Microbiology Research Journal International

27(2): 1-8, 2019; Article no.MRJI.25362 ISSN: 2456-7043 (Past name: British Microbiology Research Journal, Past ISSN: 2231-0886, NLM ID: 101608140)

Microbial Enzymes: Therapeutic Applications

C. V. Reshma1*

1Department of Life Sciences, University of Calicut, Malappuram, Kerala, India.

Author’s contribution

The sole author designed, analyzed and interpreted and prepared the manuscript.

Article Information

DOI: 10.9734/MRJI/2019/v27i230093 Editor(s): (1) Dr. Raúl Rodríguez-Herrera, Autonomous University of Coahuila, México. Reviewers: (1) Mahmoud Balbaa, Department of Biochemistry, Alexandria University, Egypt. (2) Dr. Sanjay Mishra, IFTM University, India. (3) Dr. A. Bhaskar Rao, Indian Institute of Chemical Technology, India. Complete Peer review History: http://www.sdiarticle3.com/review-history/25362

Received 14 November 2016 Review Article Accepted 12 February 2017 Published 01 April 2019

ABSTRACT

Enzymes are biomolecules with highly specialized catalytic functions produced by all living organisms and are responsible for biochemical reactions in plants, animals, microorganisms and human beings. Nowadays enzymes are considered as core of biotechnology because they are the main tools for the application of basic biotechnological techniques, they act as the target of the therapeutic drugs and are indispensable intermediates in all biotechnological processes. The concept of the therapeutic enzymes has been around for at least 40 years. Microbial enzymes are preferred over other sources and in this review different types of microbial enzymes are discussed for their therapeutic applications.

Keywords: Biomolecules; therapeutic drugs; microbial enzymes; pharmacology.

1. MICROBIAL ENZYMES: THERAPEUTIC microorganisms and human beings. The use of APPLICATIONS enzyme in processing raw materials from plants and animals have been practiced for a long time. Enzymes are biomolecules with highly The first observation of the enzymatic specialized catalytic functions produced by all degradation was in 1783 by Spallanzani. In 1814 living organisms and are responsible for Kirchhoff found that the barley contain a biochemical reactions in plants, animals, substance that convert starch in to sugars. The

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*Corresponding author: E-mail: [email protected];

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term enzyme was coined by Kuhne in 1878. which include phenolic compounds (from plants), Enzyme preparations were used in ancient times endogenous enzyme inhibitors and proteases [6]. without much knowledge about the nature and properties of enzymes. Today industrial Microbial enzymes have found wide application application of enzymes began with Jokichi in medicine and pharmacology and their use in Takamine, who developed an enzyme this field is recognized recently. Therapeutic preparation takadiastase a mixture of enzymes have a wide variety of specific uses carbohydrases and proteases [1]. such as oncolytics, thrombolytics, or anticoagulants and as replacements for Enzymes have been used as catalysts in various metabolic deficiencies, anti-inflammatory agents industries like brewing, tanning, bakery, diary etc etc (Gurung et al. 2013). Various microbial along centuries. Nowadays the enzymes are therapeutic enzymes are described below. considered as core of biotechnology because they are the main tools for the application of 1.2 L- asparginase basic biotechnological techniques, the targets of the therapeutic drugs and the indispensable L-Asparaginase(EC 3.5.1.1) is broadly intermediates in all biotechnological processes. distributed among the plants, animals and Apart from the function as targets in therapy, microorganisms. Microbes are preferred source enzymes are novel in that they find application as of L-asparaginase, because they can be cultured therapeutic molecule itself [2]. This review easily and the extraction and purification of L- focuses on the application of various microbial asparaginase is also comfortable with the large- enzymes as therapeutic agents. scale production. A wide range of bacteria, fungi, yeast, actinomycetes and algae are very potent 1.1 Microbial Therapeutic Enzymes producers of L-asparaginase [7,8].

Enzymes were largely ignored as drugs until L- asparginase from Erwinia carotovora or Emmerich and his associates observed in 1902 Escherichia coli is used in the treatment of acute that an extracellular secretion of Bacillus lymphocytic leukemia [9]. Its activity depends pyocyaneus was capable of killing anthrax bacilli. upon the fact that tumour cells lack aspartate- He deduced that the secretions contain ammonia ligase activity, which stops the nucleases which is the responsible element for synthesis of nonessential amino acid L- the bacterial lysis. This milestone study gradually asparagine (Gurung et al. 2013). Hence, they are opened the way for the use of enzymes in the extracted from body fluids. Thus leukemic cells treatment first of infections, then of cancer and require L –aspargine, unlike normal cells, for finally of a diverse spectrum of diseases [3]. their survival [10]. By injecting L- asparginase the

