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Research review paper
From bacteria to human: A journey into the world of chitinases
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Sina Adrangi a, Mohammad Ali Faramarzi b,⁎a Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iranb Department of Pharmaceutical Biotechnology, Faculty of Pharmacy and Biotechnology Research Center, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran 14176, Iran
PROChitinases, the enzymes responsible for the biological degradation of chitin, are found in a wide range of
organisms from bacteria to higher plants and animals. They participate in numerous physiological processessuch as nutrition, parasitism, morphogenesis and immunity. Many organisms, in addition to chitinases, produceinactive chitinase-like lectins that despite lacking enzymatic activity are involved in several regulatory functions.Most known chitinases belong to families 18 and 19 of glycosyl hydrolases, however a few chitinases that belongto families 23 and 48 have also been identified in recent years. In this review, different aspects of chitinases andchi-lectins from bacteria, fungi, insects, plants and mammals are discussed.
Chitin is the second most abundant natural carbohydrate polymerafter cellulose and consists of β-(1 → 4)-linked units of N-acetylglucosamine (GlcNAc). It is a major component of fungal cellwalls and invertebrate exoskeletons. In nature, chitin occurs in twodifferent crystalline forms, α and β (Aam et al., 2010). α-Chitin is thedominant form and it is composed of linear chains of GlcNAc arrangedin anantiparallelmanner. On theother hand,β-chitin consists of parallel
chains. Chitinolytic enzymes are produced by awide range of organismsincluding bacteria, fungi, insects, plants and animals for differentpurposes such as nutrition, morphogenesis, and defense against chitin-containing pathogens (Adrangi et al., 2010). Many of theses organismspossess several genes that encode chitinolytic enzymes. For example,most filamentous fungi have 10 to 20 different chitinolytic genes,while in mycoparasitic species the number of such genes may reach30 or even higher (Hartl et al., 2012). These enzymes act in a synergeticor successive manner to degrade chitin (Patil et al., 2000). Higherorganisms such as Arabidopsis have also been reported to contain alarge number of chitinolytic genes (Hossain et al., 2010). However, notall of these gene codes are for active enzymes. Many organismsincluding plants, invertebrates and higher animals express genesencoding so called chitinase-like lectins (chi-lectins) that are devoid ofchitinolytic activity due to substitutions in their key catalytic residues(Arakane and Muthukrishnan, 2010; Hossain et al., 2010; Vega and
: A journey into theworld of chitinases, Biotechnol Adv (2013), http://
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Kalkum, 2012). Despite lacking catalytic activity, these proteins retainthe capacity to bind chitin. Owing to their widespread presence anddiverse biological functions, chitinolytic enzymes have found severalapplications. For example they can be used in the production ofsingle-cell proteins, isolation of fungal protoplasts, estimation offungal biomass, development of 3D cell culture scaffolds, biocontrolof plant-pathogenic fungi and insect vectors, and the production ofchitooligosaccharides, glucosamine, GlcNAc, neoglycoproteins and arti-ficial polysaccharides (Adrangi et al., 2010; Jamialahmadi et al., 2011; Liet al., 2008; Lu et al., 2012; Ortiz-Rodriguez et al., 2010; Tajdini et al.,2010; Zakariassen et al., 2011). Recent studies in the field of chitinolyticenzymes have demonstrated that both the diversity and the physiolog-ical roles of these enzymes are far beyond those previously recognized.
2. Classification, structure and catalytic mechanism
Based on theirmode of action, chitinolytic enzymes are classified intotwo categories: chitinases (EC 3.2.1.14) that cleave the chitin chain atinternal sites in a random manner, and β-N-acetylhexosaminidases(EC 3.2.1.52) that catalyze the successive removal of GlcNAc residuesfrom the non-reducing end of the chain (Adrangi et al., 2010). Chitinasesoccur in families 18, 19, 23, and 48 of glycosyl hydrolases (GH), whileβ-N-acetylhexosaminidases are included in GH3, GH18, GH20, andGH84 (Table 1). The classification of GH families is based on sequencehomology and a continuously updated list of these families is availablethrough the CAZy database (Cantarel et al., 2009). The catalytic domainsof members of each GH family fold into a common three-dimensionalstructure (Fig. 1). Families GH18, GH20, and GH84 all have similar(β/α)8 barrel domains (Sumida et al., 2011). On the other hand, GH19andGH23 enzymes adopt anα+β structure, while the catalytic domainof GH3 enzymes has a bipartite structure comprising a (β/α)8 barrelfollowed by an (α/β)6 sandwich (Wohlkonig et al., 2010; Yoshidaet al., 2010). Some GH3 enzymes, however, lack the (α/β)6 sandwich(Yoshida et al., 2010). Finally, GH48 enzymes have an (α/α)6 barrelstructure characterized by six centralα-helices surrounded by six exter-nalα-helices (Yennamalli et al., 2011). Most chitinases aremodular pro-teins that, in addition to a catalytic domain, contain auxiliary domainssuch as the carbohydrate-binding module (CBM) (Guillen et al., 2010).The CBM enhances the activity of the enzyme towards insoluble sub-strates by anchoring the enzyme to the substrate and disrupting thecrystalline structure of the substrate resulting in the formation of freechain ends (Guillen et al., 2010; Vaaje-Kolstad et al., 2005). Like catalyticmodules, CBMs are classified into families of homologous proteinswhichmay be accessed at the CAZy database. A second feature that helps toovercome the low accessibility of insoluble substrates is the presenceof a deep and narrow substrate-binding cleft lined with aromaticresidues in some chitinolytic enzymes (Fig. 2) (Horn et al., 2006a,b;Zakariassen et al., 2010). Such enzymes act in a processive manner,meaning once attached to a substrate chain, they thread the chainthrough their catalytic cleft performing several hydrolytic cuts insteadof releasing the substrate after each cleavage. The aromatic residues
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Table 1Characteristics of chitinolytic enzymes belonging to different GH families.
