Where is chitin found in the body

This review summarises latest advances in the analysis of chitin synthesis regulation in the context of fungal pathogenesis. Chitin is an essential component of the cell walls and septa of all pathogenic fungi, and occurs in the cyst walls of pathogenic amoebae, the egg-shells and gut lining of parasitic nematodes and the exoskeletons of invertebrate vectors of human disease including mosquitoes, sand flies, ticks and snails. Despite the fact that chitin is only outweighed in abundance in nature by cellulose and is present and essential in so many parasites and pathogens, fundamental information about its biosynthesis and recognition by the immune system is lacking.

The nascent primary polysaccharide of fungi folds back on itself to form anti-parallel chains, which form intra-chain hydrogen bonds that further stiffen the carbohydrate into immensely strong fibrous microfibrils tougher than any other molecule in nature, and stronger, weight-for-weight, than bone or steel Figure 1.

A variable proportion of fungal chitin is synthesised and then deacetylated to chitosan by the action of one or more chitin deacetylases. Chitin deacetylation may make the polymer more elastic and protect it from the action of hostile chitinases. Chitin structure and diversity in fungi. Examples of shadow cast electron microscopy images of chitin from a Neurospora crassa ; b Coprinus cinereus ; c chitin—chitosan from Mucor mucedo ; and d Candida albicans.

In e and f , the structure of chitin from C. The apparent simplicity of the chitin primary structure belies a complex underlying biosynthetic process.

Chitin is synthesised by large families of chitin synthase CHS enzymes that fall into seven discernable classes Table 1. The functional significance of all CHS classes is not clear and seems to differ in different fungi [ 1,2 ]. Class I enzymes are most readily measured in in vitro biochemical assays, yet they normally make only a minor fraction of cell wall chitin, and mutants lacking class I CHS genes are invariably viable with mild phenotypes under non-stressed conditions [ 1 ].

Class II enzymes often are immeasurable in enzyme assays, and make little chitin, but their deletion results in marked deleterious effects on cell viability through effects on vital processes such as primary septum formation [ 10 ]. Class IV enzymes often make substantial amounts of wall chitin, but mutants are usually viable although sometimes attenuated in virulence [ 11 ]. The multiplicity of CHS enzymes suggests that they may have redundant roles in cell wall synthesis. This is the case for some but not all CHS enzymes.

It is clear that the expression and activity of CHS is highly regulated both throughout the cell cycle and under conditions of stress, such as in response to potentially lethal challenges to cell integrity imposed by lytic enzymes or antibiotics or oxidants that are generated by the respiratory burst within the phagolysomes of lymphocytes. In most fungi, chitin and cell wall synthesis occurs at sites of polarised growth. During early bud growth, cell wall material is deposited at the bud tip [ 12 ].

A period of isotropic growth occurs in large budded cells where material is deposited over the entire bud surface. Following nuclear division, a repolarisation phase begins where material is directed towards the mother-bud neck to prepare for cytokinesis. In hyphal or filamentous forms, cell extension is a continuous and indefinite process of apical growth [ 13 ]. Accordingly, chitin synthesis must be regulated both temporally and spatially in relation to the cell cycle.

The S. A genome-wide analysis of cell cycle regulation at the mRNA level using synchronised S. Transcription during the cell cycle of an opaque C. Disruption of cell wall biosynthetic genes or treatments with cell wall perturbing agents often results in compensatory alterations in the cell wall, including activation of chitin synthesis, in an attempt to maintain cellular integrity reviewed in [ 17 ].

Defects in the cell wall are sensed in S. A second MAP kinase cascade, the high osmolarity glycerol response HOG pathway, has also been suggested to play a role in regulating cell wall architecture [ 19 ] Figure 2. Signalling pathways that regulate Candida albicans CHS gene expression.

Activation of the calcineurin pathway results in de-phosphorylation of the Ca Crz1 transcription factor. Ca Crz1 then moves to the nucleus and induces expression of genes with CDREs calcium-dependent response elements within their promoter sequences. Promoter dissection experiments have defined the regulatory regions of the class I CHS promoter sequences and revealed that C. Upregulation of chitin synthesis in response to cell wall stress may be clinically relevant.