The concept of the therapeutic enzyme has been availability of the aminoacid is reduced, so the around for at least 40 years. For example, a leukemic cells fail to survive [11]. therapeutic enzyme was described as part of replacement therapies for genetic deficiencies in 1.3 Collagenase (Ec 3.4.24.3) the 1960s by de Duve [4]. Enzymes as drugs have two important features i) they often bind True bacterial collagenases are consensually and act on their targets with great affinity and described as enzymes that cleave helical regions specificity and ii) they are catalytic and convert of fibrillar collagen molecules under physiological multiple target molecules to the desired products. conditions [12]. Microbial collagenases belong to These two features make enzymes specific and the MEROPS peptidase family M9 (INTERPRO: potent drugs for a wide range of disorders [5]. IPR002169; PFAM: PF01752), which comprises bacterial metalloproteinases (predicted to be Sources of therapeutic enzymes include animals, zinc-dependent) from Vibrio and Clostridium with plants and microorganisms (bacteria and fungi). presumable collagenolytic activity [13]. Microbial enzymes are preferred because they Collagenases are applied in the pharamaceutical are generally cheaper to produce, their enzyme world for the treatment of various disorders listed content is more predictable and controllable and below. the availability of reliable supplies of raw materials of constant composition. As they are 1.4 Treatment of Damaged Tissues foreign in nature, some of them are unadapted with the human body. Plant and animal sources For treating damaged tissues, several studies, contain more harmful materials than microbes comparing the use of enzymatic methods with

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surgical/ mechanical procedures as well as treatment of chronic total occlusions (CTO) in comparing the effect between several enzymes animal models [22,23]. CTO is defined as a 3- were made. Data are controversial, while a few month-old total obstruction of a coronary artery, studies state that wound debridement is more and is one of the more difficult challenges for efficient by using enzymatic procedures, coronary interventionists [24]. It consists of reducing hospital staying and the demand for various degrees of fibroatheromatous plaque and surgical debridement [14]. thrombus, depending on the occlusion mechanism and its duration, and occurs in Enzymatic debriding agents are effective approximately 30% of the patients with coronary alternative for removing necrotic material from artery disease. Presently, clinical trials have pressure ulcers, leg ulcers, and partial-thickness showed that in human subjects, local delivery of wounds. They may be used to debride both collagenase into coronary chronic total occlusion adherent slough and eschar. Enzymatic agents is feasible and safe [23]. may be used as the primary technique for debridement in certain cases, especially when 2. PROTEASES different approach such as surgical or conservative sharp wound debridement (CSWD) Proteases constitute the single most important are not feasible due to bleeding disorders or group of industrially important microbial enzymes other considerations [15]. which are capable of hydrolysing peptide bonds For the removal of dead skin of burns, the use of in to aminoacids based on the size of the a large number of bacterial and plant enzymes molecules they can attack or preferably attack. have been studied. Among the microbial These may be proteinases or petidases. Since enzymes, a proteolytic enzyme from Vibrio the later years of the nineteenth century, crude proteolyticus was found to be effective, and it proteases are used for the treatment of successfully finished phase1b clinical trials in gastrointestinal disorders. Microbial proteases 2004. Now it is used under the trade name are used either directly or indirectly in the field of Vibrilase TM, especially for the serious medicine for diagnostic or therapeutic purposes secondary burn treatments (Gurung, 2013). [25].

1.5 Dupuytren’s Disease (DD) 2.1 Streptokinase (EC 3.4.24.29)

Clostridium collagenase (Ec 3.4.24.3) is also Pathologies involving a failure of hemostasis and applied in the treatment of Dupuytren’s the clot formation require clinical intervention disease. .Dupuytren’s disease is a consisting of intravenous administration of fibroproliferative disorder of the palmar fascia thrombolytic agents [26,27,28] Streptokinase is that limits hand functions, ultimately disabling the one such agent. hand, and lowering life’s quality [16]. This progressive disorder results in the permanent Streptokinase is an extrcellular enzyme and symptomatic flexion contracture of the digits. produced by ß hemolytic streptococci. Streptokinase, produced by certain strains of Although some side reactions have been noted streptococcus, is used as a therapeutic agent in for injectable C. histolyticum collagenase like the treatment of cardiovascular diseases. It is a skin lacerations, edema, hemorrhage, injection single chain polypeptide that exhibits its site pain and bruising and less frequently tendon fibrinolytic action by indirectly activating the and pulley rupture [17,18], its effectiveness has circulating plasminogen. Streptokinase is used in been proved by several in vivo studies [19,20], the treatment acute myocardial infarction, it is with contracture reduction in more than 60% of certainly more cost effective, however its use is the patients injected with injectable clostridial not risk free. collagenase [16]. Collagenase injection is more worthwhile than surgical fasciotomy [20], has When Streptokinase binds with circulatory less and milder side-effects, and demonstrated a plasminogen or plasmin, the resulting 1:1 better total reduction of Dupuytren’s contracture stoichiometric complex is a high specificity leading to higher patient satisfaction [21]. protease that proteolytically activate other 1.6 Chronic Total Occlusions (CTO) plasminogen molecules to plasmin [29]. Comparative clinical trials and cost effective Microbial collagenases (more precisely clostridial considerations suggest that streptokinase is the collagenases) have also been applied to the drug of choice for thrombolytic therapy [30].