Family Catalytic mechanism Proton donor Base/nucleoph
ChitinasesGH18 Retaining Glu Substrate acetGH19 Inverting Glu Glu/aspGH23 Inverting Glu Not known
Please cite this article as: Adrangi S, FaramarziMA, From bacteria to humandx.doi.org/10.1016/j.biotechadv.2013.09.012
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provide the necessary environment for the flexible binding and move-ment of the substrate through the active site. Although processivitycomprises an efficient strategy for the hydrolysis of insoluble substrates,it is usually associated with reduced activity towards soluble or moreaccessible polymeric substrates (Aam et al., 2010).
Like other glycosyl hydrolases, chitinolytic enzymes generally cata-lyze the depolymerization of their substrate through one of the twopathways known as single- and double-displacement mechanisms(Aam et al., 2010; Andersen et al., 2005; Cantarel et al., 2009; Li andGreene, 2010; Slamova et al., 2010; Tang et al., 2004; Udaya Prakashet al., 2010). In both pathways, two distinct catalytic groups areinvolved. One of these is a carboxyl group that acts as a proton donorand is usually provided by a conserved glutamate residue at the activesite of the enzyme, although in some cases, for example in familyGH84, an aspartate residue may fulfill this role (Table 1). The secondcatalytic group may act either as a base (as in the single-displacementmechanism) or a nucleophile (as in the double-displacement mecha-nism). This group may be a carboxyl moiety provided by a conservedglutamate or aspartate residue, or it may be the N-acetyl group of thesugar positioned in the −1 subsite of the enzyme (Aam et al., 2010;Udaya Prakash et al., 2010). Subsites are numbered from –n to +n,where negative sign represents the non-reducing end of the chain withcleavage occurring between the −1 and +1 subsites (Davies et al.,1997). Since the single-displacementmechanism results in the inversionof the anomeric configuration of the hydrolyzedGlcNAc residue, it is alsoknown as the inverting mechanism. On the other hand, in the double-displacement mechanism, also referred to as the retaining mechanism,the anomeric configuration is retained.
3. Bacterial chitinases
Bacterial chitinases occur in families GH18, GH19, andGH23 (Dahiyaet al., 2006; Udaya Prakash et al., 2010; Ueda et al., 2009).Most bacterialchitinases belong to the GH18 family (Larsen et al., 2011) (Fig. 3). Basedon sequence homology, bacterial GH18 chitinases are classified intothree subfamilies A, B and C (Li and Greene, 2010). It should be notedthat the nomenclature of bacterial chitinases does not follow this classi-fication; for example, chitinase B from Serratia marcescens belongs tosubfamily Awhile Bacillus circulans chitinase D is classified in subfamilyB (Watanabe et al., 1999). Some bacterial GH18 chitinases besidescatalytic and CBM domains contain a fibronectin type III-like domainwhich plays a role in substrate binding (Horn et al., 2006a). On theother hand, the distribution of GH19 chitinases among bacteria appearsto be restricted to actinobacteria and purple bacteria (Udaya Prakashet al., 2010). It has been proposed that actinobacteria and purple bacte-ria may have acquired GH19 chitinase genes from plants and, in turn,transferred them to arthropods and nematodes (Udaya Prakash et al.,2010). To date, only one GH23 chitinase has been identified in bacteria(Ueda et al., 2009). This enzyme was isolated from Ralstonia sp.A-471 and comprises an N-terminal chitin-binding domain linked toa C-terminal catalytic domain that shows homology to goose-type
ile Structure Reference
amido group (β/α)8 CAZY; Sumida et al. (2011)α+ β CAZY; Wohlkonig et al. (2010)α+ β CAZY; Wohlkonig et al. (2010);
Arimori et al. (2013)(α/α)6 CAZY; Yennamalli et al. (2011)
(β/α)8+ (α/β)6 CAZY; Yoshida et al. (2010)amido group (β/α)8 CAZY; Sumida et al. (2011)amido group (β/α)8 CAZYamido group (β/α)8 CAZY
: A journey into theworld of chitinases, Biotechnol Adv (2013), http://
Fig. 1. Three-dimensional structure of representative GH enzymes. (A) A GH18 chitinase from Aspergillus fumigatus showing a (β/α)8 barrel (PDB ID: 2XVP). (B) A GH19 chitinase fromCarica papaya showing α+ β structure (PDB ID: 3CQL). In most cases, like this example, the β regions are actually composed of isolated bridges rather than extended strands (residuesshown in stick representation). (C) A GH3 glucohydrolase from Hordeum vulgare showing a bipartite domain consisting of a (β/α)8 barrel (lower right) and an (α/β)6 sandwich (upperleft) (PDB ID: 1IEQ). (D) AGH48 cellobiohydrolase from Clostridium thermocellum showing an (α/α)6 barrel (PDB ID: 1L1Y). All figureswere prepared using VMD (Humphrey et al., 1996).
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lysozyme. The gene encoding this enzyme also appears to be acquiredvia horizontal gene transfer (Ueda et al., 2009).
