Int J Pharm Pharm Sci, Vol 10, Issue 11, 1-5Review Article


ARTHROBACTER AS BIOFACTORY OF THERAPEUTIC ENZYMES

SHABNAM, WAMIK AZMI*

Department of Biotechnology, Himachal Pradesh University, Summer Hill, Shimla, Himachal Pradesh, India
Email: wamikazmi@rediffmail.com

Received: 14 Mar 2018 Revised and Accepted: 04 Oct 2018

ABSTRACT

Therapeutic enzymes are proteins which can be used to treat rare and deadly diseases. They represent a small but profitable market. Therapeutic enzymes are superior to non-enzymatic drugs owing to their high specificity toward the target and also their ability to multiple substrate conversion. They are essential for speeding up all the metabolic processes and many a life-supporting chemical inter-conversions. Actinomycetes including Arthrobacter form an enormous reservoir of secondary metabolites and enzymes. The characterization of L-asparaginase, β-glucosidase, urate oxidase, methionine γ-lyase, acetyl cholinesterase, and arginase activities from actinomycetes Arthrobacter clearly demonstrate the potential of Arthrobacter as potent producer of therapeutic enzymes. These metabolic enzymes can be used either separately or in combination with other therapies for the treatment of several diseases such as leukemia, gout, asthma, and neurological disorders. The objective of this review is to compile the information on the application of therapeutic enzymes produced by Arthrobacter and their future prospects as drugs.

Keywords: Actinomycetes, Arthrobacter, Diseases, Therapeutic enzymes, Therapies

© 2018 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open-access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijpps.2018v10i11.25933

INTRODUCTION

Among new drug substances, the use of proteins as pharma-ceuticals is steadily increasing [1]. Microbes contribute to the production of the majority of commercially important bioactive compounds. The microorganisms have proved to be very efficient and economical source of therapeutic enzyme and are preferred over plants and animals, owing to their economic cultivation, stability, flexibility in process modification and optimization. All these characteristics facilitate the large-scale microbial production of enzymes [2]. Actinomycetes are widely distributed in the earth’s ecosystem and are the most potent resource of biotechnological and pharmaceutical studies [3]. Previous studies conducted on actinomycetes were directed mainly on antibiotic production, only a few reports citing the potential of actinomycetes for the production of enzymes have been listed.

Microbial isolates belonging to genus Arthrobacter are a notable source for the production of therapeutic enzymes. The Arthrobacter genus constituted by Conn and Dimmick [4] consisting of more than 84 species exhibiting high G+C content ranging from 59 to 66 mol% [5]. The species of Arthrobacter genus are most prevalent amongst soil bacteria. The member species of genus Arthrobacter are Gram-positive and obligate aerobes. They form a soft and smooth colony which is yellow to white in coloration [6, 7]. They undergo rod-coccus growth cycle. However, some members of the genus are spherical in shape, occurring in pairs and tetrad similar to A. agilis [4]. A. atrocyaneus, A. citreus and A. simplex exhibit mobility initially, but become non-motile after attaining coccoid morphology [8]. The Arthrobacter genus is metabolically versatile producing many different enzymes and also resilient to undesirable environmental conditions. They are prolific sources of medically important enzymes with multifarious applications. They are also used in the bioremediation of groundwater contaminated with pesticides and herbicides [9]. Arthrobacter sp. genera serve as bioindicators of contaminated habitats and also act as agents for bioremediation of contaminants, mostly by facilitating the synthesis of proteins for cellular survival [10].

The application of microbial enzymes as the drug is an important aspect of the present-day pharmaceutical industry. A very high degree of purity is needed for therapeutic enzyme preparations. Usually, enzymes with low Km and high Vmax value are selected because of their maximal efficiency even at a very low concentration of enzyme and substrate. Thus, the selection of sources for the production of such enzymes is crucial [2]. A number of medically useful enzymes have been reported from genus Arthrobacter. Subsequently, isolates of Arthrobacter genus gained much attention of researchers. Taking into consideration the importance of therapeutic enzymes, the enzymes produced by the members of the genus Arthrobacter can be classified into three categories. These are pharmaceutical enzymes where the protein directly acts as the therapeutic agent, prodrug-activating enzymes where the protein indirectly results in a clinical effect and diagnostic enzymes where the protein is highly selective and specific to target and provide merit over available analytical methods (fig. 1). The information on the application of medically important enzymes produced by the members of the genus Arthrobacter is compiled in this review to explore the future prospects of these therapeutic enzymes as drugs.