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Streptokinase is a non human protein and its L-glutamine resulting in the production of L- introduction in to the circulatory system can elicit glutamic acid and ammonia. L-Glutaminases are severe anaphylatic response including death [31]. ubiquitous in the biological world [36,37] and This immunogenicity restricts multiple applica- organisms ranging from bacteria to human tions of the streptokinase. beings have the enzyme.

2.2 Staphylokinase (EC 3.4.99.22) Acinetobacter glutaminisificans, Bacillus licheniformis, Bacillus subtilis, Erwinia cartowora, Staphylokinase is a protein produced by certain Microccus luteus etc are some of the strains of staphylococcus and possesses representatives of the microbial world with fibrinolytic activities. Staphylokinase is a single potential glutaminase production capacities polypeptide chain with a molecular weight of [38,39,40]. approximaltely 15.5 KDa and length of 163 amino acids. Natural staphylokinase has been L-Glutaminase, in combination with or as an purified from S. aureus strains that were alternative to asparaginase, could be of transformed with bacteriophages containing significance in enzyme therapy for cancer the staphylokinase gene, or that had especially acute lymphocytic leukemia [41]. undergone lysogenic conversion to Glutaminase from microbes exhibit antitumour staphylokinase production [32]. activity and recombinant glutaminase from Pseudomonas is patented for its activity against Staphylokinase converts inactive proteolytic HIV and cancer therapy. enzyme plasminogen to its active form, plasmin.

Staphylokinase is used for the treatment of myocardial infarction. It can stimulate the lysis of 2.6 Lysostaphin (EC 3.4.24.75) both erythrocyte rich and platelet rich clots [33]. Lysostaphin is a 27 KDa zinc metalloenzyme 2.3 Serrazime (EC 3.4.24.40) secreted by certain strains of Staphylococcus simulans which has a specific lytic action against Serrazyme, a proteolytic enzyme from Staphylococcus aureus. It posess two functional Aspergillus oryzae and Aspergillus meeus, is domains an N terminal catalytic peptidase used as an alternative of serratiopeptidase and is domain and a C terminal targeting domain which used as a dietary supplement for cardiovascular, bind to the peptidoglycan substarte. Lysostaphin antiinflammatory or immune support. has activities of three enzymes namely, glycylglycine endopeptidase, endo-β-N-acetyl 2.4 Serrapeptase (EC 3.4.24.40) glucosamidase and N-acteyl muramyl-L-alanine amidase. Glycylglycine endopeptidase Serrapeptase is available for clinical use more specifically cleaves the glycine–glycine bonds, than a decade. Serratiopeptidase binds to alpha - unique to the interpeptide cross-bridge of the S. 2-macroglobulin in the blood in the ratio of 1:1, aureus cell wall [42]. which helps to mask its antigenicity but retains its enzymatic activity and is slowly transferred to site Due to its unique specificity, lysostaphin could of inflammation. Serratiopeptidase hydrolyses have high potential in the treatment of antibiotic- bradykinin, histamine and serotonin responsible resistant staphylococcal infections [43]. for the oedematic status. Serratiopeptidase Lysostaphin is found to reduce surface reduces swelling, improves microcirculation and colonization by S. aureus and S. epidermidis. expectoration of sputum, etc [34]. Thus the drug is more effective in preventing the nasal colonization of S. aureus. Lysostaphin acts Serrapeptase or serratiopeptidase from Serratia synergistically with some membrane active marcescens is used as a therapeutic enzyme agents plymixin and ranalexin against MRSA. and possesses applications, as antiinflammatory Recombinant lysostaphin was found effective in agent, for treating carpel tunnel syndrome, for the treatment of aortic endocarditis [35]. fibrocystic treatment and as agent to enhance the activity of antibiotics against biofilm formation [35]. 2.7 Laccases