Bacteria produce chitinases for different purposes such as nutritionand parasitism (Dahiya et al., 2006; Faramarzi et al., 2009). For somespecies, chitinases may play an essential role in providing the bacteriumwith required nutrients or precursors. The spirochete Borrelia burgdorferi,for example, is unable to produce GlcNAc required for cell wall synthesisand in an environment such as the tick midgut where free GlcNAc is notavailable, the ability to degrade the chitin-rich peritrophic membranewould allow the bacterium to obtain the necessary GlcNAc (Rhodeset al., 2010). It has also been shown that the chitinase system ofPseudoalteromonas is involved in nitrogen metabolism (Delpin andGoodman, 2009). However, for many other heterotrophic bacteriachitinases are probably not crucial in this respect since in most habitatsdifferent nutrient sources are available (Cottrell et al., 2000). On theother hand, autotrophic microorganisms such as the cyanobacteriumAnabaena probably produces chitinolytic enzymes as part of their allelo-pathic system to inhibit the growth of competitor organisms such asfungi (Prasanna et al., 2010). Chitinases are also involved in bacterialpathogenesis. In cases where the host is known to contain chitin, suchas in insects, the mechanism seems straightforward. For example, theentomopathogenic bacterium Yersinia entomophaga produces an ABC-type protein toxin complex that can kill the host within 72h of infection(Busby et al., 2012; Landsberg et al., 2011). It has been shown that thiscomplex includes two subunits with chitinase activity that anchor thecomplex to, and facilitate its penetration through the peritrophicmembrane (Busby et al., 2012). Vector-borne bacterial pathogens ofnon-chitinous organisms such as mammals and plants also producechitinases to colonize the insect vector by digesting the peritrophic
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Fig. 2. Substrate-binding cleft of processive and non-processive chitinases. (A) A processive chitbrasiliensis (PDB ID: 1KQY). Cocrystallized substrates are shown in stick representation.
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Omembrane (Chandler et al., 2011; Killiny et al., 2010). However, evenin non-chitinous hosts, chitinases may directly contribute to bacterialvirulence, probably by binding to alternative substrates such as thecarbohydrate moieties of glycoproteins involved in the host's immuneresponse (Chaudhuri et al., 2010). In the human pathogen Listeriamonocytogenes, the virulence gene regulator PrfA induces, among othergenes, chitinase expression indicating that the biological functions ofthis enzyme are not limited to the external environment (Larsen et al.,2010). Chitinase production is also stimulated by the quorum-sensingLuxR–LuxI homologous system that is involved in virulence, biofilmformation and surface motility in some pathogens such as Pseudomonasaeruginosa and Chromobacterium violaceum (Alipour et al., 2010; Stauffand Bassler, 2011). Clostridium difficile produces a bifunctional proteinwith chitinase and peroxiredoxin activities that appears to be partlyresponsible for the symptoms of C. difficile infection (Permpoonpattanaet al., 2011).
Bacteria also produce chitin-binding proteins comprised exclusivelyof non-catalytic CBMs. For example, S. marcescens secretes a proteinnamed CBP21 that belongs to CBM family 33 and seems to be involvedin chitin digestion despite lacking hydrolytic activity (Vaaje-Kolstadet al., 2005). CBP21 probably promotes the degradation of insolublechitin via non-enzymatic disruption of the crystalline structure of thesubstrate. Nevertheless, recent studies suggest that CBP21may actuallypossess oxidoreductase activity (Tran et al., 2011; Vaaje-Kolstad et al.,2010). The majority of bacterial CBM proteins belong to the CBM33family while their eukaryotic counterparts mostly belong to CBM fami-lies 14 and 18 (Purushotham et al., 2012; Tran et al., 2011).
It has been shown that some bacteria such as Streptomyces andBacillus licheniformis produce different chitinase inhibitors; however
inase from Serratia marcescens (PDB ID: 1E6N). (B) A non-processive chitinase from Hevea
: A journey into theworld of chitinases, Biotechnol Adv (2013), http://
Fig. 3.A cladogramshowing the relationship of selected chitinases fromall bacterial genera representedwith at least oneGH18 chitinase sequence in theNCBI RefSeq database. Chitinase Dfrom Bacillus circulans (Swiss-Prot Accession: P27050) was used as query for a BLAST search against the RefSeq database. A total number of 439 chitinase sequences from 68 bacterialgenera were obtained (E value b 0.01) and aligned using MEGA5 (Tamura et al., 2011). For each genus, the entry showing the highest degree of similarity to the query sequence wasselected and included in the cladogram. It should be noted that most of these genera are represented in RefSeq with several species and each species with more than one chitinase;as a result, depending on the selected sequences, the topology of the resulting tree may vary.
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RREthe biological functions of these inhibitors are not completely clarified
(Kumar and Rao, 2010; Suzuki et al., 2008). Allosamidin is apseudotrisaccharide produced by some Streptomyces species thatmimics the structure of chitin and competitively inhibits GH18chitinases. Although allosamidin can suppress chitinase activity inallosamidin-nonproducer strains, it is not secreted to the medium bythe producer strain and rather tends to accumulate in the myceliawhere it probably acts as a signal molecule for chitinase production(Suzuki et al., 2008). The peptidic aspartic protease inhibitor ofB. licheniformis, on the other hand, is secreted to the medium andshows a non-competitive inhibition pattern (Kumar and Rao, 2010).
