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PubMed1984

Cancer therapy with chemically modified enzymes. II. The therapeutic effectiveness of arginase, and arginase modified by the covalent attachment of polyethylene glycol, on the taper liver tumor and the L5178Y murine leukemia.

Monomethoxypolyethylene glycol (PEG) was attached covalently to arginase. PEG-arginase was effective in prolonging the survival times of mice injected with the Taper liver tumor, whereas unmodified arginase was ineffective. PEG-arginase was more effective than arginase in the in vitro destruction of L5178Y mouse leukemia. However, neither PEG-arginase nor arginase inhibited the in vivo growth of this tumor.

Animals↗
PubMed1999

Crystal structures of Bacillus caldovelox arginase in complex with substrate and inhibitors reveal new insights into activation, inhibition and catalysis in the arginase superfamily.

BACKGROUND: Arginase is a manganese-dependent enzyme that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. In ureotelic animals arginase is the final enzyme of the urea cycle, but in many species it has a wider role controlling the use of arginine for other metabolic purposes, including the production of creatine, polyamines, proline and nitric oxide. Arginase activity is regulated by various small molecules, including the product L-ornithine. The aim of these structural studies was to test aspects of the catalytic mechanism and to investigate the structural basis of arginase inhibition. RESULTS: We report here the crystal structures of arginase from Bacillus caldovelox at pH 5.6 and pH 8.5, and of binary complexes of the enzyme with L-arginine, L-ornithine and L-lysine at pH 8.5. The arginase monomer comprises a single compact alpha/beta domain that further associates into a hexameric quaternary structure. The binary complexes reveal a common mode of ligand binding, which places the substrate adjacent to the dimanganese centre. We also observe a conformational change that impacts on the active site and is coupled with the occupancy of an external site by guanidine or arginine. CONCLUSIONS: The structures reported here clarify aspects of the active site and indicate key features of the catalytic mechanism, including substrate coordination to one of the manganese ions and an orientational role for a neighboring histidine residue. Stereospecificity for L-amino acids is found to depend on their precise recognition at the active-site rim. Identification of a second arginine-binding site, remote from the active site, and associated conformational changes lead us to propose a regulatory role for this site in substrate hydrolysis.

Arginase↗
PubMed2004

Remission of hepatocellular carcinoma with arginine depletion induced by systemic release of endogenous hepatic arginase due to transhepatic arterial embolisation, augmented by high-dose insulin: arginase as a potential drug candidate for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is auxotrophic for the semi-essential amino acid arginine, depletion of which leads to tumor death. In humans, arginine is not an essential amino acid since many adult somatic cells can re-synthesize it from other sources, such as citrulline. Enzymes capable of depleting arginine in vitro include the urea cycle enzyme arginase, which is found in abundance in human liver. For over three decades, arginase has not been considered as a potential drug candidate because of its low substrate affinity, short circulatory half-life and sub-optimal enzymatic activity at physiological pH, though its in vitro anti-tumor activities in certain tumors have been amply reported. Arginine deiminase, a bacterial enzyme from Mycoplasma hominus has been shown to induce HCC remission through the mechanism of arginine depletion. We report here an innovative treatment approach for the treatment of locally advanced and metastatic HCC with transhepatic arterial embolisation (TAE) of the liver tumor with lipiodol and gel foam as a means of inducing a leakage of hepatic arginase from the liver into the circulation. Hepatic arginase released into the systemic circulation rapidly depleted plasma arginine. High-dose insulin was included to induce a state of hypoaminoacidaemia to augment arginine depletion. With this protocol, we have treated seven patients with locally advanced and/or metastatic HCC. Five patients achieved arginine depletion, ranging from 0 to 20 microM (normal plasma level 100-120 microM); all had varying degrees of tumor remission in their primary tumors and extra-hepatic sites in the lymph nodes, lungs and bones, suggesting systemic anti-cancer effect of arginine depletion. The two non-responders did not show significant reduction in plasma arginine. Based on our findings, we propose that the urea cycle enzyme, arginase, is a good drug candidate for the treatment of HCC.

Adult↗
PubMed2006

Arginase-flotillin interaction brings arginase to red blood cell membrane.

Flotillin-1 and arginase are both up-regulated in red blood cell membrane of type 2 diabetic patients. For studying why the soluble arginase can bind to the membrane and whether such binding would modify arginase activity, the arginase1 and related proteins were cloned and expressed. The results showed that flotillin-1 can interact with arginase1, and hence arginase activity was up-regulated by 26.8%. It was estimated that about 61% of arginase1 is bound to the membrane mediated by flotillin-1. The arginase activity in diabetic patients was significantly higher than that of the controls (752.4+/-38.5 U/mg protein vs 486.7+/-28.7 U/mg protein).

Adult↗
PubMed1983

Hybridization of subunits of rat liver arginase A1 and rat kidney arginase A4.

