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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.
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Methoxypolyethylene glycol of 5000 daltons (PEG) was attached covalently to bovine liver arginase using 2,4,6-trichloro-s-triazine as the coupling agent. The conjugate (PEG-arginase), with PEG attached to 53% of the amino groups, retained 65% of its original enzymatic activity. Mice were injected intravenously with arginase or PEG-arginase for periods of one to three months. The blood-circulating life of PEG-arginase was greatly extended over that of arginase. The half-life of injected arginase at day 30 was less than 1 h, whereas that of the PEG-enzyme was 12 h. Antisera from mice injected with native arginase reacted against arginase but not against PEG-arginase when tested by immunodiffusion. Antisera from animals injected with PEG-arginase reacted neither with native arginase nor PEG-arginase. The data indicate that arginase modified by PEG has been rendered both non-immunogenic and non-antigenic when tested in mice. The injection of PEG-arginase into mice did not induce tolerance toward the native enzyme. Injected PEG-arginase, in the presence of precipitating antibody directed against native arginase, circulated at the same level as in virgin animals. The attachment of PEG to arginase altered its kinetic properties.
Chicken kidney contains two arginases with different sedimentation coefficients and substrate specificity. The ligher of these arginases, which hydrolyses only L-arginine, has been purified about 3000-fold. Like the "ureotelic" arginase, developed in chicken liver after starvation, it displays many of the properties of the arginase of the "ureotelic" species. This seems to exclude the possibility that ureotelism and uricotelism are characterized by a specific type of arginases. Both liver and kidney arginases are located in the mitochondrial matrix. The rate of hydrolysis of arginine thus not only depends on the arginase activity but also on the rate of transport of arginine into the matrix. This last process therefore is of regulatory significance.
Arginase, the enzyme responsible for arginine degradation in Saccharomyces cerevisiae, is an inducible protein whose inhibition of ornithine carbamoyl-transferase has been studied extensively. Mutant strains defective in the normal regulation of arginase production have also been isolated. However, in spite of these studies, the macromolecular biosynthetic events involved in production of arginase remain obscure. We have, therefore, studied the requirements of arginase induction. We observed that: (i) 4 min elapsed between the addition of inducer (homoarginine) and the appearance of arginase activity at 30 degrees C; (ii) induction required ribonucleic acid synthesis and a functional rna1 gene product; and (iii) production of arginase-specific synthetic capacity occurred in the absence of protein synthesis but could be expressed only when protein synthesis was not inhibited. Termination of induction by inducer removal, addition of the ribonucleic acid synthesis inhibitor lomofungin, or resuspension of a culture of organisms containing temperature-sensitive rna1 gene products in a medium at 35 degrees C resulted in loss of ability for continued arginase synthesis with half-lives of 5.5, 3.8, and 4.5 min, respectively. These and other recently published data suggest that a variety of inducible or repressible proteins responding rapidly to the environment may be derived from labile synthetic capacities, whereas constitutively produced proteins needed continuously throughout the cell cycle may be derived from synthetic capacities that are significantly more stable.
The final products of the arginine catabolism that can be utilized as a nitrogen source in Neurospora crassa are ammonium, glutamic acid, and glutamine. The effect of these compounds on arginase induction by arginine was studied. In wild-type strain 74-A, induction by arginine was almost completely repressed by glutamic acid plus ammonium, whereas ammonium or glutamic acid alone had only moderate effects. Arginine products of catabolism also repressed arginase induction. A mutant, ure-1, which lacks urease activity, hyperinduced its arginase with arginine as a nitrogen source. The addition of either ammonium or glutamine produced effects similar to those in the wild-type strain. The effect of ammonium on arginase induction is mediated through its conversion into glutamine. This was demonstrated in mutant am-1, which lacks L-glutamate dehydrogenase activity. In this mutant, the effect of glutamic acid was reduced, and, with ammonium, it was completely lost. The addition of glutamine or glutamic acid plus ammonium to this strain decreased by threefold the induction of arginase by arginine. Proline, a final product of arginine catabolism, competitively inhibited arginase activity. This effect and the repression of arginase by glutamine are examples of negative modulation of the first enzyme in a catabolic pathway by its final products.
Bacillus licheniformis has two pathways of arginine catabolism. In well-aerated cultures, the arginase route is present, and levels of catabolic ornithine carbamoyltransferase were low. An arginase pathway-deficient mutant, BL196, failed to grow on arginine as a nitrogen source under these conditions. In anaerobiosis, the wild type contained very low levels of arginase and ornithine transaminase. BL196 grew normally on glucose plus arginine in anaerobiosis and, like the wild type, had appreciable levels of catabolic transferase. Nitrate, like oxygen, repressed ornithine carbamoyltransferase and stimulated arginase synthesis. In aerobic cultures, arginase was repressed by glutamine in the presence of glucose, but not when the carbon-energy source was poor. In anaerobic cultures, ammonia repressed catabolic ornithine carbamoyltransferase, but glutamate and glutamine stimulated its synthesis. A second mutant, derived from BL196, retained the low arginase and ornithine transaminase levels of BL196 but produced high levels of deiminase pathway enzymes in the presence of oxygen.
The unknown biochemical role of arginase in epidermal metabolism was probed by examining the association of elevated arginase activity with epidermal hyperplasia and hyperkeratinization. Epidermal hyperplasia was induced experimentally by topical application of 1-decanol to the right side of male hairless mice while the contralateral side served as control. Arginase activity, incorporation of 3H-thymidine into DNA, DNA and protein content were measured in the separated control and experimental epidermis six hours and on days 1 through 5 and 7 after 1-decanol application. After six hours, the epidermis appears damaged histologically, and DNA synthesis is inhibited. By day 1, incorporation of 3H-thymidine into DNA is elevated and a new hyperplastic epidermis has formed beneath the original epidermis. Epidermal arginase is elevated two through seven days after 1-decanol application and always is associated with continuing epidermal hyperplasia. The stimulation of DNA synthesis, which parallels the induction of epidermal hyperplasia by 1-decanol, precedes the induction of epidermal arginase activity. An attempt to relate these results with polyamine synthesis and other metabolic events is made.