4. Fungal chitinases
Fungal chitinases are members of the GH18 family (Hartl et al.,2012). They can be further divided into three subgroups, namely A, B,and C (not to be confused with bacterial GH18 chitinase subfamilies).This classification scheme primarily makes use of sequence similaritybut other distinctive features have also been described (Seidl, 2008).Subgroup A chitinases contain a single catalytic domain and no CBMs.These are processive enzymes with a deep substrate-binding cleft. Sub-group B chitinases are non-processive and in addition to their catalyticdomain comprise either a C-terminal CBM or an unstructured serine/threonine-rich domain. Subgroup C chitinases consist of an N-terminalCBM linked to a C-terminal catalytic domain. Like subgroup A, subgroupC chitinases have a deep narrow substrate-binding cleft that indicatesa processive nature. An interesting feature of subgroup C chitinases isthe presence of several LysM (lysin motif; also known as CBM50)domains (Hartl et al., 2012). The LysM domain was first identified in
Please cite this article as: Adrangi S, FaramarziMA, From bacteria to humandx.doi.org/10.1016/j.biotechadv.2013.09.012
bacteriophage and bacterial cell wall degrading enzymes as a substrate(peptidoglycan) binding domain (Bateman and Bycroft, 2000). It waslater shown to bind other glycans such as chitooligosaccharides aswell (Buist et al., 2008). In plants, specific LysM-containing cell surfacereceptors (known as LysM-RLK) are involved in the perception of rhizo-bial nodulation (Nod) factors (Radutoiu et al., 2003). Nod factors arelipochitooligosaccharide signaling molecules secreted by Rhizobiumbacteria that induce the formation of symbiotic root nodules in legumi-nous plants (Knogge and Scheel, 2006). Since these molecules aresubjected to species-specific substitutions, they are believed to play amajor role in the specific recognition of Rhizobium species by the hostplants (Gressent et al., 2002; Streng et al., 2011). In fact, it has beenshown that the heterologous expression of the enzymes involved inthe acylation of Nod factors may be used to extend the host range ofRhizobium bacteria (Pacios Bras et al., 2000). Plant LysM-RLKs alsoplay a role in defense against fungal pathogens (Brotman et al., 2012;Petutschnig et al., 2010). Based on thesefindings, aswell as the observa-tion that subgroup C chitinases are present at higher numbers inmycoparasitic fungi, it was hypothesized that it may be possible tocategorize fungal chitinases as self- and non-self degrading enzymes(Gruber and Seidl-Seiboth, 2012). However, detailed analysis of theexpression profile of subgroup C chitinases from several mycoparasiticTrichoderma species revealed that these enzymes are not expressed ina mycoparasitism-specific manner suggesting that they are involved inthe degradation of both self and non-self cell walls (Gruber and Seidl-Seiboth, 2012; Gruber et al., 2011a,b). The protection of the fungus'sown cell wall is probably achieved by limiting the accessibility ofchitin by cell wall proteins rather than the speciation of individualchitinases (Gruber and Seidl-Seiboth, 2012). In situations where self
: A journey into theworld of chitinases, Biotechnol Adv (2013), http://
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cell wall degradation is required, e.g. in hyphal branching, a localizedde-protection of chitin occurs. In addition to mycoparasitic fungi, non-mycoparasitic fungi have also been shown to secret proteins withchitinolytic activity in order to inhibit the growth of competitive fungi.For example, the α subunit of Kluyveromyces lactis killer toxin, whichis essential for the antifungal activity of the toxin, is actually achitinolytic enzyme (Colussi et al., 2005).
In nature, entomopathogenic fungi play an important role in control-ling insect pests, especially those that are resistant to viral and bacterialinfections (Fang et al., 2012; Schrank and Vainstein, 2010). Sincechitinases are an important part of the enzymatic arsenal of thesefungi, improved strains overexpressing native or engineered chitinaseshave been produced and demonstrated to exhibit increased virulenceagainst insects (Fan et al., 2007; Fang et al., 2005). Such improvedstrains can potentially be used in the biocontrol of pest and diseasevector insects (Fang et al., 2012; Jami Al Ahmadi et al., 2008;Tasharrofi et al., 2011). An alternative approach is to use fungal orbacterial chitinases directly as biopesticides (Binod et al., 2007; Kimand Je, 2010; Martinez et al., 2012). The insecticidal activity of suchpreparations may be improved by the addition of adjuvants such aspolyoxyethylene-(3)-isotridecyl ether that promote the penetration ofthe enzymes through epicuticle (Kim et al., 2010). In practice, however,the applicability of this method is limited by several factors includingthe rapid evaporation of the aqueous phase especially under dryingconditions. Nematode-pathogenic fungi such as Clonostachys roseathat produce several proteases and chitinases to target eggs and larvaehave also been exploited as biological control agents to suppressplant or even animal parasitic nematodes (Baloyi et al., 2012; Zouet al., 2010).
Invasive fungal infections are amajor cause of mortality in immuno-suppressed patients mostly due to the fact that current diagnosticmethods usually fail to detect fungal infections at early stages (Vegaand Kalkum, 2012). It has been proposed that radiolabeled chitinasesand chitin-binding proteins may be used for the early detectionof such infections (Lupetti et al., 2011). Other methods that detectthe host responses to fungal infections such as the use of immuno-fluorescence stains for chitinase have also been investigated (Guoet al., 2012). Nevertheless, further studies are needed before theseapproaches are ready for clinical use.
