GC-rich sequence. Two different sets of nitrogen source-dependent sites are also required: the first consists of two GATAA-containing UASNTR sites that mediate nitrogen catabolite repression-sensitive transcription, and the second is arginine dependent and consists of three UAS1 elements that activate transcription only when arginine is present. A single URS1 site mediates repression of CAR1 arginine-independent upstream activator site (UAS) activity in the absence of arginine and the presence of a poor nitrogen source (a condition under which the inducer-independent Gln3p can function in association with the UASNTR sites). When arginine is present, the combined activity of the UAS elements overcomes the negative effects mediated by URS1. Mutation of the classes of sites either singly or in combination markedly alters CAR1 promoter operation and control, supporting the idea that they function synergistically to regulate expression of the gene.

Arginase↗

PubMed2007

Increased arginase activity and endothelial dysfunction in human inflammatory bowel disease.

Nitric oxide (.NO) generation from conversion of l-arginine to citrulline by nitric oxide synthase isoforms plays a critical role in vascular homeostasis. Loss of .NO is linked to vascular pathophysiology and is decreased in chronically inflamed gut blood vessels in inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis). Mechanisms underlying decreased .NO production in IBD gut microvessels are not fully characterized. Loss of .NO generation may result from increased arginase (AR) activity, which enzymatically competes with nitric oxide synthase for the common substrate l-arginine. We characterized AR expression in IBD microvessels and endothelial cells and its contribution to decreased .NO production. AR expression was assessed in resected gut tissues and human intestinal microvascular endothelial cells (HIMEC). AR expression significantly increased in both ulcerative colitis and Crohn's disease microvessels and submucosal tissues compared with normal. TNF-alpha/lipopolysaccharide increased AR activity, mRNA and protein expression in HIMEC in a time-dependent fashion. RhoA/ROCK pathway, a negative regulator of .NO generation in endothelial cells, was examined. The RhoA inhibitor C3 exoenzyme and the ROCK inhibitor Y-27632 both attenuated TNF-alpha/lipopolysaccharide-induced MAPK activation and blocked AR expression in HIMEC. A significantly higher AR activity and increased RhoA activity were observed in IBD submucosal tissues surrounding microvessels compared with normal control gut tissue. Functionally, inhibition of AR activity decreased leukocyte binding to HIMEC in an adhesion assay. Loss of .NO production in IBD microvessels is linked to enhanced levels of AR in intestinal endothelial cells exposed to chronic inflammation in vivo.

ADP Ribose Transferases↗

PubMed2004

Ornithine metabolism in male and female rat kidney: mitochondrial expression of ornithine aminotransferase and arginase II.

In the kidney, L-ornithine is reabsorbed along the proximal convoluted tubule (PCT), transported by basolateral carriers, and produced by arginase II (AII). Here, the renal metabolic fate of L-ornithine was analyzed in male and female rats. Kidneys and renal zones were dissected and used for Western blot analysis, immunofluorescence, and electron microscopic studies. Ornithine aminotransferase (OAT) and AII were localized using specific antibodies. Ornithine oxidation was determined by incubating microdissected tubules with L-[1-14C] or L-[U-14C]ornithine in the presence or absence of energy-providing substrates. Ornithine decarboxylase (ODC) mRNAs were localized by in situ hybridization. The 48-kDa OAT protein was detected in male and female kidneys, but its level was fourfold higher in the latter. OAT relative distribution increased from the superficial cortex toward the outer medulla to reach its highest level. Almost all OAT protein was localized in cortical and medullary proximal straight tubules (CPST and OSPST, respectively). In proximal straight tubule (PST), AII protein distribution overlapped that of OAT. No gender difference in AII protein level was found. OAT and AII were colocalized within PST mitochondria. L-[1-14C]ornithine decarboxylation occurred in all tubules, but predominantly in proximal tubules. L-[1-14C]ornithine decarboxylation was enhanced when L-[1-14C]ornithine was given to tubules as the sole substrate. The use of L-[U-14C]ornithine demonstrated the complete oxidation of ornithine. In conclusion, the OAT gene was expressed more in female rat proximal tubules than in male. Because OAT and AII proteins overlapped in PST mitochondria, L-arginine-derived ornithine may be preferentially converted to L-glutamate, as proven by ornithine oxidation. However, the coexpression of ODC, glutamate decarboxylase, and glutamine synthetase in PST suggests that L-ornithine can also be metabolized to putrescine, GABA, and L-glutamine. The fate of L-ornithine may depend on the cellular context.

