Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate
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 Phagocyte bacteria), and others are secreted into the extracellular medium. For those that directly kill microbes, their mechanism of action varies from disruption of the microbial cell membrane to metabolic disruption.
Varieties
The name 'defensin' was coined in the mid-1980s, though the proteins have been called 'Cationic Antimicrobial Proteins,' 'Neutrophil peptides,' 'Gamma thionins' amongst others.
Proteins called 'defensins' are not all evolutionarily related to one another.
Trans-defensins
Vertebrate defensins are primarily
Alpha defensin and
Beta defensin. Some primates additionally have the much smaller
Theta defensin. 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.
form a single
beta hairpin structure and represent a distinct group. Only alpha and beta-defensins are expressed in humans.
Table of human defensins
! style="width:70px" | Type
! Gene Symbol
! style="width:120px" | Gene Name
! style="width:140px" | Protein Name
! Description |
| | Alpha defensin]] | DEFA1 | Defensin, alpha 1 | Neutrophil defensin 1 | 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. |
| | DEFA1B | Defensin, alpha 1B | Defensin, alpha 1 |
| | DEFA3 | Defensin, alpha 3, neutrophil-specific | Neutrophil defensin 3 |
| | DEFA4 | Defensin, alpha 4, corticostatin | Neutrophil defensin 4 |
| | DEFA5 | Defensin, alpha 5, Paneth cell-specific | Defensin-5 |
| | DEFA6 | Defensin, alpha 6, Paneth cell-specific | Defensin-6 |
| | Beta defensin]] | DEFB1 | Defensin, beta 1 | Beta-defensin 1 | 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. |
| | DEFB2 | Defensin, beta 2 | Beta-defensin 2
|
| DEFB3 | Defensin, beta 3 | Beta-defensin 3
|
| | DEFB103A | Defensin, beta 103B | Beta-defensin 103 |
| | '''...''' | '''...''' | '''...''' |
| | DEFB106A | Defensin, beta 106A | Beta-defensin 106A |
| | DEFB106B | Defensin, beta 106B | Beta-defensin 106B |
|
DEFB107B
| Defensin, beta 107A | Beta-defensin 107 |
| DEFB110
| Defensin, beta 110
| Beta-defensin 110
|
| ...
| '''...'''
| ...
|
| DEFB136
| Defensin, beta 136
| Beta-defensin 136
|
| | Theta defensin]] | DEFT1P | Defensin, theta 1 pseudogene | not expressed in humans | Are rare, and thus far have been found only in the leukocytes of the [[rhesus macaque]] |
Although the most well-studied defensins are from vertebrates, a family of trans-defensins called 's' are found in
molluscs,
arthropods and
.
Cis-defensins
Arthropod defensins are the best-characterised defensins from invertebrates (especially those from insects).
Other invertebrates known to produce defensins from this protein superfamily include
molluscs,
and
cnidaria.
were discovered in 1990 and have subsequently been found in most plant tissues with antimicrobial activities, with both antifungal and antibacterial examples.
were first identified in 2005.
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.
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;
they act via a completely different mechanism to their antimicrobial relatives, from binding directly to
to disrupting
. Examples include the
crotamine toxin in
snake venom,
many
,
some sea anemone toxins,
and one of the toxins in
platypus venom.
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.
Signalling
In vertebrates, some α- and β-defensins are involved in signalling between the innate immune and adaptive immune systems.
In plants, a specialised family of DLPs is involved in signalling to detect if
self-pollination has occurred and induce self-incompatibility to prevent inbreeding.
Enzyme inhibitors
Some antimicrobial defensins also have
activity, and some DLPs function primarily as enzyme inhibitors, acting as
(discouraging animals from eating them).
Function
In immature
marsupials, because their
immune system is underdeveloped at the time of birth, defensins play a major role in defense against
pathogens. 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.
The human genome contains theta-defensin genes, but they have a premature stop codon, hampering their expression. An artificial human theta-defensin,
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.
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.
Pathology
The
alpha defensin peptides are increased in chronic inflammatory conditions.
Alpha defensin are increased in several cancers, including colorectal cancer.
An imbalance of defensins in the skin may contribute to acne.
A reduction of ileum defensins may predispose to Crohn's disease.
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.
Defensins are found in the human skin during inflammatory conditions like psoriasis
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.
In addition, defensins can enhance the effectiveness of conventional antibiotics.
Defensin-mimetics
Defensin
Mimesis, also called host defense peptide (HDP) mimetics, are completely synthetic, non-peptide, small molecule structures that mimic defensins in structure and activity.
[ Business Wire] Similar molecules, such as
brilacidin, are being developed as
,
anti-inflammatories for oral
mucositis,
and
antifungals, especially for
candidiasis.
See also
-
Host defense peptides, to which defensins belong
External links
