Table 1: Microbial sources of L- arginase

Microbial sources	Microbes	Authors
Bacterial	Bacillus licheniformis	Laishley and Bernlohr, ¹³
	Bacillus subtilis KY 3281	Nakamura et al.,¹⁴
	Agrobacterim Ti plasmid C58	Schrell et al.. ¹⁵
	Bacillus caldovelox	Patchett et al. ¹⁶
	Streptomyces clavuligerus and Nocardia lactamdurans	Fuente et al. ¹⁷
	Bacillus brevis	Kanda et al. ¹⁸
	Cyanobacterium synechocystis sp.strain PCC 6803	Quintero et al. ¹⁹
	Arthrobacter sp.KUJ 8602	Arakawa et al. ²⁰
	Helicobacter pylori	McGree et al. ²¹
	Rhodobacter	Igeno et al. ²²
	Cyanobacteria	Flores and Herrero 2005 ²³
	Bacillus anthracis	Raines et al. ²⁴
	Chlamydia pneumonia	Hartenbach et al. ²⁵
Fungal sources	Aspergillus nidulans	Dzikowska et al. ²⁶
	Xanthoria parietina	Molina et al. ¹⁰
	Trichoderma sp.	El-Meleigy et al. ²⁷
	Agaricus bisporus	Wagemaker et al. ²⁸
	Neurospora crassa	Turner and Weiss ¹¹
Protozoan	Entamoeba histolytica	Elnekave et al. ²⁹
Protozoan	Plasmodium falciparum	Muller et al. ³⁰
Yeast	Schizosaccharomyces pombe strain 972	Kang ³¹
	Sacchromyces cerevisiae ATCC- 9763	Chan and Cossins ³²
	Evernia prunastri and Xanthoria parietina	Legaz et al. ³³
	Peltigera canina	Diaz et al. ³⁴
	Leptogium corniculatum	Vivas et al. ³⁵

Table 2: Plant sources of L- arginase

Plant sources	Authors
Lathyrus sativus seeds	Cheema et al. ⁴¹
Vicia faba	Kolloffel and Van Dijke ⁴²
Vitis vinifera	Roubelakis and Kliewer ⁴³
Canavalia ensiformis	Kavanaugh et al. ⁴⁴
Glycine max	Kang and Cho ⁴⁵
Actinidia deliciosa var. deliciosa	Hale et al. ⁴⁶
Pisum sativum	De-Ruiter and Kolloffel ⁴⁷
Panax ginseng	Hwang et al. ⁴⁸
Pinus taeda L.	Todd et al. ⁴⁹
Lycopersicon esculatum	Chen et al. ⁵⁰
Saccharum officinarum	Millanes et al. ⁵¹
Vigna catjang	Snehal et al. ⁵²
Arabidopsis	Palemeiri et al. ⁵³

Animal Sources

Arginase has been isolated from gut of earthworm, Pheretima communissima ⁵⁴. Gills and foot muscle tissues of Chiton Latus, a common mollusk has been used as a source of arginase ⁵⁵, as have enterocytes of pigs ⁵⁶.

Hemolymph of giant African land snail, Archachatina marginata is another source that has been used to extract arginase ⁵⁷. Mammals express 2 isoforms of arginase, arginase-1, a component of urea cycle found in cytosol and arginase-2 found in mitochondria and among the tissues. As the role of arginase-2 in mammalian arginase is unknown, an attempt was made to study a mouse kidney source, which indicated that arginase-2 plays an important role in arginine homeostasis ⁵⁸. To check the effect of level of arginase in rainbow trout, 2 types of arginase genes, Type I, Onmy-ARG01 and Type II, Onmy-ARG02, were influenced under varied conditions. No change in mRNA levels in Type I genes was observed, but it increased by 2-fold in Type II Onmy-ARG02 genes. The activity of liver arginase was also increased by 3-fold ⁵⁹. Other animal sources are given in Table 3