Arginase was isolated from human liver and erythrocytes. The purification procedure used acetone precipitation, heat-treatment, (NH4)2SO4 precipitation, DEAE-cellulose chromatography and gel filtration on Sephadex G-200 in the presence of 2-mercaptoethanol. Both enzymes migrated to the anode at pH8.3 on polyacrylamide-gel electrophoresis. After incubation at pH8.0 and 37 degrees C the purified anionic liver arginase migrated to the cathode on polyacrylamide-gel electrophoresis. It is assumed that the multiple forms of the enzyme reported in the literature are partly artifacts of the purification procedure. The liver arginase showed a mol.wt. of 107000 determined by gel filtration and a sedimentation coefficient of 5.9S. Treatment of the liver enzyme with 0.25% sodium dodecyl sulphate at pH10 demonstrated an oligomeric structure of the enzyme with a mol.wt. of the subunit of 35000. The kinetic properties determined for the purified liver arginase showed an optimum pH of 9.3 and an optimal MnCl2 concentration of 2mM. The Km for L-arginine was 10.5 mM and for L-canavanine 50mM, and L-lysine exhibited a competitive type of inhibition with a Ki of 4.4mM. L-Homoarginine was not a substrate for liver arginase.
Experiments were carried out to study urea excretion during arginine or ornithine infusion into wing veins of hens previously fed diets that induced different arginase levels in their kidneys. Urea excretion was found to increase as plasma arginine increased. Hens with high levels of arginase activity in their kidneys had a greater increase in urea excretion than hens with low kidney arginase activity. Arginine degradation was also dependent on both the kidney arginase activity and on the plasma level of arginine. Ornithine infusion did not inhibit urea excretion even when high levels of plasma ornithine were reached. Even though ornithine was an in vitro inhibitor of arginase, no evidence was obtained of in vivo inhibition.
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.
1. Arginase was found to be present in the intestine in all species of Annelida, Arthropoda and Chordata studied. 2. The activity of intestinal arginase differs from species to species, the differences reaching two orders of magnitude (100 x). 3. The highest activity of intestinal arginase was observed in the rodents (mouse, rat, hamster). 4. In animals in which the enzyme activity was high or moderately high, arginase activity showed topographical differentiation along the long axis of the intestine.
1. The enzyme arginase in chicken kidney is associated with mitochondria and the mitochondrial membranes must be disrupted to obtain maximum activity. 2. When the membranes were disrupted by sonication, approximately 30% higher 2. When the membranes were disrupted by sonication, approximately 30% higher arginase activity was observed than with the nonsonicated samples. 3. The optimum pH for assay of chick kidney arginase was 9.7-9.8. Prior heat treatment with Mn2+ decreased arginase activity. 4. Highest enzyme activity was obtained by using sonicated preparations and measuring initial reaction velocity during the first 1-2 min of incubation.
1. The anionic calf liver arginase, like the cationic rat liver enzyme, is inactivated by EDTA-treatment. The activity is fully restored by Mn2+. A smaller effect is observed with Cd2+, Ni2+ and Co2+. 2. The EDTA-inactivated calf liver arginase, unlike the rat liver enzyme, does not dissociate into subunits, and its mol.wt. (120 000) is unchanged. 3. The reactivation of rat liver arginase subunits (mol.wt. 30 000) by Ni2+ is accompanied, similarly as in the case of Mn2+, by reassociation to the form of mol.wt. 120 000, i.e. the same as for the native enzyme. 4. It is suggested that Mn2+ in arginase is bound at the active site and at the site responsible for maintenance of the oligomeric structure. In calf liver enzyme this binding site is inaccessible to the chelating agent.
Experimental corneal herpes is always accompanied by the accumulation of arginine, the substrate of arginase, in tears, ensuring the multiplication of the herpes hominis virus. The main source of the large amount of arginine is the desquamating corneal epithelium, since after the epithelium of the cornea is abraded the arginine content of the tears again equals that of healthy tears. The low arginase content of rabbit tears can be supplemented by arginase applied as eyedrops, and this results in the cure of the herpetic process.
Incubation of soluble human liver arginase (L-arginine amidinohydrolase, EC 3.5.3.1) with p-hydroxymercuribenzoate resulted in the dissociation of the enzyme into active dimers. Addition of 2-mercaptoethanol resulted in the regeneration of the tetrameric enzyme. When arginase, bound covalently to nylon, was incubated with p-hydroxymercuribenzoate, matrix-bound dimers were obtained. Incubation of these species with 2-mercaptoethanol resulted in stable, unmodified dimers. Based on this dissociation of arginase, a model with D2-symmetry is suggested for this enzyme. The specific activity, the Km value for arginine, pH optimum and the inhibition constants for ornithine and lysine were determined for monomeric, dimeric and tetrameric forms. It is concluded that the behaviour of the active sites of the monomers is not substantially altered by the interaction of these species in the oligomeric molecule.
A technique for arginase determination in body fluids in the presence of urea is described. [14C]Arginine is hydrolysed by arginase to [14C]urea and ornithine. [14C]Urea is separated with paper chromatography and measured in a liquid scintillation counter. The experimental conditions including the pH, substrate concentration, activator, solvent for chromatography, urea inhibition, and arginase in hemolysates, are discussed.