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PubMed2005

The activity of ornithine transcarbamoylase and arginase during mechanical jaundice in the rat model.

BACKGROUND: The pathogenesis of morbidity and mortality associated with intervention of the biliary system in patients with obstructive jaundice is unknown. Mechanical jaundice initiates the development of morphological changes in hepatocytes with concomitant disturbances in metabolism. These are followed by changes in enzyme activity in hepatocytes and peripheral blood. MATERIAL AND METHODS: Wistar rats were divided into three groups: group 1, sham-operated controls; group 2, rats with permanent jaundice; and group 3, rats with temporary mechanical jaundice. The animals were examined at 2 weeks (groups A), 4 weeks (groups B) and 6 weeks (groups C) after surgery. We explored the impact of induced mechanical jaundice on the activity of selected urea cycle enzymes (arginase [E.C.3.5.3.1] and ornithine transcarbamoylase (OTC) [E.C.2.1.3.3]). RESULTS: Mechanical jaundice was found to induce changes in hepatocytic metabolism, which in turn led to disturbances in the urea cycle and the process of transamination. After relief of the mechanical jaundice (recanalization of the common bile duct), the urea cycle activity in the liver was greatly increased despite the normalization of the basic biochemical indices. CONCLUSION: The results of the experiment confirmed the hypothesis that long-term mechanical jaundice causes lasting disturbances in hepatocytic metabolism. We conclude that the rate of nitrogen metabolism is higher after recanalization of the bile duct.

Alkaline Phosphatase↗
PubMed2006

Ornithine deficiency in the arginase double knockout mouse.

Knockout mouse models have been created to study the consequences of deficiencies in arginase AI and AII, both individually and combined. The AI knockout animals die by 14 days of age from hyperammonemia, while the AII knockout has no obvious phenotype. The double knockout (AI(-/-)/AII(-/-)) exhibits the phenotype of the AI-deficient mice, with the additional absence of AII not exacerbating the observed phenotype of the AI knockout animals. Plasma amino acid measurements in the double knockout have shown arginine levels increased roughly 100-fold and ornithine decreased roughly 10-fold as compared to wildtype. Liver ornithine levels were reduced to 2% of normal in the double knockout with arginine very highly elevated. Arginine and ornithine were also altered in other tissues in the double knockout mice, such as kidney, brain, and small intestine. This is the first demonstration that the fatal hyperammonemia in the AI knockout mouse is almost certainly due to ornithine deficiency, the amino acid needed to drive the urea cycle. Others have shown that the expression of ornithine aminotransferase (OAT) rapidly decreases in the intestine at the same age when the AI-deficient animals die, indicating that this enzyme is critical to the maintenance of ornithine homeostasis, at least at this early stage of mouse development. Although most human AI-deficient patients have no symptomatic hyperammonemia at birth, it is possible that clinically significant ornithine deficiency is already present.

Animals↗
PubMed2003

Arginase 1 overexpression in psoriasis: limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation.

Abnormal proliferation of keratinocytes in the skin appears crucial to the pathogenesis of psoriasis, but the underlying mechanisms remain unknown. Nitric oxide (NO), released from keratinocytes at high concentrations, is considered a key inhibitor of cellular proliferation and inducer of differentiation in vitro. Although high-output NO synthesis is suggested by the expression of inducible NO synthase (iNOS) mRNA and protein in psoriasis lesions, the pronounced hyperproliferation of psoriatic keratinocytes may indicate that iNOS activity is too low to effectively deliver anti-proliferative NO concentrations. Here we show that arginase 1 (ARG1), which substantially participates in the regulation of iNOS activity by competing for the common substrate L-arginine, is highly overexpressed in the hyperproliferative psoriatic epidermis and is co-expressed with iNOS. Expression of L-arginine transporter molecules is found to be normal. Treatment of primary cultured keratinocytes with Th1-cytokines, as present in a psoriatic environment, leads to de novo expression of iNOS but concomitantly a significant down-regulation of ARG1. Persistent ARG1 overexpression in psoriasis lesions, therefore, may represent a disease-associated deviation from normal expression patterns. Furthermore, the culturing of activated keratinocytes in the presence of an ARG inhibitor results in a twofold increase in nitrite accumulation providing evidence for an L-arginine substrate competition in human keratinocytes. High-output NO synthesis is indeed associated with a significant decrease in cellular proliferation as shown by down-regulation of Ki67 expression in cultured keratinocytes but also in short-term organ cultures of normal human skin. In summary, our data demonstrate for the first time a link between a human inflammatory skin disease, limited iNOS activity, and ARG1 overexpression. This link may have substantial implications for the pathophysiology of psoriasis and the development of new treatment strategies.

