Defensins are small
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, s ...
-rich
cationic
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respondi ...
across cellular life, including
vertebrate
Vertebrates () comprise all animal taxon, taxa within the subphylum Vertebrata () (chordates with vertebral column, backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the ...
and
invertebrate
Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
animals,
plants
Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclud ...
, and
fungi
A fungus (plural, : fungi or funguses) is any member of the group of Eukaryote, eukaryotic organisms that includes microorganisms such as yeasts and Mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified ...
. They are
host defense peptides
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for an ...
, with members displaying either direct
antimicrobial activity,
immune
In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...
signalling activities, or both. They are variously active against
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
,
fungi
A fungus (plural, : fungi or funguses) is any member of the group of Eukaryote, eukaryotic organisms that includes microorganisms such as yeasts and Mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified ...
and many enveloped and nonenveloped
viruses
A virus is a submicroscopic infectious agent that replicates only inside the living cells
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room ...
. They are typically 18-45
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s in length, with three or four highly conserved
disulphide bonds
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
.
In animals, they are produced by cells of the
innate immune system
The innate, or nonspecific, immune system is one of the two main immunity strategies (the other being the adaptive immune system) in vertebrates. The innate immune system is an older evolutionary defense strategy, relatively speaking, and is th ...
and
epithelial cells
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
, 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 granulocyte
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
s to kill
phagocytosed
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is c ...
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
A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
cell membrane
The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (the ...
to metabolic disruption.
Varieties
The name 'defensin' was coined in the mid 1980s, though the proteins have been variously called 'Cationic Antimicrobial Proteins', 'Neutrophil peptides', 'Gamma thionins' amongst others.
Proteins called 'defensins' are not all evolutionarily related to one another.
Instead fall into two broad
superfamilies, each of which contains multiple
families
Family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other relationship). The purpose of the family is to maintain the well-being of its members and of society. Idea ...
.
One superfamily, the ''trans''-defensins, contains the defensins found in humans and other vertebrates
as well as some invertebrates. The other superfamily, ''cis''-defensins, contains the defensins found in invertebrates, plants and fungi. The superfamilies and families are determined overall tertiary structure and each family usually has a conserved pattern of disulphide bonds.
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.
Trans-defensins
Vertebrate defensins are primarily
α-defensins and the
β-defensins. Some primates additionally have the much smaller
θ-defensins. In general, both α- and β-defensins are encoded by two-
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...
genes, where the first exon encodes for a hydrophobic leader sequence (that is removed after
translation
Translation is the communication of the Meaning (linguistic), meaning of a #Source and target languages, source-language text by means of an Dynamic and formal equivalence, equivalent #Source and target languages, target-language text. The ...
) 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.
Theta defensin
Theta-defensins (θ-defensins, retrocyclins, or demidefensins) are a family of mammalian antimicrobial peptides. They are found in non-human 'Old World' primates, but not in human, gorilla, bonobo, and chimpanzee.
Structure
θ-defensins are cy ...
s form a single
beta hairpin
The beta hairpin (sometimes also called beta-ribbon or beta-beta unit) is a simple protein structural motif involving two beta strands that look like a hairpin. The motif consists of two strands that are adjacent in primary structure, oriented in ...
structure and therefore also represent a distinct group. Only alpha and beta defensins are expressed in humans.
Although the most well-studied defensins are from vertebrates, a family of trans-defensins called 's' are found in
molluscs
Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000 extant species of molluscs are recognized. The number of fossil species is esti ...
,
arthropods
Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and cuticle made of chitin, oft ...
and
lancelet
The lancelets ( or ), also known as amphioxi (singular: amphioxus ), consist of some 30 to 35 species of "fish-like" benthic filter feeding chordates in the order Amphioxiformes. They are the modern representatives of the subphylum Cephalochorda ...
s.
Cis-defensins
Arthropod defensin
Arthropod defensins are a family defensin proteins found in mollusks, insects, and arachnids. These cysteine-rich antibacterial peptides are primarily active against Gram-positive bacteria and fungi in vitro. However ''Drosophila'' fruit flies m ...
s are the best-characterised defensins from invertebrates (especially those from insects). Other invertebrates known to produce defensins from this protein superfamily include
molluscs
Mollusca is the second-largest phylum of invertebrate animals after the Arthropoda, the members of which are known as molluscs or mollusks (). Around 85,000 extant species of molluscs are recognized. The number of fossil species is esti ...