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5. Insect chitinases
With the exception of a GH48 chitinase identified in the leaf beetleGastrophysa atrocyanea (Fujita et al., 2006), all known insect chitinasesbelong to the family GH18 (J. Zhang et al., 2011). Based on sequencehomology and domain architecture, GH18 insect chitinases have beenassigned into eight distinct groups denoted by Roman numerals I–VIII(Arakane and Muthukrishnan, 2010; H. Zhang et al., 2011). Group Iare characterized by the presence of an N-terminal catalytic domainjoined to a CBM14 domain via a serine/threonine-rich linker. The linkerregion serves as a site for glycosylation which increases the stability ofthe enzyme against proteases. Group II are much larger proteins with4–5 catalytic domains and 4–7 CBMs. Some catalytic domains of groupII chitinases seem to be enzymatically inactive as their catalytic asparticacid residue is replaced by other residues such as histidine or serine(Arakane and Muthukrishnan, 2010). Group III chitinases consist oftwo catalytic domains and a single CBM. Groups IV, V, VII and VIII havea single catalytic domain and usually no CBM, and are distinguishedfrom each other by sequence homology. Group V includes chitinase-like proteins such as the imaginal disk growth factors (IDGFs) that lackchitinase activity and are involved in growth regulation and immunity.Group VI chitinases have one catalytic domain, one CBM and a longC-terminal stretch with a high percentage of serine and threonineresidues. Other features such as transmembrane and signal regionsmay also be present in all groups.
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Insect chitinases play an important role in chitin turnover especiallyduring molting. However, their expression should be tightly controlledsince premature exposure can lead to growth inhibition and mortality(H. Zhang et al., 2011). To achieve such a control, insects produce severalfunctionally specialized chitinases that are differentially expressedthrough the various stages of metamorphosis (Zhu et al., 2008). Atleast some of these enzymes are regulated by hormonal control(Merzendorfer and Zimoch, 2003; Royer et al., 2002; Takahashi et al.,2002; Zheng et al., 2003). For example, in Tribolium castaneum, TcCHT5is required for pupal–adult molting only while TcCHT10 is involved inlarval–larval, larval–pupal and pupal–adult molting (Zhu et al., 2008).Since during a normal molting cycle the synthesis of the new cuticleand the degradation of the old cuticle occur simultaneously, it is alsoimportant to protect the nascent cuticle from chitinases and othermolting enzymes (Chaudhari et al., 2011). This is mainly achievedthrough the action of specific proteins that colocalize and directly inter-act with newly synthesized chitin and organize it into laminae confer-ring resistance to chitinolytic enzymes (Chaudhari et al., 2011; Petkauet al., 2012). Knickkopf is one such protein that shows homology tothe CBM9 family (Chaudhari et al., 2011; Iyer et al., 2007). Thecolocalization of Knickkopf with chitin appears to be controlled by yetanother protein known as Obstructor-A which is encoded by a memberof the obstructor multigene family (Petkau et al., 2012). The obstructorfamily was first identified in Drosophila melanogaster and shown tocode for putative chitin-binding proteins (Behr and Hoch, 2005).Chitinases (and chi-lectins) are also produced by the venomand salivaryglands of some insect species (Arakane and Muthukrishnan, 2010).In endoparasitoid wasps such as Chelonus inanitus and Toxoneuronnigriceps the venom chitinases are probably involved in the degradationof the host cuticle facilitating the egression or ingression of parasitoidlarvae through such barriers (Consoli et al., 2005; Vincent et al., 2010).However, it has been shown that the venom of ectoparasitoid specieslike Nasonia vitripennis also contains chitinases (Danneels et al., 2010).Since in ectoparasitoids no larval egression or ingression occurs, otherfunctions should be ascribed to these enzymes (Danneels et al., 2010).The physiological role of chi-lectins found in the saliva of some insectssuch as the anopheline mosquito is not well understood either. Ithas been proposed that these chi-lectins may be involved in the self-defense mechanism of the anopheline mosquito against malariaparasites through a complex sequence of events (Owhashi et al.,2008). Plasmodium falciparum, the causative parasite of malaria, duringits sporogonic cycle in the midgut of the anopheline vector, produces achitinase that disrupts the peritrophic membrane and allows theparasite to migrate to the salivary glands of the vector (Giansanti et al.,2007). Inhibition of this enzyme results in complete disruption ofsporogonic development (Bhatnagar et al., 2003; Isaacs et al., 2012).Following a mosquito bite, the mosquito saliva proteins includingchi-lectins are introduced to the immune system of the host wherethey induce antibody production. Such anti-chitinase antibodies arefrequently encountered in the sera of residents of malaria-endemicareas (Owhashi et al., 2008). Ingestion of these antibodies from bloodmeals may contribute to the defense mechanism of mosquitoes byinhibiting the chitinolytic activity of malaria parasites (Owhashi et al.,2008). Insect chi-lectins have been shown to contribute to otherprocesses such as growth regulation and immunity as well (Aronsteinet al., 2010; Nakabachi et al., 2010).