Fig. 1: Schematic illustration of different therapeutic enzymes reported from Arthrobacter sp

Therapeutic enzymes producing Arthrobacter sp. of terrestrial origin

Soil represents a promising habitat for discovering and isolating new natural products, and only<1% of soil bacterial species are currently known [11]. The Arthrobacter genus is an indigenous flora of soil and usually consists of an important section of the rhizosphere microflora. A key characteristic of Arthrobacter is their nutritional versatility with simple nutritional needs together with the ability to exploit a number of compounds as a source of carbon and nitrogen. The main features of Arthrobacter held responsible for their prominent ecological presence in arid soils are the minimum growth rate, the rapid decrease in endogenous metabolism, the accumulation of a considerable amount of reserve material, the high resistance to desiccation in soil, the small spheroidal shape of cells and the long survival times during starvation [12].

Cold-active β-galactosidase producing Arthrobacter sp. SB has been reported from Antarctic soil samples. This enzyme has an optimal growth temperature of 15-20 °C at pH 7.0 and a subunit molecular mass of 114 kDa. It is specific for lactose and not inhibited by calcium or sodium ions present in milk [13]. All these properties render it useful for the production of low-lactose milk for lactose intolerant people and can also be used as a supplement along with amylase, lipase, and protease in lactose intolerant people. Other species, namely A. psychrolactophilus F2, Arthrobacter sp. 32cB, Arthrobacter sp. 20B and Arthrobacter sp. ON14 were also reported for production of cold-active β-galactosidase [14]. Arthrobacter sp. SD5 isolated from oil containing soil samples with lipase activity possess pharmaceutical applications. They studied medium composition and culture conditions for improved production of lipase. Olive oil (2.5%) as a carbon source, peptone (1.0 %) as a nitrogen source and Tween-80 (0.2%) as biosurfactant gave the optimal lipase yield [15]. Arthrobacter sp. strain PF01 obtained from Penguin feathers collected from Elephant Island, Antartica was found to produce keratinase with potential medical use [16]. Isolated a bacterium from ornithogenic soil and feather fragments with keratinolytic activity in low temperature (5°C). Arthrobacter sp. strain PF1 was identified based on morphological and biochemical tests and 16S rRNA sequencing. e bacterium presented optimum growth at 4 and 25 °C, but not at 37 °C. Proteolytic activity was observed at 4 and 25 °C in pH 7 an

Therapeutic enzyme producing Arthrobacter sp. of aquatic origin

Over billions of years, the ocean has been regarded as the origin of life on the Earth. Thereby marine microbial enzymes can offer novel biocatalyst with extraordinary properties. The best marine source of bacteria is sediment and also reported from water, sand, rocks, marine plants, mangrove sediment, and deep sediment. The psychrotrophic bacterium Arthrobacter sp. 32c isolated from Antarctic Ocean reported to produce cold-adapted β-D-galactosidase. The enzyme is active at 4-8 °C and of molecular weight of 195 kDa and 75.9 kDa for native protein and monomer subunit respectively [17]. The lactose intolerance person is not able to metabolise lactose due to a congenital deficiency of the enzyme β-galactosidase [18]. The β-galactosidase enzyme can be used to treat lactose intolerance. The bacterium A. oxydans producing dextranase was isolated from sea mud samples. This dextranase was reported for removal of dental plague and to treat dental caries [19].

An Arthrobacter sp. strain MAT3885 efficiently degrading chondroitin sulfate was isolated from marine environments. The optimum activity of chondroitin sulphate lyase was at pH 5.5-7.5 and 40 °C, with 10 min of reaction time. The native enzyme was found to be a monomer [20]. It has been exposed analytically that chondroitin lyases inhibit melanoma invasion, proliferation, angiogenesis and to treat invertebral disc protrusion. It fosters the reclamation of axons of the central nervous system after injury [21]. The bacterium A. ilicis isolated from the marine sponge Spirastrella sp. produces extracellular serine-type acetylcholinesterase. The maximum activity of acetyl cholinesterase was found at pH 8.0 and 45 °C [22]. Arthrobacter sp. strain TAD20, a chitinolytic organism, was isolated from the sea bottom along the Antarctic ice shell. The bacterium secretes two major chitinases, ChiA and ChiB in response to chitin induction [23]. These chitinases exhibit medical functions like elicitor action and anti-tumor activity and to treat human diseases like asthma [24].

Production of enzymes with biomedical applications by Arthrobacter

The major therapeutic enzymes produced by Arthrobacter along with their applications have been presented in table 1.

L-asparaginase an important therapeutic enzyme belongs to amidase group. It accounts for about 40% of the global total enzyme sale. It is engrossed for the treatment of childhood acute lymphoblastic leukemia [25]. Its antileukemic effect work on the fact that tumor cells are incapable of synthesizing L-asparagine due to lack of aspartate-ammonia ligase activity. Administration of asparaginase depletes free exogenous L-asparagine thus left tumor cells in a state of fatal starvation [2].