,
annelid
The annelids (Annelida , from Latin ', "little ring"), also known as the segmented worms, are a large phylum, with over 22,000 extant species including ragworms, earthworms, and leeches. The species exist in and have adapted to various ecol ...
s and
cnidaria
Cnidaria () is a phylum under kingdom Animalia containing over 11,000 species of aquatic animals found both in Fresh water, freshwater and Marine habitats, marine environments, predominantly the latter.
Their distinguishing feature is cnidocyt ...
.
Plant defensins were discovered in 1990 and have subsequently been found in most plant tissues with antimicrobial activities, with both antifungal and antibacterial examples.
They have been identified in all major groups of
vascular plant
Vascular plants (), also called tracheophytes () or collectively Tracheophyta (), form a large group of land plants ( accepted known species) that have lignified tissues (the xylem) for conducting water and minerals throughout the plant. They ...
s, but not in ferns, mosses or algae.
Fungal defensins were first identified in 2005. Studied examples mainly have anti-bacterial activities and have been found in both main
divisions of fungi (
Ascomycota
Ascomycota is a phylum of the kingdom Fungi that, together with the Basidiomycota, forms the subkingdom Dikarya. Its members are commonly known as the sac fungi or ascomycetes. It is the largest phylum of Fungi, with over 64,000 species. The de ...
and
Basidiomycota
Basidiomycota () is one of two large divisions that, together with the Ascomycota, constitute the subkingdom Dikarya (often referred to as the "higher fungi") within the kingdom Fungi. Members are known as basidiomycetes. More specifically, Basi ...
), as well as in the more basal groups of
Zygomycota
Zygomycota, or zygote fungi, is a former division or phylum of the kingdom Fungi. The members are now part of two phyla: the Mucoromycota and Zoopagomycota. Approximately 1060 species are known. They are mostly terrestrial in habitat, living ...
and
Glomeromycota
Glomeromycota (often referred to as glomeromycetes, as they include only one class, Glomeromycetes) are one of eight currently recognized divisions within the kingdom Fungi,
with approximately 230 described species. Members of the Glomeromyco ...
.
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
ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ...
s to disrupting
nerve signal
An action potential occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, ...
s. Examples include the
crotamine
Crotamine is a toxin present in the venom of the South American rattlesnake ('' Crotalus durissus terrificus''). It is a 42-residue long protein containing 11 basic residues (9 lysines, 2 arginines) and 6 cysteines. It has also been isolated from t ...
toxin in
snake venom
Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is injected by unique fangs during a bite, whereas some species are a ...
, many
scorpion toxin
Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, volt ...
s, some
sea anemone toxins,
and one of the toxins in
platypus venom
The platypus is one of the few living mammals to produce venom. The venom is made in venom glands that are connected to hollow spurs on their hind legs; it is primarily made during the mating season. While the venom's effects are described as ...
.
Indeed, an insect defensin has been experimentally converted into a toxin by deletion of a small loop that otherwise
sterically hindered
Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
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
Self-pollination is a form of pollination in which pollen from the same plant arrives at the stigma of a flower (in flowering plants) or at the ovule (in gymnosperms). There are two types of self-pollination: in autogamy, pollen is transferred t ...
has occurred and induce
self-incompatibility
Self-incompatibility (SI) is a general name for several genetic mechanisms that prevent self-fertilization in sexually reproducing organisms, and thus encourage outcrossing and allogamy. It is contrasted with separation of sexes among individual ...
to prevent inbreeding.
Enzyme inhibitors
Some antimicrobial defensins also have
enzyme inhibitor
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a s ...
y activity, and some DLPs function primarily as enzyme inhibitors, acting as
antifeedant
Antifeedants are organic compounds produced by plants to inhibit attack by insects and grazing animals. These chemical compounds are typically classified as secondary metabolites in that they are not essential for the metabolism of the plant, but i ...
s (discouraging animals from eating them).
Function
In immature
marsupials
Marsupials are any members of the mammalian infraclass Marsupialia. All extant marsupials are endemic to Australasia, Wallacea and the Americas. A distinctive characteristic common to most of these species is that the young are carried in a ...