Coordinated synthesis of chitin also requires the localisation of the enzymes to be regulated throughout the cell cycle. For example, in C. It is localised to the tip of growing buds and hyphae and relocates to sites of septum formation before cytokinesis [ 24 ]. Similarly, in A. Both the localisation and stability of CHS enzymes can be regulated by phosphorylation. Recent work has shown that protein kinases and the establishment of cell polarity appear to be important for cell wall regulation in C.

Deletion of these phospho-sites resulted in Sc Chs2 degradation [ 28 ], indicating that phosphorylation regulates chitin synthesis by Sc Chs2 at specific stages of the cell cycle, either by regulating the cellular localisation or stability of the protein. Three of the four CHS enzymes are phosphorylated in C. Phosphorylation of Candida albicans Chs3 on a specific serine residue is required to target the CHS to sites of polarised growth.

Ca Chs3 was tagged with yellow-fluorescent protein YFP and the localisation of the CHS in growing hyphae was observed by time-lapse fluorescence microscopy. Export of Sc Chs3 from the ER is controlled by the chaperone Sc Chs7 and transportation from the Golgi to the plasma membrane PM occurs in specialised vesicles called chitosomes [ 31,32 ].

Sc Chs3 is targeted to the bud neck for septum formation at an appropriate time in the cell cycle through interactions with Sc Chs4, Sc Bni4, Sc Glc7 and the septins [ 14,34—38 ]. In addition to mechanisms involving post-translational modifications or protein—protein interactions, some CHSs are hybrid proteins with N-terminal myosin motor-like domains MMD and C-terminal CHS domains.

Using their MMD, these enzymes appear to localise themselves to sites of polarised cell wall expansion in an actin-dependent manner [ 40,42—44 ]. The MMD may not possess the motor activity of traditional myosins [ 43 ], however, in the plant pathogen Ustilago maydis , the myosin-like domain of the class V Um Mcs1 enzyme has been shown to be essential for its apical localisation and is involved in retention of Um Mcs1 in the apical dome G Steinberg, personal communication.

The immune system has evolved to detect conserved, basic molecular components of microorganisms called pathogen associated molecular patterns PAMPs. What therefore is the immunological role of chitin, the other highly conserved signature molecule in the inner cell wall? Recent studies have begun to reveal a complex picture regarding the immunological properties of chitin [ 49 ]. Immune responses seem to be highly dependent on the size of the chitin fragments used to stimulate immune cells [ 50 ].

All of these particles are quite large relative to the sizes of fungal cells and the molecular scale of immune receptor—ligand interactions. Also, such experiments have yet to accommodate the fact that the structure of chitin microfibrils varies significantly in different organisms and even in different parts of the cell wall [ 24 ] Figure 1. Size-dependent immune reactivity helps explain the importance of chitin-degrading proteins, such as acidic mammalian chitinase [ 52 ] and chitotriosidase [ 53,54 ] in allergic immune responses.

These enzymes presumably digest chitin into smaller particles, capable of mediating allergic responses. Reciprocally, it appears as though certain human proteins sequester chitin to dampen immune responses [ 56 ].

Recently, several candidate mediators of chitin mediated immune responses have been identified. Peptidoglycans are chemically related to chitin in so far as they are N -acetylglucosamine containing polysaccharides and the two molecules can activate some common cellular responses [ 58 ].

The requirement for acetylation suggests that this receptor is unresponsive to chitosan, which is known to be able to activate dendritic cells via a TLR4-dependent mechanism [ 60 ]. This is important because fungal pathogens such as the zygomycetous fungi and C. Therefore further chitin and chitosan immune receptors remain to be identified and the role of fungal chitin in immune recognition requires investigation. Chitin and chitosan are hallmark polysaccharides that are present in all known fungal pathogens and not in humans.

Inhibition of chitin synthesis has therefore been proposed as an attractive target for antifungal therapies. However, no CHS inhibitor has ever progressed into clinical practice [ 61 ].

Existing CHS inhibitors such as the nikkomycins and polyoxins are most potent and specific against class I enzymes but are less effective inhibitors of other classes of CHS enzymes, and of fungal growth in vivo [ 61,62 ]. The discovery of the essential role of C. This highlighted the possibility of compensatory functions for different CHS enzymes and was reinforced by the observation that C.

A common response to cell wall damage is strengthening of the wall by the production of excess chitin, primarily by the class IV enzymes such as Sc Chs3 and Ca Chs3 [ 20,64 ]. Enhanced chitin levels reduces susceptibility to echinocandin drugs in C.

