In animals, they are produced by cells of theinnate immune system andepithelial cells, whereas in plants and fungi they are produced by a wide variety of tissues. An organism usually produces many different defensins, some of which are stored inside the cells (e.g. inneutrophil granulocytes to killphagocytosed bacteria), and others are secreted into the extracellular medium. For those that directly kill microbes, their mechanism of action varies from disruption of themicrobialcell membrane to metabolic disruption.
Trans-defensin superfamily: In yellow, the two most conserved disulphides link a beta strand to two different secondary structure elements (motif = CC). On the right, an example structure (PDB:1IJV).
Cis-defensin superfamily: In yellow, the two most conserved disulphides link a beta strand to the same alpha helix (motif = CxC...CxxxC). On the right, an example structure (PDB:1MRR4).
The name 'defensin' was coined in the mid-1980s, though the proteins have been called 'Cationic Antimicrobial Proteins,' 'Neutrophil peptides,' 'Gamma thionins' amongst others.[6]
Proteins called 'defensins' are not all evolutionarily related to one another.[7] Instead fall into two broadsuperfamilies, each of which contains multiplefamilies.[7][8] One superfamily, thetrans-defensins, contains the defensins found in humans and other vertebrates,[9][10] as well as some invertebrates.[11][12] The other superfamily,cis-defensins, contains the defensins found in invertebrates, plants, and fungi.[13][14][15] The superfamilies and families are determined by the overall tertiary structure, and each family usually has a conserved pattern of disulphide bonds.[9][16] All defensins form small and compact folded structures, typically with a high positive charge, that are highly stable due to the multiple disulphide bonds. In all families, the underlying genes responsible for defensin production are highlypolymorphic.[citation needed]
Vertebrate defensins are primarilyα-defensins andβ-defensins. Some primates additionally have the much smallerθ-defensins. In general, both α- and β-defensins are encoded by two-exon genes, where the first exon encodes for a hydrophobic leader sequence (removed aftertranslation) and the cysteine-rich sequence (the mature peptide). The disulfide linkages formed by the cysteines have been suggested to be essential for activities related to innate immunity in mammals, but are not necessarily required for antimicrobial activity.[17][18]Theta defensins form a singlebeta-hairpin structure and represent a distinct group. Only alpha and beta-defensins are expressed in humans.[19]
Are expressed primarily inneutrophils as well as inNK cells and certain T-lymphocyte subsets.DEFA5 andDEFA6 are expressed inPaneth cells of the small intestine, where they may regulate and maintain microbial balance in the intestinal lumen.
Are the most widely distributed, being secreted byleukocytes andepithelial cells of many kinds. For example, they can be found on the tongue, skin, cornea, salivary glands, kidneys, esophagus, and respiratory tract. It has been suggested (but also challenged) that some of the pathology ofcystic fibrosis arises from the inhibition of β-defensin activity on the epithelial surfaces of the lungs and trachea due to higher salt content.
Are rare, and thus far have been found only in the leukocytes of therhesus macaque[20] and the olive baboon,Papio anubis, the gene coding for it is corrupted in humans and other primates.[21][22]
Although the most well-studied defensins are from vertebrates, a family of trans-defensins called 'big defensins' are found inmolluscs,arthropods andlancelets.[7][8]
Arthropod defensins are the best-characterised defensins from invertebrates (especially those from insects).[23] Other invertebrates known to produce defensins from this protein superfamily includemolluscs,annelids andcnidaria.[24]
Plant defensins were discovered in 1990 and have subsequently been found in most plant tissues with antimicrobial activities, with both antifungal and antibacterial examples.[25] They have been identified in all major groups ofvascular plants, but not in ferns, mosses or algae.[25]
Bacterial defensins have also been identified, but are by far the least studied. They include variants with only four cysteines, whereas defensins from eukaryote defensins almost all have six or eight.[28]
In addition to the defensins involved in host defence, there are a number of related Defensin-Like Peptides (DLPs) that have evolved to have other activities.
There appear to have been multiple evolutionary recruitments of defensins to be toxin proteins used in the venoms of animals;[29] they act via a completely different mechanism to their antimicrobial relatives, from binding directly toion channels to disruptingnerve signals. Examples include thecrotamine toxin insnake venom,[30] manyscorpion toxins,[31] somesea anemone toxins,[10] and one of the toxins inplatypus venom.[29] Indeed, an insect defensin has been experimentally converted into a toxin by deletion of a small loop that otherwisesterically hindered interactions with the ion channels.[32]
Some antimicrobial defensins also haveenzyme inhibitory activity, and some DLPs function primarily as enzyme inhibitors, acting asantifeedants (discouraging animals from eating them).[36][37][38]
In immaturemarsupials, because theirimmune system is underdeveloped at the time of birth, defensins play a major role in defense againstpathogens.[citation needed] They are produced in the milk of the mother as well as by the young marsupial in question.
In human breast milk, defensins play a central role in neonate immunity.[39]
The human genome contains theta-defensin genes, but they have a prematurestop codon, hampering their expression. An artificial human theta-defensin,[40]retrocyclin, was created by 'fixing' thepseudogene, and it was shown to be effective againstHIV[41] and other viruses, includingherpes simplex virus andinfluenza A. They act primarily by preventing these viruses from entering their target cells.
Also interesting is the effect of alpha-defensins on theexotoxin produced by anthrax (Bacillus anthracis). Chun Kim et al. showed how anthrax, which produces ametalloprotease lethal factor (LF) protein to targetMAPKK, is vulnerable to human neutrophil protein-1 (HNP-1). This group showed HNP-1 to behave as a reversible noncompetitive inhibitor of LF.[42]
They have generally been considered to contribute to mucosal health; however, it is possible that these peptides can be considered biological factors that can be upregulated by bioactive compounds present in human breast milk. In this sense, the intestinal production of antimicrobial peptides as hBD2 and hBD4 by trefoil from milk might play an important role on neonate colonization, thereby enhancing the immune response of newborns against pathogens with which they may come in contact.[39][43]
In one small study, a significant increase inalpha defensin levels was detected inT cell lysates ofschizophrenia patients; in discordant twin pairs, unaffected twins also had an increase, although not as high as that of their ill siblings. The authors suggested that alpha-defensin levels might prove a useful marker for schizophrenia risk.[48]
Defensins are found in the human skin during inflammatory conditions likepsoriasis[49] and also duringwound healing.
At present, the widespread spread of antibiotic resistance requires the search and development of new antimicrobial drugs. From this point of view, defensins (as well as antimicrobial peptides in general) are of great interest. It was shown that defensins have pronounced antibacterial activity against a wide range of pathogens.[50] In addition, defensins can enhance the effectiveness of conventional antibiotics.[50]
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^Clinical trial numberNCT02324335 for "Phase 2 Study to Evaluate the Safety & Efficacy of Brilacidin Oral Rinse in Patients With Head and Neck Cancer (Brilacidin)" atClinicalTrials.gov