Table 3: Animal sources of L- arginase

Animal sources	Authors
Human heart	Baranczyk et al. ⁶⁰
Genypterus maculates	Carvajal et al. ⁶¹
Human erythrocytes	Ikemoto et al. ⁶²
Teleost fish (Clarias batrachus)	Singh et al. ⁶³
Enterocytes of pigs	Wu ⁵⁶
Mus booduga	Prasad et al. ⁶⁴
Human saliva	Ozmeric et al. ⁶⁵
Buffalo liver	Snehal et al. ⁵²
Notothenia rossii and Notothenia neglecta	Rodrigues et al. ⁶⁶
Rhamdia quelen	Bibiano et al. ⁶⁷
Fruit bat	Nkechi and Kayode ⁶⁸
Tissues of cat (Felis catus)	Aminlari et al. ⁶⁹
Rana temporaria	Nikolaeva et al. ⁷⁰

Production of L-Arginase

Bacillus subtilis KY 3281 has been maintained on a bouillon agar slant for the production of L-arginase ¹⁴. Cells of Sacchromyces cerevisiae ATCC 9763 were cultured aerobically at 30⁰C in a defined medium containing arginine as the sole source of nitrogen to produce L-arginase³². Vicia faba cotyledons possess ~80% of the total arginase activity ⁴². Vitis vinifera tissues, usually leaves or seedlings, have been used for extraction of arginase ⁴³. Cotyledons from peas have been ground in a pestle and mortar with sand and an extraction medium; the supernatant obtained by centrifugation of the extract contained arginase ⁴⁷. To extract arginase from soybean cells, Glycine max, 0.5 M Tris-HCl buffer (pH 8.7) was used ⁷¹. Neurospora crassa strain LA1 (wild type) was grown at 30⁰C in Vogel’s minimal medium without ammonium nitrate, but supplemented with 1.5% sucrose and 0.1% arginine as carbon and nitrogen sources to obtain an extract containing arginase ⁷². E.coli K-12 strain KY1436 cells containing pTAA 12 were grown in Luria broth containing ampicillin at 30⁰C. The suspended cells were sonicated and centrifuged to collect a supernatant containing arginase ⁷³. For the production of arginase from Schizosaccharomyces pombe, the yeast was grown in YE medium containing 1mM L-arginine ³¹. Arginase from Aspergillus nidulans was extracted from mycelium of proA6, paba A9, biA1 strain grown at 30⁰C in a minimal medium supplemented with proline, PABA, biotin and 10 mM arginine as the sole nitrogen source ²⁶. Cotyledons of Vigna catjang were homogenized in a chilled mixer with Tris-HCl buffer (pH 7.5) to produce arginase. Buffalo liver was homogenized with chilled Tris-HCl buffer (pH 7.5) and centrifuged to collect supernatant containing enzyme ⁵². A crude extract containing arginase was obtained from snails by cutting open the shells and using the hemolymph ⁵⁷.

Arginase is involved in the allergen-induced airway remodeling, inflammation and hyper-responsiveness (from a guinea pig model of chronic asthma), using the specific arginase inhibitor, 2(S)-amino-6-borono-hexanoic acid ⁷⁴. Arginase plays an important role in the pathogenesis of pulmonary disorders, e.g. asthma, through dysregulation of L-arginine metabolism and modulation of nitric oxide homeostasis ⁷⁵. cAMP has an inhibitory effect on hypoxia in human that induces arginase expression of activity and proliferation of human pulmonary artery smooth muscle cells ⁷⁶.

Purification and characterization of enzyme

Many of the procedures for extracting arginases from different living sources follow very similar lines, but with minor variations that might make a difference in each case. Perhaps these alternative methods might be used on one source to which ones give the best purification, yield, molecular weights and Kms. These could also help in confirming the subunit composition.