, because their
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as Tumor immunology, cancer cells and objects such ...
is underdeveloped at the time of birth, defensins play a major role in defense against
pathogens
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a ger ...
. 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
In molecular biology (specifically protein biosynthesis), a stop codon (or termination codon) is a codon ( nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in ...
, hampering their expression. An artificial human theta-defensin, retrocyclin, was created by 'fixing' the
pseudogene
Pseudogenes are nonfunctional segments of DNA that resemble functional genes. Most arise as superfluous copies of functional genes, either directly by DNA duplication or indirectly by reverse transcription of an mRNA transcript. Pseudogenes are ...
, and it was shown to be effective against
HIV
The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immu ...
and other viruses, including
herpes simplex virus
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and ''Human alphaherpesvirus 2'', are two members of the Herpesviridae#Human herpesvirus types, human ''Herpesviridae'' family, a ...
and
influenza A
'' A virus'' (''IAV'') causes influenza in birds and some mammals, and is the only species of the genus ''Alphainfluenzavirus'' of the virus family ''Orthomyxoviridae''. Strains of all subtypes of influenza A virus have been isolated from wild ...
. They act primarily by preventing these viruses from entering their target cells.
Also interesting is the effect of alpha-defensins on the
exotoxin
An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, sim ...
produced by anthrax (''
Bacillus anthracis
''Bacillus anthracis'' is a gram-positive and rod-shaped bacterium that causes anthrax, a deadly disease to livestock and, occasionally, to humans. It is the only permanent (obligate) pathogen within the genus '' Bacillus''. Its infection is ...
''). Chun Kim et al. showed how anthrax, which produces a
metalloprotease
A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myog ...
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
Alpha defensins are a family of mammalian defensin peptides of the alpha subfamily. In mammals they are also known as cryptdins and are produced within the small bowel. ''Cryptdin'' is a portmanteau of ''crypt'' and ''defensin''.
Defensins are 2- ...
peptides are increased in chronic inflammatory conditions.
Alpha defensin
Alpha defensins are a family of mammalian defensin peptides of the alpha subfamily. In mammals they are also known as cryptdins and are produced within the small bowel. ''Cryptdin'' is a portmanteau of ''crypt'' and ''defensin''.
Defensins are 2- ...
are increased in several cancers, including colorectal cancer.
An imbalance of defensins in the skin may contribute to acne.
A reduction of
ileal defensins may predispose to
Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension, ...
.
In one small study, a significant increase in
alpha defensin
Alpha defensins are a family of mammalian defensin peptides of the alpha subfamily. In mammals they are also known as cryptdins and are produced within the small bowel. ''Cryptdin'' is a portmanteau of ''crypt'' and ''defensin''.
Defensins are 2- ...
levels was detected in
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell ...
lysates of
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wi ...
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
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complet ...
and also during
wound healing
Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier aga ...
.
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
mimetics
Mimesis (; grc, μίμησις, ''mīmēsis'') is a term used in literary criticism and philosophy that carries a wide range of meanings, including ''imitatio'', imitation, nonsensuous similarity, receptivity, representation, mimicry, the act ...
, also called host defense peptide (HDP) mimetics, are completely synthetic, non-peptide, small molecule structures that mimic defensins in structure and activity. Similar molecules, such as
brilacidin, are being developed as
antibiotic
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting pathogenic bacteria, bacterial infections, and antibiotic medications are widely used in the therapy, ...
s,
anti-inflammatories for oral
mucositis
Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal ...
, and
antifungals
An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cry ...
, especially for
candidiasis
Candidiasis is a fungal infection due to any type of '' Candida'' (a type of yeast). When it affects the mouth, in some countries it is commonly called thrush. Signs and symptoms include white patches on the tongue or other areas of the mouth ...
.
See also
*
Host defense peptides
Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for an ...
, to which defensins belong
References
External links
*
Defensins Database, Singaporeat
Western Kentucky University
Western Kentucky University is a public university in Bowling Green, Kentucky. It was founded by the Commonwealth of Kentucky in 1906, though its roots reach back a quarter-century earlier. It operates regional campuses in Glasgow, Elizabet ...
* - Vertebrate defensins and related sea anemone sodium channel toxins
* - Defensins from insects and plants and scorpion toxins
*
{{Pore-forming toxins
Antimicrobial peptides
Cysteine-rich proteins