Urate oxidase is an effective curative agent in gout treatment and act as a therapeutic drug to regulate uric acid levels. Urate oxidase was also used as a reagent to monitor uric acid levels in body fluids [26]. ElitekTM is commercially available intravenous dosage form of urate oxidase, which not only resolves the deposition of newly synthesized urate but also eliminates the long-standing tissue deposits [27, 28].

β-glucosidase obtained from A. chlorophenolicus catalyzes efficient biotransformation of major ginsenosides to highly active minor ginsenosides like F2, Rh1,F1, etc. These minor ginsenosides show highly significant pharmacological activities including anti-fatigue, anti-inflammation, anti-neoplastic, anti-fatigue, anti-oxidant and anti-diabetic effects. The enzymatic transformation on these compounds is advantageous as it results in fewer byproducts, better environmental protection and higher stereo-specificity [29].

Methionine γ-lyase (MGL) is used as a drug target for contagious ailments evoked by parasitic protozoa and anaerobic periodontal bacteria. Recombinant MGL also administered to cause a decline in the concentration of methionine essential for the growth of cancer cells. MGL degrades sulphur containing amino acids to α-keto acids, ammonia and volatile thiols [30].

Acetylcholinesterase is mainly found at neuromuscular junctions where it serves to terminate synaptic transmission by hydrolyzing acetylcholine to inactive components namely choline and acetic acid. It is necessary for the conduction of impulses along the nerve and muscle fibers. It is used as a vaccine against Dictyocaulus viviparous and as a pretreatment drug in organophosphorus poisoning [22]. It is considered to be an important neurotransmitter in the regulation of cognitive function [31]. This enzyme regulates the acetylcholine levels, an anti-inflammatory molecule associated with the inflammatory response during parasitic diseases [32].

Chondroitin lyase obtained from Arthrobacter sp. MAT3885 is effective in enhancing the regeneration of the central nervous system after injury and also help in improving keloid pathology. It is a chondroitin sulfate degrading enzyme results in production of chondroitin sulfate oligo or disaccharides which have a broad biological activity like in symptomatic treatment of osteoarthritis, known for its anti-inflammatory action, anti-oxidant activity and potent 2, 2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity [20].

Dextranase is known to prevent dental caries and repress dental plague. Dextranase obtained from Arthrobacter sp. strain B7 hydrolyzed dextran and glucan from the dental plague. Dextranase works efficiently at temperatures of about 37 °C and are widely used in medical and dental industries. It is used in oral care products like toothpaste and mouthwash for effective dental caries prevention. It is also used in the manufacturing of blood substitutes [33, 34, 35].

Arginase obtained from Arthrobacter sp. KUJ 8602 catalyses the hydrolysis of L-arginine. It involves in nutritional starvation therapy for treatment of human hepatocellular carcinoma, prostate cancer, and melanoma. In addition to anticancer activity, it was proved to be effective in the treatment of acute neurological disorders, rheumatoid arthritis and allergic asthma [36].

Inulase II Arthrobacter sp. H65-7 produces the enzyme inulase II that converts inulin into difructose anhydride (DFA). DFA is a promising nutrient for fighting osteoporosis because it helps absorption of calcium in the intestines [37, 38].

Hyaluronate lyase was obtained by cultivating A. globiformis strain A152. The optimum pH and temperature values for hyaluronate lyase activity were pH 6.0 and 42 °C, respectively [39]. It has been successfully utilized in ophthalmic surgery and dermatosurgery. It has been applied as a local adjuvant to expand the diffusion capacity of local anesthetics, thus enhancing the analgesic efficacy and the anesthetized area, especially in the first few minutes following injection, mitigating intra and postoperative pain [40].

Cyclodextrin glycosyltransferase (CGTase) was obtained from A. mysorens isolated from paddy field soil. CGTase catalyzes cyclisation of α-1, 4-glucans to produce cyclodextrins. Cyclodextrins are carrier molecules useful in pharmaceuticals for preparation of immediate release oral dosage forms. The molecular weight of the purified protein as determined by SDS-PAGE was 75kDa; purified CGTase was thermostable and stable over a wide pH range. Dissolution studies on β-cyclodextrin-Irbesartan complex revealed that β-CDs form was useful in preparing immediate release oral dosage forms of the drug [41].