Arginases from Bacillus anthracis and Staphylococcus have been purified by autolysis of the acetone dehydrated bacteria, gel filtration on Sephadex G-25 column and electrophoresis horizontal zone on Sephadex G-200. This resulted in 2 crystalline forms that differed ⁷⁷. Cells of Bacillus subtilis were purified by manganese treatment, heat treatment, n-propanol fractionation, DEAE cellulose chromatography, ammonium sulfate treatment, and Sephadex G-100 chromatography to yield the purified enzyme of up to 85-fold greater specific activity, a molecular weight 115 of KDa, and a yield of 23% ¹⁴. S. cerevisiae arginase was partially purified by gel filtration on Sephadex G-200, giving maximal activity at pH 9.2, with a Km of 12.5 mM in glycinate buffer and of 120 KDa molecular weight ³²; it could be inhibited by L-ornithine. Iris bulbis arginase purified by chromatographic separation on DEAE-sephacel, aminohexyl-sepharose 4B and gel filtration had an optimal pH of 9.0, with a remarkable 25,340-fold increase in specific activity ³⁸. Xenopus laevis arginase was purified by heat treatment, acetone fractionation and isoelectric focusing, giving an isoelectric point of 7.3 for the main component and 7.8 for the minor component. Molecular weight determined by gel filtration on Sephadex G-200 was 76 KDa and subunits by SDS of 18 KDa, indicating that the enzyme is a tetramer ⁷⁸. Arginase from Pheretima communissima was purified ~10,000-fold, with a molecular weight determined by gel filtration on sephadex G-100 of 25 KDa, and a Km of 8.5 mM at pH 9.5 ⁵⁴. The crude extract was purified by streptomycin sulfate precipitation, heat treatment, ammonium sulphate precipitation, DE52 cellulose salt gradient chromatography, DE52 cellulose salt gradient chromatography, and HPLC; the resultant enzyme was purified ~450-fold, had a molecular weight of 266 KDa and a Km of 131 mM at pH 9.5 ⁷². Arginase enzyme purified from muscle tissues of mollusc Chiton latus is a dimeric molecule of about 79 KDa, and a Km of 3 mM at pH 9.5⁵⁵. Arginase from soybean, Glycine max axes, purified by chromatographic separation on Sephadex G-200, DEAE-sephacel, hydroxypatite and an arginine affinity column yielded an enzyme purified to ~150-fold with a maximal activity at pH 9.5 and a Km of 83 mM. It proved to be stable at 4⁰C for 1 month ⁴⁵. Arginase from jack bean leaves was purified by ammonium sulfate precipitation, DEAE cellulose column, sephadex G-200, arginine linked sepharose, giving a Km of 28 mM ⁴⁴. When arginase from Rhodobacter capsulatus was purified to electrophoretic homogeneity, it had molecular parameters and kinetic constants similar to those of S. cerevisiae and not to bacterial arginases ⁷.

Fungal arginase from Aspergillus nidulans has been purified by heat treatment, ammonium sulphate precipitation, Bio-Gel P-60 gel filtration, DEAE-cellulose salt gradient chromatography and extracted from polyacrylamide gels to give a purification factor of 50 ²⁶. Arginase from kiwi fruit was purified by ammonium sulphate precipitation, DEAE cellulose column gave a 60-fold purification, an optimal pH 8.8, with its activity being highly dependent upon the presence of Mn²⁺ ⁴⁶. Loblolly pine arginase was purified by chromatographic separation on DE-52 cellulose, matrix green and arginine linked sepharose 4B to give a 150 fold purified enzyme ⁴⁹. Purification of cotyledon and buffalo liver arginase was carried out by ammonium sulphate precipitation, chromatographic separation on Bio-gel P-150, DEAE cellulose, arginine linked affinity with a 2,030 fold purification and 18% recovery, with a molecular weight (by SDS-PAGE) of 52 KDa for Vigna catjang and 43 KDa for buffalo liver, and Kms of 42 mM and 2 mM for cotyledon and liver respectively ⁵².