These studies highlight the potential of combination therapies that target the synthesis of the two major structural polysaccharides found in most fungi, in achieving fungicidal regimens that would prevent the emergence of resistance mechanisms. In addition, cell wall synthase inhibitors, applied in combination with antagonists of the signalling pathways that regulate synthase expression and activity, may have potential as potent antifungal combination therapies. For example, the calcineurin pathway is important for regulation of chitin synthesis in C.

The primary structure of chitin comprises a single sugar type and a single inter-sugar linkage. None-the-less it is diverse in structure and form and is assembled by different classes of enzymes encoded by families of genes whose expression is regulated in a cell cycle-dependent manner at the transcriptional and post-transcriptional levels.

The relevance of fungal chitin synthesis in human disease is also evident in emerging research defining the role of this fungal signature molecule in immune recognition mechanisms. Papers of particular interest, published within the annual period of review, have been highlighted as:.

National Center for Biotechnology Information , U. Sponsored Document from. Current Opinion in Microbiology.

Curr Opin Microbiol. Author information Copyright and License information Disclaimer. Neil AR Gow: ku. This article has been cited by other articles in PMC.

Abstract Chitin is an essential part of the carbohydrate skeleton of the fungal cell wall and is a molecule that is not represented in humans and other vertebrates. Rather than building a protective covering, chitinase is an enzyme that breaks down chitin.

Viruses, bacteria, fungi, insects, plants, and mammals all hold a similar enzyme that hydrolyzes chitin. Insects produce the most forms of chitinases, which they need during molting - the process of shedding their exoskeleton, which they do several times in their life. The main function of chitinase in organisms is immunity defense, digestion, and arthropod molting.

For instance, chitinase has an amazing ability to degrade chitin in fungal cell walls and insect exoskeletons. Therefore, chitinase is antimicrobial, antifungal , and essentially an insecticide. Unsurprisingly, chitin is quite popular in the food industry. Apart from consumption, the biopolymer is a fantastic emulsifier and stabilizer in products.

Due to being antifungal, chitin also acts as a perfect edible preservation agent. Thankfully, certain forms of chitin have great flavors. In particular, microcrystalline chitin is used as a food additive for flavor enhancement. Chitin also has a broad application within the medical field. For example, contact lenses, artificial skin, and even dissolvable surgical stitches are derived from some form of chitin.

If you have never eaten chitin, you may have still used it. Chitin is also a major component of fertilizers. It triggers an immune response in plants, stimulating growth. Chitin is also extremely green. The biopolymer is biodegradable, biocompatible, and non toxic.

Several studies have even discovered that chitin can absorb pollutant metals from water. From shrimp to plants, chitin and its derivatives provide protection and immunity defense to organisms. When consumed, chitin imparts pre-biotic and antioxidant properties. The structure of chitin was described by Albert Hoffman in The word "chitin" derives from the French word chitine and Greek word chiton , which mean "covering.

A related molecule is chitosan, which is made by deacetylation of chitin. Chitin is insoluble in water, while chitosan is soluble. Hydrogen bonding between monomers in chitin make it very strong. Pure chitin is translucent and flexible. However, in many animals, chitin is combined with other molecules to form a composite material.

For example, in mollusks and crustaceans it combines with calcium carbonate to form hard and often colorful shells. In insects, chitin is often stacked into crystals that produce iridescent colors used for biomimicry, communication, and to attract mates. Chitin is primarily a structural material in organisms. It is the main component of fungal cell walls. It forms the exoskeletons of insects and crustaceans. It forms the radulae teeth of mollusks and the beaks of cephalopods. Chitin also occurs in vertebrates.

Fish scales and some amphibian scales contain chitin. Plants have multiple immune receptors to chitin and its degradation products. When these receptors are activated in plants jasmonate hormones are released that initiate an immune response. This is one way plants defend themselves against insect pests. In agriculture, chitin may be used to boost plant defenses against disease and as a fertilizer. Humans and other mammals do not produce chitin. However, they have an enzyme called chitinase that degrades it.

Chitinase is present in human gastric juice, so chitin is digestible. Chitin and its degradation products are sensed in the skin, lungs, and digestive tract, initiating an immune response and potentially conferring protection against parasites. Allergies to dust mites and shellfish are often due to a chitin allergy. Because they stimulate an immune response, chitin and chitosan may be used as vaccine adjuvants. Chitin may have applications in medicine as a component of bandages or for surgical thread.