6. Plant chitinases
Based on sequence similarity, plant chitinases are classified intoseven classes I–VII (Kasprzewska, 2003; Patil et al., 2009; Sarma et al.,2012). Class I, II, IV, VI, and VII chitinases belong to the GH19 familywhile class III and V chitinases are members of the GH18 family(Ohnuma et al., 2011, 2012). Chitinases comprise an important part ofpathogenesis-related (PR) proteins; a group of proteins includinghydrolytic enzymes, enzyme inhibitors, and membrane-permeabilizing
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peptides that are produced by plants in response to invading pathogensand abiotic factors (Ebrahim et al., 2011; Edreva, 2005; Li and Yi, 2012;Sels et al., 2008). It should be noted that although this definition includesabiotic factors, induction by such factors alone is not a sufficient criterionfor categorizing a particular protein as a PR protein (Edreva, 2005). PRproteins show antifungal, antibacterial, insecticidal, nematicidal, andantiviral effects and participate in the systemic acquired resistance(SAR) of plants against a broad range of pathogens. PR proteins arecurrently classified into 17 families with chitinases occurring in familiesPR-3, PR-4, PR-8, and PR-11 (Sels et al., 2008). Considering the impor-tant role of chitinases in plant defense against chitin-containing patho-gens, efforts have been made to produce transgenic plants expressingseveral chitinases or a combination of chitinases and other PR proteinsto increase their resistance against such pathogens and promisingresults have been achieved (Al Ahmadi et al., 2008; Amian et al., 2011;Ramana Rao et al., 2011). An alternative approach is to clone chitinasegenes in symbiotic rhizobacteria such as Burkholderia vietnamiensis(Zhang et al., 2012). There are legitimate concerns about the environ-mental consequences of using such procedures; nevertheless field stud-ies have demonstrated that these methods do not negatively affectthe decomposition dynamics of the plants or the soil fungal biomass(Duc et al., 2011; Stefani et al., 2010).
In addition to their role in defense against pathogens, plantchitinases also serve several other physiological functions that maynot be directly related to their hydrolytic activity. For example, someplant chitinases show ice structuring activity (Goni et al., 2010; Yaishet al., 2006). Ice structuring proteins (ISPs) are a group of proteinsproduced by different organisms including plants that bind ice crystalsand affect their growth and morphology providing cold or freezingtolerance for the organism (Hassas-Roudsari and Goff, 2012). ISPsprobably interactwith crystals through an icebinding surface composedof charge-conserved amino acids located apart from the enzyme'sactive site (Yaish et al., 2006). Plant chitinases are also up-regulatedby certain heavy metals such as lead and cadmium (Cai et al., 2011;Walliwalagedara et al., 2010). This may simply represent a commonstress response, although there is some evidence that chitinases maycounteract oxidative stress (Walliwalagedara et al., 2010). It has alsobeen shown that chitinases can act as calcium storage proteins. Yanget al. (2011) have isolated a class III chitinase from Punica granatumseeds that binds calcium ionswith high capacity. Although the presenceof calcium improves the stability of P. granatum seed chitinase, it hasnegligible effect on its activity. The subcellular localization pattern ofthis enzyme is also in agreement with a role in calcium storage.
Chi-lectins are produced by a broad range of plants and, like activechitinases, appear to be involved in different physiological processes(Van Damme et al., 2007). In Arabidopsis thaliana and Oryza sativachi-lectins play an essential role in cellulose biosynthesis (Sanchez-Rodriguez et al., 2012; Wu et al., 2012). The underlying mechanism ofthis observation is not completely understood but evidence suggeststhat chi-lectins bind to emerging cellulose microfibrils and affect theircrystallinity or the association of crystalline and amorphous regions(Sanchez-Rodriguez et al., 2012). In another study it was demonstratedthat chi-lectins affect root structure architecture in A. thaliana throughsimilar mechanisms (Hermans et al., 2010). On the other hand, studieson fruit ripening in banana have shown that some chi-lectins mayserve as storage proteins to support the synthesis of ripening-associated proteins by providing the required amino acids (Peumanset al., 2002). Plant chi-lectins also showantifungal and insecticidal activ-ity (Vasconcelos et al., 2011;Wasano et al., 2009). It has been proposedthat the antifungal activity of chi-lectins results from their ability toinhibit fungal glycosidases such as xylanases, however other mecha-nisms may also be involved (Vasconcelos et al., 2011). With regard totheir insecticidal activity, chi-lectins probably exert their toxic effect bydisrupting the formation of the peritrophic membrane (Wasano et al.,2009). Plant chi-lectins are up-regulates in response to abiotic stressessuch as drought, heat, and high salinity as well (Kwon et al., 2007).