Table 1: Major therapeutic enzymes produced by Arthrobacter

S. No. Enzymes Microorganisms Applications Reference
1 Acetylcholinesterase A. ilicis Used as a pretreatment drug in organophosphorus poisoning and as a vaccine against Dictyocaulus viviparous 22
2 Amine transaminase Arthrobacter sp. KNK168 Synthesis of sitagliptin and medicine for type-2 diabetes 42
3 Arginase Arthrobacter sp. KUJ 8602 Anticancer activity 36
4 Chitinase Arthrobacter sp. Antifungal agent 43
5 Cholesterol oxidase A. simplex U-S 3011 Diagnosis of arteriosclerosis and determination of serum cholesterol 44
6 Chondroitin lyase Arthrobacter sp. MAT3885 Effective against keloid pathology and in the regeneration of central nervous system after injury 20
7 Creatinase A. nicotianae 23710 Application in clinical diagnosis of renal function 45
8 Cyclodextrin glycosyltransferase A. mysorens Production of β-cyclodextrin useful in preparing immediate release oral dosage forms 41
9 Deaminase A. oxydans Used in anticancer and antibacterial therapies 46
10 Dehydrogenase A. simplex 156 Steroid drug biotransformation 47
11 Dextranase Arthrobacter sp. Dental caries-preventing agent 34
12 D-threonine aldolase Arthrobacter sp. DK-38 Production of bioactive molecules 48
13 Ethanolamine oxidase Arthrobacter sp. Detection of phosphatidylethanolamine levels in serum 49
14 Fibrinolytic enzyme FA-I A. aurescens strain DR-536 Used as a thrombolysis agent 50
15 Hyaluronate lyase  A. globiformis A152 Used in ophthalmic surgery and dermatosurgery 39, 40
16 Keratinase Arthrobacter sp. strain PF01 Transmissible spongiform encephalopathies treatment 16, 51
17 L-arabinose isomerase Arthrobacter sp. Produce D-tagatose which acts as a drug for anti-diabetic and obesity control 52
18 L-asparaginase A. kerguelensis VL-RK_09 Antileukemic effect 25
19 Levanfructo-transferase

A. ureafaciens K2032

 Production of DFA IV, which act as a low-calorie sweetener, inhibit tooth decay, increase mineral absorption 53
20 Lipase Arthrobacter sp. MTCC 5125 Resolution of chiral drugs and their intermediates 54
21 Methionine γ-lyase Arthrobacter sp. Anti-parasitic and anti-cancer effects 30
22 N-acylhomoserine lactonase Arthrobacter sp. IBN110 Block quorum sensing 55
23 Oxidoreductases Arthrobacter sp. Production of enantiomerically pure alcohols 56
24 Penicillin acylase A. viscosus ATCC15294 Production of semisynthetic penicillins 57
25 Protease A. luteus Potential target for developing therapeutic agents against fatal diseases such as cancer and AIDS 58, 59
26 Serine hydroxymethyl-transferase Arthrobacter sp. Produce L-serine which is used to treat hereditary sensory, autonomic neuropathy type 1 60, 61
26 Tyramine oxidase Arthrobacter sp B-0813 Diagnosis of Leucine aminopeptidase activity in serum 62
27 Urate oxidase A. globiformis FERM BP-360 Gout treatment and detection of uric acid in serum 63
28 Xanthine oxidase Arthrobacter sp. Used in amperometric biosensors for detection of xanthine and hypoxanthine 64
29 β-1, 3-glucanase Recombinant A. luteus Paratransgenic control of Chagas disease 65
30 β-galactosidase A. psychrolactophilus Production of low lactose milk for treatment of hypolactasia 66
31 β-glucosidase A. chlorophenolicus Produce active minor ginsenosides having anti-neoplastic, anti-fatigue, anti-oxidant and anti-diabetic effects 29

CONCLUSION

The member species of Arthrobacter genus have evolved as a group with vast metabolic and genomic diversity. Attempts should be aimed to explore the potential of Arthrobacter sp. as a source to produce novel therapeutic enzymes. The results of research on the use of Arthrobacter group for the production of therapeutic enzymes targeting various diseases have been presented. Although, symbolic progress in the discovery of different medically important enzymes has been conducted, but their large-scale commercial production is yet to be worked out. Purification is the primary step in the processing of therapeutic enzymes. Successful reports on medically important enzymes from terrestrial and aquatic Arthrobacter are available, but their commercial production conditions are yet to be investigated. In order to generate therapeutic enzymes as commercial products, different biosynthetic pathways need to be analyzed, then respective genes should be metabolically engineered, cloned into the desired host and bioprocess parameters have to be optimized.

ACKNOWLEDGMENT

Author Shabnam is thankful to the department of biotechnology (DBT), Govt. of India, for Senior Research Fellowship.

AUTHORS CONTRIBUTIONS

All the author have contributed equally

CONFLICTS OF INTERESTS

The authors have declared that no conflict of interest exists

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