Liver arginase from fruit bat was purified by ion exchange chromatography on DEAE cellulose and CM sephadex columns and gel filtration on Bio-gel P-100, giving a Km of 17mM and a Vmax of 1.4µmol/ml/min at pH 9.0. Its molecular weight on Sephadex G-200 column was 80 KDa, comprising 2 subunits with molecular weights of 34 and 52 KDa, suggesting that enzyme exists as dissimilar subunits or as a multimer ⁶⁸. Human erythrocyte arginase has been purified by hydrophobic and immunoaffinity chromatography to yield 0.7 mg of homogeneous arginase protein. Its molecular weight determined by gel filtration on Sephadex G-150 column was 105 KDa, with subunits of 35 KDa ⁶². Arginase from A. marginata was purified by reactive blue2-agarose chromatography and gel filtration on biogel P-200, giving a 4-fold purification and a 55% yield ⁵⁷.

Applications of L –arginase

Arginine biosensors

For monitoring a change in pH, a fiber-optic sensor based on immobilization of phenol red, cresol red and bromophenol dyes in sol-gel techniques have been developed ⁷⁹. A hybrid arginine biosensor was developed by co-immobilization of bovine liver and Cajanus cajan tissue acting as a source of arginase and urease, respectively, on a modified stainless steel electrode⁸⁰.

A novel plant system based biosensor for detecting environmental hazards has been described ⁸¹. Furthermore, arginase and urease have been immobilized on the surface of a pH electrode by using a gelatin membrane that has been cross- linked with glutaraldehyde ⁸². The fiber is used to guide the output light to the detector where reflected, emitted or absorbed light can be measured by a fluorimeter and a spectrophotometer ⁸³. A sol–gel film based on TEOS, doped with fluorescein and phenol red indicator, has been produced for sensing NH₄⁺ ⁸⁴.

A potentiometric urea biosensor has been developed for clinical purposes ⁸⁵. A potentiometer L-arginine bi-enzyme biosensor has also been developed based on recombinant human liver arginase-1 ⁸⁶. Co-immobilization of arginase and urease allows the conductimetric detection of L-arginine. Another highly sensitive biosensor is based on crosslinking with glutaraldehyde⁸⁷.

L-arginase: An enzyme currently of considerable therapeutic value in medicine

L-arginase, when considered from medical viewpoint, has been used for the treatment of various disorders, including neurological disorders, rheumatoid arthritis, asthma therapy and cancer therapy. Hyperargininemia is caused by arginase deficiency and being an inherited urea cycle disorder ⁸⁹. Arginine contributes significantly to immune function by increasing white blood cells; while dietary supplementation of breast cancer patients with arginine enhances NK cell activity and lymphokine cytotoxicity, it did not lead to any remission ⁸⁸.

Arginase is essential for the treatment of acute neurological disorders ⁹⁰. Ornithine produced by arginase in the urea cycle is essential for collagen production, which can be useful in the treatment of rheumatoid arthritis ⁹¹. HeLa, L1210 and many other cancer cells in culture are vulnerable to arginase in the same way just as they are to culturing in arginine-free medium, whereas normal cells survive by moving out of cycle ⁹². Arginase also possesses high oncolytic activity without showing any side-effects ⁹³. The process of arginine hydrolysis regulates the synthesis of polyamines and proline, which are essential compounds for cell proliferation and growth ⁹⁴. Arginase-1 is expressed in human granulocytes and shows fungicidal activity by anti-microbial effector pathway ⁹⁵. Arginine is synthesized from epithelial cells of small intestine and kidney, but in deficiency conditions due to dysfunction of the kidneys or small intestine, it may not be synthesized in sufficient amounts and therefore needs to be supplied through the diet ⁹⁶. The control of hepatocarcinogenesis has been described by the means of altering arginine metabolism through changes in arginase activity ⁹⁷. Even in normal development in mammals, there are growth supports during which arginine becomes a limiting factor, which is why it must be provided in the diet - hence its designation as a semi-essential amino acid.

Nitric oxide (NO) is used as a biomarker for asthma, and small molecule arginase inhibitors may have some potential as in therapy of the condition, as also seen in recent work on the role of L-arginase mediated L-arginine metabolism ⁹⁸.