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7. Mammalian chitinases
All known mammalian chitinases belong to the GH18 family(Shuhui et al., 2009). The first human chitinase to be identified was achitotriosidase produced by macrophages of Gaucher patients (Bootet al., 1995). Since this enzyme showed antifungal properties, it wasproposed that it may be involved in defense against chitin-containingpathogens. This observation was supported by other studies (Bussinket al., 2006). In contrast to these findings, later studies revealed thatabout 5% of Caucasian populations are completely deficient in activechitotriosidase suggesting that this enzyme may no longer be a directeffector of the innate immune response (Boot et al., 2005). This deficiencyresults from a 24-bp duplication in the CHIT1 gene (the gene encodinghuman chitotriosidase) that leads to aberrant splicing and, consequently,the production of an enzymatically inactive protein. Despite the factthat the relatively high incidence of this polymorphism precludes adirect defensive function for chitotriosidase, this enzyme still appearsto affect the host's defense system through other mechanisms. In arecent study, it was shown that the aforementioned duplication eventis strongly associatedwith an increased rate of decline in the lung func-tion of smokers with chronic obstructive pulmonary disease (COPD)(Aminuddin et al., 2011). This suggests a protective role against rapiddisease progression for human chitotriosidase although the underlyingmechanism still remains to be elucidated. Chitotriosidase may alsoexert some protective effects against atherosclerosis (Kitamoto et al.,2013). A few years after the discovery of chitotriosidase, a secondchitinase named acidic mammalian chitinase (AMCase) was isolatedand shown to be expressed primarily in the gastrointestinal tract andlung of both mouse and human (Boot et al., 2001). Based on its expres-sion profile, a dual function in innate immunity and chitin digestionwasproposed for AMCase (Bussink et al., 2007). Recent studies performedon several bat species suggest that AMCase may actually be involvedin chitin digestion in insectivorous mammals (Strobel et al., 2013).This is probably not the case for humans, however, as AMCase expres-sion level in the human gastrointestinal tract is significantly lowerthan that observed in mouse (Ohno et al., 2013). In the respiratorytract, AMCase also appears to be involved in Th2-mediated inflamma-tion (Kawada et al., 2007). Originally, it was hypothesized that inresponse to Th2 cytokines such as IL-13, airway epithelial cells andmacrophages produce AMCase that in turn induces the production ofseveral chemokines resulting in the recruitment of T cells, eosinophilsand macrophages (Lee, 2009; Shuhui et al., 2009; Zhu et al., 2004).This assumption was based on the observation that neutralizingAMCase with anti-AMCase serum or chitinase inhibitors reducedinflammatory infiltration in mouse asthma models (Shuhui et al.,2009). However, a recent study has shown that AMCase may actthrough altering the Th1/Th2 balance in lungs (Fitz et al., 2012). Oneshould note that some of the physiological functions of AMCase areindependent from its enzymatic activity (Hartl et al., 2009), hence,considering the different nature of the neutralizing agents used inthese studies, it can be assumed that these two proposed mechanismsmay represent two different pathways through which AMCase exertsits effects. AMCase and/or chitotriosidase may also be implicated inconjunctivitis, nasal polyp pathogenesis, adenoid hypertrophy, neuro-myelitis, and gastritis (Bucolo et al., 2011; Correale and Fiol, 2011;Cozzarini et al., 2009; Heo et al., 2011; Park et al., 2011). Both AMCaseand chitotriosidase, in addition to an N-terminal catalytic domain, con-tain a C-terminal CBM that belongs to the CBM14 family (Funkhouserand Aronson, 2007), and the genes coding for both enzymes havebeen identified in all mammals for which complete genome data areavailable (Bussink et al., 2007).
In addition to active chitinolytic enzymes, mammalian genomesalso code for enzymatically inactive chi-lectins (Shuhui et al., 2009). Inhumans three chi-lectins have been identified: human chitinase 3-likeprotein 1 (CHI3L1; also known as YKL-40), human chitinase 3-like pro-tein 2 (CHI3L2; also known asYKL-39), and oviductin (OVGP1) (Bussink
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et al., 2007; Shuhui et al., 2009). The mouse genome contains at leastseven chi-lectin genes. The physiological function of chi-lectins is notcompletely understood but they appear to be involved in different pro-cesses such as tissue remodeling, fertilization, and innate immunity(Bussink et al., 2006; Vega and Kalkum, 2012). For example, it hasbeen shown that CHI3L1 mediates mammary tissue remodeling duringinvolution possibly by inhibiting epithelial cell differentiation andpolarization and inducing cell motility (Scully et al., 2011). However,elevated levels of CHI3L1 are also associated with pathologic conditionssuch as breast malignancies which are characterized by poor differenti-ation (Scully et al., 2011). In fact, the murine homologue of CHI3L1 wasfirst discovered in breast cancer cells and named breast regressionprotein 39 (BRP-39) (Lee et al., 2009). In Th2-dependent immuneresponses, on the other hand, CHI3L1 appears to be involved in macro-phage and dendritic cell activation and apoptosis prevention (Lee et al.,2009), and thus it is not surprising that increased expression ofchi-lectins has been reported in several inflammatory diseases such asneuromyelitis (Correale and Fiol, 2011), colitis (Aomatsu et al., 2011),COPD (Sakazaki et al., 2011), and hepatitis (Lebensztejn et al., 2007).CHI3L1 appears to exert its effect by binding to interleukin-13 receptorα2 (He et al., 2013). It has been proposed that chi-lectins may be usedas biomarkers to evaluate the stage, prognosis and therapeutic responseof different diseases (Agapov et al., 2009; Roslind and Johansen, 2009).For example, CHI3L1 plasma level may be used to estimate the severityof preeclampsia (Seol et al., 2009), to evaluate the prognosis of chronicheart failure (Bilim et al., 2010), or to monitor the therapeutic responseof psoriasis (Imai et al., 2011). A limitation to this strategy is that inmany cases the plasma concentration of the chi-lectin does not directlycorrelate with the clinical parameters of the disease under investigation(Lebensztejn et al., 2007;Mathiasen et al., 2011). Itmay also be possibleto use chi-lectins as diagnostic biomarkers. However, since chi-lectinsare overexpressed in a wide range of inflammatory and oncogenicpathologies, they are of little diagnostic value when used alone. Thesensitivity and selectivity of diagnosis can be increased by measuringa panel of biomarkers at the same time (Chang et al., 2009). Changet al. (2009) have developed a multiplex proximity ligation assayusing three biomarkers (CHI3L1, osteopontin, and carbohydrate antigen19-9) for the diagnosis of pancreatic cancer. In another study, a similarapproach was used to improve the accuracy of ovarian cancer diagnosis(Fredriksson et al., 2008). Further studies are required before thesemethods can be exploited in clinic.
