In animals, they are produced by cells of the
innate immune system and
epithelial 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. in
neutrophil granulocytes to kill
phagocytosed bacteria), and others are secreted into the extracellular medium. For those that directly kill microbes, their mechanism of action varies from disruption of the
microbialcell membrane to metabolic disruption.
Varieties
Characteristic disulphide linkages
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 broad
superfamilies, each of which contains multiple
families.[7][8] One superfamily, the trans-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 highly
polymorphic.[citation needed]
Trans-defensins
Vertebrate defensins are primarily
α-defensins and
β-defensins. Some primates additionally have the much smaller
θ-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 after
translation) 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 single
beta-hairpin structure and represent a distinct group. Only alpha and beta-defensins are expressed in humans.[19]
Are expressed primarily in
neutrophils as well as in
NK cells and certain T-lymphocyte subsets.
DEFA5 and
DEFA6 are expressed in
Paneth cells of the small intestine, where they may regulate and maintain microbial balance in the intestinal lumen.
Are the most widely distributed, being secreted by
leukocytes and
epithelial 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 of
cystic 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 the
rhesus 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 in
molluscs,
arthropods and
lancelets.[7][8]
Cis-defensins
Arthropod defensins are the best-characterised defensins from invertebrates (especially those from insects).[23] Other invertebrates known to produce defensins from this protein superfamily include
molluscs,
annelids and
cnidaria.[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 of
vascular 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]
Related defensin-like proteins
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.
Toxins
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 to
ion channels to disrupting
nerve signals. Examples include the
crotamine toxin in
snake venom,[30] many
scorpion toxins,[31] some
sea anemone toxins,[10] and one of the toxins in
platypus venom.[29] Indeed, an insect defensin has been experimentally converted into a toxin by deletion of a small loop that otherwise
sterically hindered interactions with the ion channels.[32]
Some antimicrobial defensins also have
enzyme inhibitory activity, and some DLPs function primarily as enzyme inhibitors, acting as
antifeedants (discouraging animals from eating them).[36][37][38]
Function
In immature
marsupials, because their
immune system is underdeveloped at the time of birth, defensins play a major role in defense against
pathogens. [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 premature
stop codon, hampering their expression. An artificial human theta-defensin,[40]retrocyclin, was created by 'fixing' the
pseudogene, and it was shown to be effective against
HIV[41] and other viruses, including
herpes simplex virus and
influenza A. They act primarily by preventing these viruses from entering their target cells.
Also interesting is the effect of alpha-defensins on the
exotoxin produced by anthrax (Bacillus anthracis). Chun Kim et al. showed how anthrax, which produces a
metalloprotease lethal factor (LF) protein to target
MAPKK, 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]
Pathology
The
alpha defensin peptides are increased in chronic inflammatory conditions.
Alpha defensin are increased in several cancers, including colorectal cancer.[44]
An imbalance of defensins in the skin may contribute to acne.[45]
In one small study, a significant increase in
alpha defensin levels was detected in
T cell lysates of
schizophrenia 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 like
psoriasis[49] and also during
wound healing.
Applications
Defensins
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]
^Tassanakajon A, Somboonwiwat K, Amparyup P (February 2015). "Sequence diversity and evolution of antimicrobial peptides in invertebrates". Developmental and Comparative Immunology. Specific immunity in invertebrates. 48 (2): 324–41.
doi:
10.1016/j.dci.2014.05.020.
PMID24950415.
^
abHollox EJ, Abujaber R (2017). "Evolution and Diversity of Defensins in Vertebrates". In Pontarotti P (ed.). Evolutionary Biology: Self/Nonself Evolution, Species and Complex Traits Evolution, Methods and Concepts. Springer International Publishing. pp. 27–50.
doi:
10.1007/978-3-319-61569-1_2.
ISBN978-3-319-61569-1.
^Zhu S (February 2008). "Discovery of six families of fungal defensin-like peptides provides insights into origin and evolution of the CSalphabeta defensins". Molecular Immunology. 45 (3): 828–38.
doi:
10.1016/j.molimm.2007.06.354.
PMID17675235.
^Dhople V, Krukemeyer A, Ramamoorthy A (September 2006). "The human beta-defensin-3, an antibacterial peptide with multiple biological functions". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1758 (9): 1499–512.
doi:
10.1016/j.bbamem.2006.07.007.
PMID16978580.
S2CID36461159.
^Fobis-Loisy I, Ivanov R, Gaude T (2012). "The S-LOCUS CYSTEINE-RICH PROTEIN (SCR): A Small Peptide with a High Impact on the Evolution of Flowering Plants". Plant Signaling Peptides. Signaling and Communication in Plants. Vol. 16. Springer Berlin Heidelberg. pp. 77–92.
doi:
10.1007/978-3-642-27603-3_5.
ISBN978-3-642-27602-6.
^Williams LK, Brayer GD (2015-11-25). "Porcine pancreatic alpha-amylase in complex with helianthamide, a novel proteinaceous inhibitor".
doi:
10.2210/pdb4x0n/pdb.
^Zhao Q, Chae YK, Markley JL (2003-01-07). "Minimized NMR structure of ATT, an Arabidopsis trypsin/chymotrypsin inhibitor".
doi:
10.2210/pdb1jxc/pdb.
^Pelegrini PB, Lay FT, Murad AM, Anderson MA, Franco OL (November 2008). "Novel insights on the mechanism of action of alpha-amylase inhibitors from the plant defensin family". Proteins. 73 (3): 719–29.
doi:
10.1002/prot.22086.
PMID18498107.
S2CID28378146.
^Münk C, Wei G, Yang OO, Waring AJ, Wang W, Hong T, Lehrer RI, Landau NR, Cole AM (October 2003). "The theta-defensin, retrocyclin, inhibits HIV-1 entry". AIDS Research and Human Retroviruses. 19 (10): 875–81.
doi:
10.1089/088922203322493049.
PMID14585219.
^Clinical trial number NCT02324335 for "Phase 2 Study to Evaluate the Safety & Efficacy of Brilacidin Oral Rinse in Patients With Head and Neck Cancer (Brilacidin)" at
ClinicalTrials.gov