Benefits of L-arginine

Arginine has multiple metabolic fates, such as a precursor of nitric oxide, polyamines, agmatine, creatine, ornithine and urea, as seen in the following circumstances:

In the skeletal-muscle system:

High intensity dynamic human muscle performance is enhanced by arginine, and the amino acid is now being promoted throughout the healthy living sector involving dietary supplements ⁹⁹. Arginine administration can reduce the effects of sepsis and infection through the NO pathway ¹⁰⁰.

In the sexual system:

Arginase supplementation plays a vital role in improving sperm count and sperm motility ¹⁰¹. Sexual performance is also enhanced by arginase in women ¹⁰². However, erectile dysfunctioning disorder in cases of arginase deficiency has been noted ¹⁰³. Prostate functioning is also improved by endogenous nitric oxide-mediated relaxation and nitrinergic innervations following arginase administration ¹⁰⁴.

In nervous system:

Arginine plays a role in regeneration of damaged axons of neurons, acting as an agent for degrading proteins damaged through axon injury ¹⁰⁵. It has been claimed that it also acts as a memory enhancer and hormonal control modulator ^{106, 107}. It is useful in the treatment of Alzheimer’s disease through its ability to increase polyamine levels and help repair damaged axons ¹⁰⁸.

In treating heatstroke and in aging process:

L-arginine increases the release of the anti-aging hormone, i.e. human growth hormone, from the pituitary gland ¹⁰⁹. A study of heatstroke in mice showed that this could be controlled by administration of an appropriate concentration of arginine and increases in the levels of hepatic and splenic arginase with time ¹¹⁰.

In the skin:

Arginine plays a role in healing wounds by stimulating proliferation of fibroblasts, the release of human growth hormone and the production of collagen ¹¹¹. Treatment increases vascular endothelial growth factor release, which is helpful in keeping the skin young and can also improve scleroderma ^{102, 112}. A high risk of infection after cardiac surgery can be reduced where healing of wounds is dramatically accelerated. An immune-enhancing nutritional supplement containing L-arginine, omega-3-polyunsaturated fatty acids and yeast RNA has been given to patients to improve the outcome of elective cardiac surgery ¹¹³.

In the excretory, digestive and immune systems:

Arginine supplementation lessens the pain and discomfort associated with interstitial cystitis ¹¹⁴. Its administration can also decrease the risk of gallstones and reduce intestinal permeability, but arginine deficiency generally causes constipation. In many cases of ulcerative colitis, arginine promotes the healing of ulcers that occur in the colon region^115,116. During sickle cell anemia, a pathogenic disease, levels of arginase are increased ¹¹⁷. It is clear from these and many other studies that disturbance of the (often) delicate balance between arginine and arginases in the body can have quite widespread effects.

Cancer:

Human liver-derived inhibitory protein (LIP) were identified and purified as cytoplasmic liver arginase; however, enzyme activity was increased by addition of manganese ions. Inhibitory effects on cell proliferation can also be reversed by arginine ¹¹⁸. Hepatitis C disease progression involves altered arginine metabolism and arginase activity which can be an important area for development of therapeutic strategies for its treatment ⁹⁷.