2.5 Glutaminase Laccase (EC 1.10.3.2) or p-diphenol oxidase is one of a few enzymes that have been studied L-glutaminase (EC.3.5.1.2) is an amidohydrolase since the 19th century. Yoshida first reported which catalyses the hydrolytical deamination of laccase in 1883 from the exudates of the

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Japanese lacquer tree, Rhus vernicifera [44]. sp. have been exploited for the production of However in 1896, for the first time, both Bertrand lipases. and Laborde demonstrated laccase to be a fungal enzyme [44]. Microbial lipases are used to enrich PUFAs from animal and plant lipids, and their mono and Laccases are copper-containing enzymes that diacylglycerides are used to produce a variety of catalyze the oxidation of a wide variety of organic pharmaceuticals. Many PUFAs are essential for and inorganic substrates, including mono-, di-, normal synthesis of lipid membranes and and polyphenols, amino phenols, methoxy prostaglandins. Free PUFAs and their mono and phenols, aromatic amines and ascorbate with the diacylglycerides are subsequently used to concomitant four electron reduction of oxygen to produce a variety of pharmaceuticals. water [45]. Laccase is a member of the large Considerable effort is being made to obtain blue copper proteins or blue copper oxidases optically pure compounds, which are [44]. The ability of laccases to oxidize phenolic pharmacologically more active than its antipode. compounds as well as their ability to reduce Profens, a class of nonsteroidal anti- molecular oxygen to water has led to intensive inflammatory drugs, are active in the (s)- studies of these enzymes [44]. Laccase activity enantiomer form. has been reported only in few bacteria, including Azospirillum lipoferum, Marinomonas Lee et al. [31] and Xie et al. [49] synthesized mediterranea, Streptomyces griseus, and pure (s)-ibuprofen using lipase-catalyzed kinetic Bacillus subtilis [46]. resolution via hydrolysis and esterification, respectively. Optically active homochiral The first bacterial laccase was detected in the intermediates for the synthesis of nikkomycin-B, plant root-associated bacterium Azospirillum non steroid anti-inflammatory drugs (naproxen, lipoferum, where laccase was associated with ibuprofen, suprofen and ketoprox), the potential the melanin production for cell pigmentation. antiviral agent lamivudine, and for the Recently some bacterial laccases have also enantiospecific synthesis of alkaloids, antibiotics, been characterized from Azospirillum lipoferum, vitamins, and anti- arteriosclerotic, anti tumour Bacillus subtilis, Streptomyces lavendulae, and antiallergic compounds [50]. Lipase from S.cyaneus and Marinomonas mediterranea. Candida rugosa is used to synthesize lovastatin, Many products generated by laccases are a drug that lowers serum cholesterol level. The antimicrobial, detoxifying or active personal-care asymmetric hydrolysis of 3-phenylglycidic acid agents. Laccase can be used in the synthesis of ester which is a key intermediate in the synthesis complex medical compounds as anesthetics, of diltiazem hydrochloride is a widely used anti-inflammatory agents, antibiotics, sedatives, coronary vasodilator and is synthesized using S. etc, including triazolo(benzo)cycloalkyl marcescens lipase [51]. thiadiazines, vinblastine, mitomycin, penicillin X dimer, cephalosporins, and dimerized vindoline 2.9 Alginate Lyase (EC 4.2.2.3) [47,48]. Alginate lyase can digest alginate through the 2.8 Lipases beta elimination of the glycosidic bond [52]. They yield various oligosaccharides with unsaturated Lipases (tri acyl glycerol acyl hydrolases E.C uronic acid at the non reducing terminus and 3.1.1.3) are hydrolases that catalyse the unsaturated duronic acid monomers. The hydrolysis of triacylglcerol to glycerol and free oligosaccharides released by the enzyme seems fatty acids over an oil water interface. Bacterial to possess biological activities like enhancing the lipases are glycoproteins but some extracellular growth of endothelial cells and stimulate lipases are lipoproteins. In addition to this, the secretion of cytokines from human macrophages. enzyme catalyzes the transesterification and The enzyme possesses pharmaceutical activity hydrolysis of other esters and also synthesis of [53,54,55]. some others. Such transformations enable them to be used in food, cosmetic and especially in One of the leading causes of illness and death in pharmaceutic industry. cystic fibrosis (CF) patients is Pseudomonas aeruginosa infection of the respiratory tract. Among bacteria, Achromobacter sp., Alcaligenes Patients colonised by mucoid, alginate-producing sp., Arthrobacter sp., Pseudomonas sp., strains have a particularly poor prognosis [56] Staphylococcus sp., and Chromobacterium and the infection is rarely eliminated by antibiotic

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