8. Concluding remarks
Chitinases and/or chi-lectins are ubiquitous proteins that are widelydistributed among all kingdoms of life. These proteins take part in awide range of physiological processes including nutrition, morphogen-esis, pathogenesis, parasitism, growth regulation, and immunity. Inmicroorganisms, they are primarily involved in the metabolism ofchitin, both endogenous (e.g. in fungi) and exogenous (e.g. in bacteria).However, in higher organisms, their regulatory function seems to bedominant. This is especially true for mammals since, as stated inSection 7, preliminary evidence suggests that mammalian chitinasesdo not directly participate in defense against chitinous pathogens. Asimilar argument can be made for plants. Although plant chitinasesare classified as PR proteins, it is not clear whether their increasedexpression in response to infections is a pathogen-specific process orit simply reflects a general stress-induced response in which chitinasesact as signaling intermediates (refer to Section 6). In this context, it istempting to look at chitinases as “living” examples of gene evolution.This idea becomes particularly attractive when we consider thatthe acquisition of (new) regulatory functions by chitinases can beexplained by both the mutation during non-functionality (MDN) andinnovation, amplification, and divergence (IAD) models of gene evolu-tion (Bergthorsson et al., 2007). Both models are based on the assump-tion that new genes always emerge from duplicated genes. The MDN
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model indicates that gene duplication precedes the acquisition of newfunctions and, in order to prevent the loss of the newly duplicatedgene due to drift or other processes, some selective pressure must bepresent. Severalmechanisms such as the protective effect of redundancy,stabilization by subfunctionalization, and the effect of increased genedosage participate in the maintenance of the duplicated gene, amongwhich the latter may have played an important role in the evolution ofchitinases. As described in Section 1,many organisms such as fungi con-tain several chitinase genes thatmight have provided them competitiveadvantage. Once a duplicated gene has been stabilized, it may, overtime, acquire the rare mutations that provide a new function. On theother hand, according to the IAD model, innovation (acquisition ofminor side activities) occurs before gene duplication. These activitiesare neither beneficial nor detrimental per se, but they may becomevaluable following a change in the surrounding environment that favorsone of these newly acquired functions. In this instance, the newfunctionmay act as a selectable trait. Such non-enzymatic side activitieshave been documented for mammalian and plant chitinases, asdiscussed in Sections 6 and 7. The IAD model can also explain theemergence of chi-lectins. It can be hypothesized that with the elimina-tion of the need for active chitinases, the selective pressure preventing“forbidden mutations” in critical regions such as the catalytic activesite of the enzyme was removed. However, these genes were stillselectively maintained for their (previously) side activities, giving riseto new non-enzymatic proteins with regulatory functions. Other exam-ples of such “dead enzymes” with regulatory functions have also beenidentified (Adrain and Freeman, 2012). Since young proteins evolvemore quickly than old proteins (Vishnoi et al., 2010), it is not surprisingthat the number and diversity of chi-lectin genes in mammaliangenomes appear to be higher than their active counterparts (refer toSection 7).
In recent years, chitinase research has made fast progress especiallyat molecular levels and chitinolytic activity, once considered to belimited to GH18 and GH19 families, and has been identified in otherGH families suggesting that the diversity of chitinases may be greaterthan previously anticipated. In a foreseeable future, with the elucidationof the different mechanisms through which they exert their physiolog-ical effects, chitinases and chi-lectins may found several medical, phar-maceutical, and agricultural applications. As discussed in Section 7,chi-lectins can potentially be used as biomarkers for the diagnosis ofdifferent types of cancers or for the evaluation of the therapeuticresponse and prognosis of several diseases in humans. Chitinase-producing microorganisms, on the other hand, have successfully beenexploited in the treatment of veterinary parasites (Section 4). Thepossibility of the direct application of parenteral chitinase preparationsin the treatment of systemic fungal infections has also been investigatedand promising results have been achieved (van Eijk et al., 2005). Alter-natively, it may be possible to control fungal infections using chitinaseinhibitors such as methylxanthines (Tsirilakis et al., 2012). However itshould be noted that these compounds may not be effective against allknown fungal pathogens. Chitinases can also be used in the biocontrolof plant pathogens and insect vectors of human diseases as describedin Sections 6 and 4, respectively. Finally, chitinases have been utilizedin the production of neoglycoproteins (Li et al., 2008) and syntheticpolysaccharides (Faijes and Planas, 2007). Neoglycoproteins are valu-able tools for structure-function studies (Kent, 2004) while syntheticpolysaccharides offer promising opportunities for the development ofprophylactic and therapeutic agents (Boltje et al., 2009). From an indus-trial viewpoint, screening alternative sources such as extreme habitatsfor chitinolytic enzymes may be advantageous as related glycosylhydrolases obtained from extremophiles often demonstrate superiorcharacteristics when catalytic reactions are performed under non-physiologic conditions such as high salinity and low water activity(Karan et al., 2012; Moshfegh et al., 2013; Niknejad et al., 2013). Thismay also be the case for chitinases. For example, such conditions maybe encountered in cases where chitinases are used as biocontrol agents
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(Barranco-Florido et al., 2002). Similarly, thermostable chitinases mayoffer considerable advantages for the production of oligosaccharides athigh temperature and low pH (Hobel et al., 2005).
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