Amino Acid Transport Systems, Basic↗
PubMed2002

Insights into the interaction of human liver arginase with tightly and weakly bound manganese ions by chemical modification and site-directed mutagenesis studies.

Diethyl pyrocarbonate (DEPC) caused a loss in the ability of inactive subunits of wild-type and H141F mutant human liver arginase (EC 3.5.3.1) to be reactivated by Mn(2+). The effect was reversed by hydroxylamine and involved a residue with a pK(a) of 6.5+/-0.1. Half activation with Mn(2+) was sufficient for total resistance of H141F and full activation was not impeded by a previous incubation of the half-active species with DEPC. The H101N and H126N mutants expressed 60 and 82% of the wild-type activity, respectively, without changes in K(m) for arginine or K(i) for lysine inhibition. After dialysis against EDTA, H126N was inactive in the absence of added Mn(2+) and contained <0.1 Mn(2+)/subunit, whereas H101N was half active and contained 1.2+/-0.1 Mn(2+)/subunit. Results support the concept that a weakly bound metal ion is needed only for conversion of active species to a more active active state.

Arginase↗
PubMed1976

The role of metal ions in the activation of arginase.

The role of metal ions as activators of arginase hydrolyzing arginine were studied. The metal ion is assumed to form a complex with arginine and to promote the enzymatic reaction. The activating ability of the metal ion appears to be governed by the chelating ability and/or the coordination numbers which determine whether the metal ion combines with the enzyme or the substrate (or both substrate and enzyme) and factors which influence the configuration of the resulting complexes.

Animals↗
PubMed2002

Interaction of anions with rat liver arginase: specific inhibitory effects of fluoride.

The inhibitory effects of anions, such as N(3)(-), NO(2)(-), BO(4)(3-), SCN(-), CH(3)COO(-), SO(4)(2-), ClO(4)(-), H(2)PO(4)(-), CN(-), I(-), Br(-), Cl(-) and F(-), on the hydrolysis of L-arginine (L-Arg) by rat liver arginase (RLA) have been studied. From all these anions, only F(-) exhibited a clear inhibitory effect at the mM level. Inhibition of RLA by F(-) is reversible and uncompetitive towards L-Arg binding with a K(i) value of 1.3+/-0.5 mM at pH 7.4. This effect is dependent on pH as the IC(50) value of F(-) towards RLA increases from 1.2 to 19 mM when increasing the pH from 7 to 10. Another specific inhibitor of RLA, N(omega)-hydroxy-L-nor-arginine (nor-NOHA), that has been recently shown to bind to RLA as a bridging ligand of its (Mn(II))(2) cluster, exhibits some similarities with F(-) in its inhibitory effects (identical pH dependence). It is thus tempting to propose that the inhibitory effects of F(-) could be due to its binding as a bridging ligand of the RLA (Mn(II))(2) cluster. However, further studies are required to determine the modes of interaction of F(-) with RLA.

Animals↗
PubMed2004

Inactivation of human liver arginase by Woodward's reagent K: evidence for reaction with His141.

Human liver arginase (EC 3.5.3.1) was totally inactivated by incubation with Woodward's reagent K (WRK). The inactivation followed pseudo-first-order kinetics, and the order of the inactivation was close to 1, consistent with reaction of one molecule of WRK with one subunit molecule for inactivation. The effect was totally reversed by 0.5 M hydroxylamine, and reactivated species were inactivated again by a second incubation with WRK. The pH dependence of the pseudo--first-order rate constants of inactivation indicated the participation of a ionizable residue with a pKa of 6.3 at 25 degrees C. Replacement of His141 with phenylalanine rendered the enzyme totally resistant to the inactivation. We conclude that His141 is the residue whose chemical modification with WRK inactivates the enzyme.

Arginase↗
PubMed1971

Arginase and glucose-6-phosphate dehydrogenase activities in spontaneous mammary carcinogenesis.

Arginase and glucose-6-phosphate dehydrogenase activities in the mammary glands of 4, 8 and 12 month old groups and in precancerous nodules and mammary tumours in (C3H Jax) virgin mice were studied. It was observed that activities of both the enzymes in different age groups of both the strains are comparable, but are significantly lower than those present in precancerous nodules and mammary tumour. Activities of both the enzymes in the precancerous nodules and tumour tissue are comparable.

Age Factors↗
PubMed1972

Molecular characteristics of chicken liver arginase.

A purification procedure for the preparation of chicken liver arginase in a homogeneous form is presented. The enzyme hydrolyses both arginine and argininic acid. Kinetic analysis reveals that the enzyme binds arginine when the amino group is protonated or unprotonated; however, the unprotonated form seems to be hydrolysed more rapidly. The enzyme exchanges with the medium approx. 1.6Mn(2+) ions per molecule.