Animals↗

PubMed2007

Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion.

Hepatocellular carcinoma (HCC) is believed to be auxotrophic for arginine through the lack of expression of argininosuccinate synthetase (ASS). The successful use of the arginine-depleting enzyme arginine deiminase (ADI) to treat ASS-deficient tumors has opened up new possibilities for effective cancer therapy. Nevertheless, many ASS-positive HCC cell lines are found to be resistant to ADI treatment, although most require arginine for proliferation. Thus far, an arginine-depleting enzyme for killing ASS-positive tumors has not been reported. Here, we provide direct evidence that recombinant human arginase (rhArg) inhibits ASS-positive HCCs. All the five human HCC cell lines we used were sensitive to rhArg but ADI had virtually no effect on these cells. They all expressed ASS, but not ornithine transcarbamylase (OTC), the enzyme that converts ornithine, the product of degradation of arginine with rhArg, to citrulline, which is converted back to arginine via ASS. Transfection of HCC cells with OTC resulted in resistance to rhArg. Thus, OTC expression alone may be sufficient to induce rhArg resistance in ASS-positive HCC cells. This surprising correlation between the lack of OTC expression and sensitivity of ASS-positive HCC cells shows that OTC-deficient HCCs are sensitive to rhArg-mediated arginine depletion. Therefore, pretreatment tumor gene expression profiling of ASS and OTC could aid in predicting tumor response to arginine depletion with arginine-depleting enzymes. We have also shown that the rhArg native enzyme and the pegylated rhArg (rhArg-peg(5,000mw)) gave similar anticancer efficacy in vitro. Furthermore, the growth of the OTC-deficient Hep3B tumor cells (ASS-positive and ADI-resistant) in mice was inhibited by treatment with rhArg-peg(5,000mw), which is active alone and is synergistic in combination with 5-fluorouracil. Thus, our data suggest that rhArg-peg(5,000mw) is a novel agent for effective cancer therapy.

Animals↗

PubMed1980

Role of glucocorticosteroid hormones on the levels of rat liver carbamoylphosphate synthase (ammonia) and arginase activity during ontogenesis.

In rats, hepatic carbamoylphosphate synthase (ammonia) and arginase activities are closely related during development. Activities increase sharply during the last 4 prenatal and first 4 postnatal days and during the 3rd postnatal week. Decreases are observed between 4 and 9 days after birth, and after weaning, during adolescence. During senescence activities increase again. Before birth, treatment and prednisolone is far less effective in increasing enzyme activities than during the first 2 postnatal weeks, when it seems to precipitate normal development of the 3rd postnatal week. In the 4th postnatal week the sensitivity to prednisolone treatment increases approximately 25-fold. During the 2nd postnatal week, dexamethasone proves to be more potent, on a molar base, than triamcinolone which is more potent than prednisolone and hydrocortisone. Increases in enzyme activities which are associated with increases in blood levels of glucocorticosteroids are also associated with 2- to 3-fold decreases in DNA content, i.e. with decreases in hepatocyte multiplication rate and increases in hepatocyte cell size. These phenomena may be sequelae of quantal cell cycles leading to changes in hormone response capacity or hormone response sensitivity.

Aging↗

PubMed1980

Role of thyroid hormones in the normal and glucocorticosteroid hormone-induced evolution of carbamoylphosphate synthase (ammonia) and arginase activity in perinatal rat liver.

Administration of thyroid hormones causes a dose-dependent increase in carbamoylphosphate synthase (ammonia) and arginase activities in fetal rat liver but not in neonatal rat liver. Simultaneous administration of thyroid and glucocorticosteroid hormones enhances enzyme accumulation still further in the fetus. When administered before birth, the relative potencies of T4 and reverse T3, compared to T3 are 20--25% and 1--20%, respectively. Both before and after birth, thyroid hormones enhance DNA content of the liver. Hypophysectomy of rat fetus reduces the carbamoylphosphate synthase activity level in hepatocytes to 30--40% of that in intact animals. Thyroid and glucocorticosteroid hormone administered individually to hypophysectomized animals stimulate enzyme activity 2- to 3-fold; and if administered simultaneously, 4- to 6-fold. Premature delivery with continuation of thyroid and/or glucocorticosteroid hormone treatment started before birth shows uninterrupted enzyme accumulation profiles. Delaying birth by progesterone treatment of the dam leads to uninterrupted but reduced rates of enzyme accumulation in hepatocytes.

Animals↗