Mouse myeloid leukemic M1 cells treated with rH-TNF (recombinant human tumor necrosis factor) induces increased arginase activity, leading to differentiation of these cells in vitro ¹¹⁹. Arginase treatment of cultured HeLa and L1210 cells proved as efficient as arginine-free (including dialysed serum) in the medium to around 1 micromolar within 20 minutes, resulting in cell death in these cultures in as short a time as 2 days in the later ⁹². Similar studies have covered dozens of other cell lines, with those that expressing argininesuccinate synthase and arginine succinate lyase to be relatively resistant. Furthermore, administration of arginase to animals (from mice to dogs) can reduce it to a similarly low level within an hour, and can be kept low for a number of days when pegylated. These findings have been confirmed by investigators at Hong Kong Polytechnic University produced a human recombinant arginase (using state-of-the-art DNA technology), and further developed protocol in the treatment of liver cancer, melanoma and acute lymphocytic leukemia in laboratory animals and the human clinic ¹²⁰. The combination of the recombinant pegylated arginase with an anti-neoplastic agent, 5 fluorouracil (5FU), for possible treatment of human malignancies, has been tested in nude mice bearing an ADI-resistant HCC xenograft and proved to be relatively effective. However, this clearly requires much work to optimize the protocol through different enzyme treatment levels and windows, as also through studies on many other possible anti-cancer drugs that work synergistically, especially where they can be used at “sub-clinical” levels to reduce side effects to a minimum ^{121, 122, 124, 125}.

Arginase activity was increased in the serum of ~85% patients suffering from colorectal cancer liver metastases (CRCLM), which led to the conclusion that arginase can be a useful marker for the diagnosis of CRCLM ¹²³. This group has further proposed the use of rhArg1 alone or in combination with chemotherapeutic drugs for treatment of liver cancer in vitro cytotoxicity of human arginase-1 by replacing the two Mn²⁺ ions normally present in the enzyme with Co²⁺ significantly lowered the Km value of the enzyme, increased its serum stability and showed its ability to eliminate human hepatocellular carcinoma and melanoma cell lines proving it to be a capable new contender for treatment of L-Arg auxotrophic tumors ¹²⁶. The potential therapeutic role of pegylated Arginase-1 in the treatment of adult patients with acute lymphoblastic T cell leukemia (T-ALL) through arginine depletion has been reported ¹²⁷. Increased argininosuccinate synthetase-1 expression by hepatocellular and pancreatic carcinoma cells for increasing L-arginine concentration was insufficient, which suggests an arginine depletion mechanism needs to be used in arginine-dependent therapeutic protocols ¹²⁸. Arginine deaminase PEG20 plays a role in the treatment of small cell lung cancer tumours and cell lines which were assessed with negative argininosuccinate synthetase ¹²⁹. Molecular mechanism of arginine deaminase activity was studied by site-directed mutagenesis. Three mutation sites were introduced into wild-type arginine deaminase gene and 4 ADI mutants, expressing the enzyme Escherichia coli BL21 (DE3) were obtained ¹³⁰. Recombinant human arginase causes cytotoxicity in prostate cancer cells by decreasing ornithine carbamoyl transferase expression ¹³¹. Arginine-depleting therapy with pegylated arginine is affected in patients who show negative argininosuccinate synthetase expression in melanoma tumours. However possitive argininosuccinate synthetase expressions results into tumour progression ¹³².

Many laboratories and clinics have now described the complex role of arginine in the treatment of cancer and cancer cell biology, but it is involved in so many metabolic pathways making precise conditions needed for the treatment of cancer and many other diseases very difficult to achieve. However, arginase (and other catabolic enzymes) have a very definite place in the arsenal of modalities that can be of therapeutic value today and in the future. One definite benefit is that the use of a homologous (non-immunogenic) enzyme, even when coupled with sub-clinical doses of anticancer drugs (or other modalities), will have far fewer side effects than the plethora seen with many (if not most) present therapeutic regimes. This part of the review on arginine and arginase in cancer is not comprehensive; indeed it cannot be so with the numerous publications on the subject over the last 12-15 years, and with a history that goes back to the early 1950s. Thus the reports chosen in this section are aimed at giving a general outline of some of the more important steps taken in these important areas of experimental and clinical investigations.

ACKNOWLEDGEMENT:

The authors wish to thank Modi Education Society, Patiala for encouragements. The Author will specially like to thank Prof. Denys N. Wheatley from BioMed ES Ltd., Aberdeen for critically reviewing and helping in preparation of manuscript.

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Received on 30.09.2013 Modified on 22.10.2013

Research J. Pharm. and Tech. 6(12): Dec. 2013; Page 1430-1438