Amino Acids↗
PubMed1985

[Polyvinylpyrrolidone iodine and arginase: effect on corneal regeneration and its antiviral effect].

PVP-iodine was found to be virucidal for adenoviruses and herpes simplex virus in a concentration of 0.5%, i.e., a 1:20 dilution of Betaisodona. Similar concentrations did not delay the healing of corneal epithelium of the rabbit after experimental lesions (Ullerich and Durchschlag, 1953), although the eyes were slightly irritated. However, a higher concentration (1.25%) caused considerable ocular irritation, and healing of the cornea was delayed or completely inhibited. Arginase, which inhibited the multiplication of adenoviruses and herpes simplex virus in cell culture, did not impair corneal healing in solutions of up to 5%.

Adenoviridae↗
PubMed1982

Interpretation of the kinetics of consecutive enzyme-catalysed reactions: studies on the arginase-ornithine carbamoyltransferase system.

A method that permits the use of measurements on the concentration of the intermediate in a coupled enzymic assay in determining the presence or absence of an interaction between the enzymes is presented. The method is shown to be closely analogous to a previously formulated procedure involving the determination of the rate of production of the final product of such a sequence and is shown to be applicable regardless of the complexity of the operative kinetic mechanisms, provided it may be assumed that all enzyme-substrate complexes are in the steady-state. Kinetic results obtained with the arginase-ornithine carbamoyltransferase couple, in which the intermediate ornithine is monitored, are examined in these terms to conclude that no heterogeneous association is operative between the enzymes.

Animals↗
PubMed2006

Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism.

Cardiac myocytes contain two constitutive NO synthase (NOS) isoforms with distinct spatial locations, which allows for isoform-specific regulation. One regulatory mechanism for NOS is substrate (l-arginine) bioavailability. We tested the hypothesis that arginase (Arg), which metabolizes l-arginine, constrains NOS activity in the cardiac myocyte in an isoform-specific manner. Arg activity was detected in both rat heart homogenates and isolated myocytes. Although both Arg I and II mRNA and protein were present in whole heart, Arg II alone was found in isolated myocytes. Arg inhibition with S-(2-boronoethyl)-l-cysteine (BEC) augmented Ca(2+)-dependent NOS activity and NO production in myocytes, which did not depend on extracellular l-arginine. Arg II coimmunoprecipited with NOS1 but not NOS3. Isolation of myocyte mitochondrial fractions in combination with immuno-electron microscopy demonstrates that Arg II is confined primarily to the mitochondria. Because NOS1 positively modulates myocardial contractility, we determined whether Arg inhibition would increase basal myocardial contractility. Consistent with our hypothesis, Arg inhibition increased basal contractility in isolated myocytes by a NOS-dependent mechanism. Both the Arg inhibitors N-hydroxy-nor-l-arginine and BEC dose-dependently increased basal contractility in rat myocytes, which was inhibited by both nonspecific and NOS1-specific NOS inhibitors N(G)-nitro-l-arginine methyl ester and S-methyl-l-thiocitrulline, respectively. Also, BEC increased contractility in isolated myocytes from WT and NOS3 but not NOS1 knockout mice. We conclude that mitochondrial Arg II negatively regulates NOS1 activity, most likely by limiting substrate availability in its microdomain. These findings have implications for therapy in pathophysiologic states such as aging and heart failure in which myocardial NO signaling is disrupted.

Animals↗
PubMed1987

Ubiquitous upstream repression sequences control activation of the inducible arginase gene in yeast.

Expression of the yeast arginase gene (CAR1) responds to both induction and nitrogen catabolite repression. Regulation is mediated through sequences that both positively and negatively modulate CAR1 transcription. A short sequence, 5'-TAGCCGCCGAGGG-3', possessing characteristics of a repressor binding site, plays a central role in the induction process. A fragment containing this upstream repression sequence (URS1) repressed gene expression when placed either 5' or 3' to the upstream activation sequences of the heterologous gene CYC1. Action of the URS and its cognate repressor was overcome by CAR1 induction when the URS was situated cis to the CAR1 flanking sequences. This was not observed, however, when it was situated downstream of a heterologous CYC1 upstream activation sequence indicating that URS function is specifically neutralized by cis-acting elements associated with CAR1 induction. Searches of sequences in various gene banks revealed that URS1-like sequences occur ubiquitously in genetic regulatory regions including those of bacteriophage lambda, yeast, mammalian, and viral genes. In a significant number of cases the sequence is contained in a region associated with negative control of yeast gene regulation. These data suggest the URS identified in this work is a generic repressor target site that apparently has been conserved during the evolution of transcriptional regulatory systems.

Arginase↗
PubMed2003

Arginine selective biosensor based on arginase-urease immobilized in gelatin.