Recombination of subunits of rat liver arginase A1 and rat kidney arginase A4 yielded a product which in polyacrylamide gel electrophoresis and DEAE-cellulose chromatography separated into five proteins with arginase activity. Proteins I and V corresponded in polyacrylamide gel-electrophoresis, DEAE-cellulose chromatography and immunological properties to the parental forms A1 and A4, respectively. Formation of five arginase hybrids proved the tetrameric structure of native arginases.

Animals↗
PubMed2004

Prenatal diagnosis for arginase deficiency by second-trimester fetal erythrocyte arginase assay and first-trimester ARG1 mutation analysis.

Hyperargininemia is a progressive neurometabolic disorder caused by deficiency of hepatic cytosolic arginase I, resulting from mutations in the ARG1 gene. We diagnosed arginase deficiency in a three-year-old male child of first-cousin Palestinian Arab parents. Prenatal diagnosis of an unaffected fetus was achieved in the second trimester of a subsequent pregnancy by cordocentesis and analysis of arginase activity in fetal erythrocytes. ARG1 mutation analysis in the proband revealed homozygosity for a deletion of 10,753 bp extending from the first intron to beyond the poly (A) site of the gene. This is the first gross deletion in the ARG1 gene to be identified and the first mutation to be described in an arginase-deficient patient of this ethnic origin. The identification of the ARG1 deletion in this family enabled first-trimester prenatal diagnosis in a subsequent pregnancy by multiplex PCR analysis performed on chorionic villous DNA.

Adult↗
PubMed1994

Inhibition of rat liver arginase by an intermediate in NO biosynthesis, NG-hydroxy-L-arginine: implications for the regulation of nitric oxide biosynthesis by arginase.

NG-hydroxy-L-arginine, an intermediate in the biosynthesis of nitric oxide (NO), has been found to be a uniquely potent competitive inhibitor of rat liver arginase. Among previously reported inhibitors of arginase and the eight arginine analogs tested herein, only NG-hydroxy-L-arginine was found to be strongly inhibitory. Significantly, the Ki (42 microM) for inhibition of rat liver arginase by NG-hydroxy-L-arginine was found to be 20-40-fold lower than the KM (1-1.7 mM) for its natural substrate, L-arginine. Since NG-hydroxy-L-arginine is the only known intermediate in the biosynthesis of NO from L-arginine, this finding may have significant implications for the regulation of NO levels in tissues or cells, such as liver or macrophages, which synthesize both NO and contain arginase.

Animals↗
PubMed1993

Arginase deficiency manifesting delayed clinical sequelae and induction of a kidney arginase isozyme.

Deficiency of liver arginase (AI) is characterized clinically by hyperargininemia, progressive mental impairment, growth retardation, spasticity, and periodic episodes of hyperammonemia. The rarest of the inborn errors of urea cycle enzymes, it has been considered the least life-threatening, by virtue of the typical absence of catastrophic neonatal hyperammonemia and its compatibility with a longer life span. This has been attributed to the persistence of some ureagenesis in these patients through the activity of a second isozyme of arginase (AII) located predominantly in the kidney. We have treated a number of arginase-deficient patients into young adulthood. While they are severely retarded and wheelchair-bound, their general medical care has been quite tractable. Recently, however, two of the oldest (M.U., age 20, and M.O., age 22) underwent rapid deterioration, ending in hyperammonemic coma and death, precipitated by relatively minor viral respiratory illnesses inducing a catabolic state with increased endogenous nitrogen load. In both cases, postmortem examination revealed severe global cerebral edema and aspiration pneumonia. Enzyme assays confirmed the absence of AI activity in the livers of both patients. In contrast, AII activity (identified by its different cation cofactor requirements and lack of precipitation with anti-AI antibody) was markedly elevated in kidney tissues, 20-fold in M.O. and 34-fold in M.U. Terminal plasma arginine (1500 mumols/l) and ammonia (1693 mmol/l) levels of M.U. were substantially higher than those of M.O. (348 mumols/l and 259 mumols/l, respectively). By Northern blot analysis, AI mRNA was detected in M.O.'s liver but not in M.U.'s; similarly, anti-AI crossreacting material was observed by Western blot in M.O. only. These findings indicate that, despite their more long-lived course, patients with arginase deficiency remain vulnerable to the same catastrophic events of hyperammonemia that patients with other urea cycle disorders typically suffer in infancy. Further, unlike those other disorders, an attempt is made to compensate for the primary enzyme deficiency by induction of another isozyme in a different tissue. Such substrate-stimulated induction of an enzyme may be unique in a medical genetics setting and raises novel options for eventual gene therapy of this disorder.

Adult↗
PubMed1975

Interaction between arginase and L-ornithine carbamoyltransferase in Saccharomyces cerevisiae. The regulatory sites of arginase.

The inhibition of ornithine carbamoyltransferase by arginase in Saccharomyces cerevisiae, which is under the control or arginine and ornithine, involves a regulatory site for arginine on the arginase distinct from its catalytic site. This regulatory site is responsible for the reinforcement effect of arginine on the inhibition of ornithine carbamoyltransferase by arginase. The binding site of ornithine carbamoyltransferase on arginase is also shown by our analysis.