Arginase and urease enzymes were immobilized on the surface of pH electrode by using gelatin membrane which is then cross-linked with glutaraldehyde. Sensor response was maximum when 2.5 mM, Tris-HCl buffer (pH 8.5) was used at 25 degrees C. The biosensor response depends linearly on arginine concentration between 0.025-0.310 mM with response time 10 min. Furthermore, application of the system for the arginine detection in serum samples was also tested.

Arginase↗
PubMed1977

Suppression of in vitro cytotoxic response by macrophages due to induced arginase.

Arginine was found to be completely depleted from cell-free supernates of mixed leukocyte cultures suppressed by the addition of excess macrophages. Partial reversal of macrophage-mediated suppression was accomplished by daily addition of a cocktail containing arginine and nonamino acid nutrients. Complete reversal of the suppression was accomplished by the addition of arginine and glucose to the medium and the nonadherent cells after their separation from the adherent macrophages. A marked increase in the enzyme arginase was found in macrophages that had been cultured 24 h in vitro in Eagle's minimum essential medium plus 10% fetal calf serum, in peritoneal cells activated by prior injection of thioglycollate, and in one spleen activated by a graft vs. host reaction.

Animals↗
PubMed2001

Activation of caspase-3 activity and apoptosis in MDA-MB-468 cells by N(omega)-hydroxy-L-arginine, an inhibitor of arginase, is not solely dependent on reduction in intracellular polyamines.

We have shown previously that (NOHA) an intermediate in the nitric oxide (NO) synthetic pathway and an inhibitor of arginase significantly reduced intracellular polyamines, activated caspase-3 and induced apoptosis in the human breast cancer cell line MDA-MB-468. These actions of NOHA were abolished in the presence of exogenous L-ornithine suggesting that a reduction in the intracellular polyamine content might be responsible for the activation of caspase-3 and apoptotic actions of NOHA. In order to further explore this possibility, we used SAM-486A and alpha-difluoromethylornithine (DFMO), which are inhibitors of S-adenosylmethionine decarboxylase (SAMDC), and ornithine decarboxylase (ODC), respectively, either alone or in combination to reduce the intracellular polyamine levels. We then assessed whether a reduction in polyamine levels by these two compounds to a similar degree to that produced by NOHA activated caspase-3 which occurs prior to the onset of apoptosis. We observed that both SAM-486A and DFMO, either alone or in combination, inhibited cell proliferation, induced p21 and arrested cells in the G(0)-G(1) phase of the cell cycle but failed to activate caspase-3 as assessed by enzymatic assay of caspase-3, western blot analysis of the proteolytic cleavage of caspase-3 protein as well as TUNEL assay. Furthermore, pre-incubation of the cells with SAM-486A and DFMO for 4 days, either alone or in combination significantly inhibited the activation of caspase-3 and apoptosis by NOHA when compared with that observed with cells treated with NOHA alone. Our results, therefore, indicate that the activation of caspase-3 and apoptosis observed with NOHA cannot be solely explained by a reduction in intracellular polyamine levels and that other mechanisms need to be also considered.

Adenosylmethionine Decarboxylase↗
PubMed2001

Overexpression of arginase alters circulating and tissue amino acids and guanidino compounds and affects neuromotor behavior in mice.

Arginine is an intermediate of the ornithine cycle and serves as a precursor for the synthesis of nitric oxide, creatine, agmatine and proteins. It is considered to be a conditionally essential amino acid because endogenous synthesis only barely meets daily requirements. In rapidly growing suckling neonates, endogenous arginine biosynthesis is crucial to compensate for the insufficient supply of arginine via the milk. Evidence is accumulating that the intestine rather than the kidney plays a major role in arginine synthesis in this period. Accordingly, ectopic expression of hepatic arginase in murine enterocytes by genetic modification induces a selective arginine deficiency. The ensuing phenotype, whose severity correlates with the level of transgene expression in the enterocytes, could be reversed with arginine supplementation. We analyzed the effect of arginine deficiency on guanidine metabolism and neuromotor behavior. Arginine-deficient transgenic mice continued to suffer from an arginine deficiency after the arginine biosynthetic enzymes had disappeared from the enterocytes. Postweaning catch-up growth in arginine-deficient mice was characterized by increased levels of all measured amino acids except arginine. Furthermore, plasma total amino acid concentration, including arginine, was significantly lower in adult male than in adult female transgenic mice. Decreases in the concentration of plasma and tissue arginine led to significant decreases in most metabolites of arginine. However, the accumulation of the toxic guanidino compounds, guanidinosuccinic acid and methylguanidine, corresponded inversely with circulating arginine concentration, possibly reflecting a higher oxidative stress under hypoargininemic conditions. In addition, hypoargininemia was associated with disturbed neuromotor behavior, although brain levels of toxic guanidino compounds and ammonia were normal.

Amino Acids↗