Agmatine↗
PubMed1980

Properties of fetal and adult red blood cell arginase: a possible prenatal diagnostic test for arginase deficiency.

Prenatal diagnosis of inborn errors of metabolism has been possible only if the enzyme affected is expressed in amniotic fluid cells grown in culture. Arginase is essentially undetectable in normal human fibroblasts, amniotic fluid, and amniotic fluid cells but is present in high amounts in red blood cells. It is absent in the red blood cells of patients with liver arginase deficiency. The properties of the enzyme in the red cells of healthy children and adults were compared to those of the enzyme obtained from cord blood red cells of 13--20-week fetuses obtained at hysterotomy. The activities, heavy metal requirements, heat stability, pH optimum, kinetic properties, and reaction with anti-arginase antibody were examined. Both enzyme species were either identical or substantially similar by all criteria. The adult and fetal enzymes are, therefore, probably determined by the same structural gene. Fetal red cells obtained during amniocentesis and amnioscopy should then be a suitable tissue to use to make the prenatal diagnosis of arginase deficiency.

Arginase↗
PubMed1987

Immunohistochemical localisation of arginase in human liver using monoclonal antibodies against human liver arginase.

Monoclonal antibodies against human liver arginase were raised in order to determine the exact distribution of arginase in human liver using a modified indirect unlabelled immunoperoxidase method. In normal human liver specific immunohistochemical staining was found in the cytoplasm of hepatocytes. Portal components (bile ducts and veins) and fibrous tissue were non-reactive, while erythrocytes were slightly positive. The specificity of the immunological reaction was confirmed by control tests. Spectrophotometry was used to quantitate the immunohistochemical reaction product, and the results indicated that arginase is homogeneously distributed in the liver lobule.

Animals↗
PubMed1995

Interaction of arginase with metal ions: studies of the enzyme from human liver and comparison with other arginases.

As determined by atomic absorption, fully activated human liver arginase contained 1.1 +/- 0.1 Mn2+/subunit. Upon dissociation to inactive subunits (< 0.01 Mn2+/subunit), there was decreased intensity and a red shift in the tryptophan fluorescence emission spectra of the enzyme, and the resulting species were markedly sensitive to thermal and proteolytic inactivation by trypsin. Arginine and lysine specifically protected the subunits from heat inactivation. Subunit activation by Mn2+ followed hyperbolic kinetics (Kd = 0.08 +/- 0.01 microM). In addition to Mn2+, Ni2+ and Co2+ converted inactive subunits into active monomers, and favoured their association to the oligomeric state of the enzyme (M(r) = 120,000 +/- 2000). The replacement of Mn2+ by Ni2+ or Co2+ resulted in significant changes in Vmax without any change in the Km values for the substrates (arginine or canavanine) or the Ki value for lysine inhibition. The results support our previous suggestion (Carvajal et al., 1994) that Mn2+ is not essential for substrate binding to arginase, and substantiates the conclusion that species differences may exist in the interaction of arginase with metal ions.

Arginase↗
PubMed1979

Studies of renal urea cycle enzymes. II. Human renal arginase activity and location of the adaptive changes of renal arginase in the protein deprived rat.

Rats fed 6% protein for 3 weeks with growth retardation and urinary concentration defect had 3 times higher arginase activity in the kidney cortex (10.8 +/- 28, M +/- SD) compared with controls fed 21% protein (3.3 +/- 0.9, M +/- SD). In the outer medulla there was a 50% increase of arginase activity whereas no change was observed in the inner medulla and papilla. Arginase activity in fresh human cortical tissue was of the same magnitude as in the rat. The results are in agreement with the hypothesis that intrarenal urea synthesis contributes to the maintenance of the intrarenal urea gradient in the protein deprived state. The response in the protein deprived rat might thus be an adaptation to a situation with substrate deficiency.

Adaptation, Physiological↗
PubMed1993

Nonidentity of subunits of human kidney arginase A1 and human liver arginase A5.

The main forms of arginase A1 from human kidney and A5 from human liver were purified to homogeneity. Molecular weight of both forms of enzyme approximates 120,000. In the presence of EDTA these arginases dissociate into single type distinct subunits. M(r) of both kinds of subunits is 30,000. Similarly as native arginase forms, they differ in electric charge and display complete immunological incompatibility.

Adult↗
PubMed1997

Brucella abortus arginase and ornithine cyclodeaminase genes are similar to Ti plasmid arginase and ornithine cyclodeaminase.

Brucella abortus arginase and ornithine cyclodeaminase genes have been cloned and sequenced. These gene sequences are located in the same operon and occur in the same order as the homologous genes in Agrobacterium tumefaciens Ti C58 plasmid. The nucleotide sequences of the two genes have 72% and 65% identity to the respective Ti plasmid genes. Both genes are present in a single copy, and expression of arginase is regulated in response to arginine.

Agrobacterium tumefaciens↗