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Alpha defensins are a family of mammalian defensin peptides of the alpha subfamily. They are also known as cryptdins and are produced within the Small intestine. Cryptdin is a portmanteau of crypt and defensin.
Defensins are 2-6 kDa, cationic, antimicrobial peptides active against many Gram-negative and Gram-positive bacteria, fungi, and , containing three pairs of intramolecular disulfide bonds. On the basis of their size and pattern of , mammalian defensins are classified into alpha, beta and theta categories. Alpha-defensins, which have been identified in humans, monkeys and several rodent species, are particularly abundant in , certain macrophage populations and Paneth cells of the small intestine.
Defensins are produced constitutively and/or in response to microbial products or proinflammatory cytokines. Some defensins are also called because they inhibit corticotropin-stimulated corticosteroid production. The mechanism(s) by which microorganisms are killed and/or inactivated by defensins is not understood completely. However, it is generally believed that killing is a consequence of disruption of the microbial membrane. The polar topology of defensins, with spatially separated charged and hydrophobic regions, allows them to insert themselves into the phospholipid membranes so that their hydrophobic regions are buried within the lipid membrane interior and their charged (mostly cationic) regions interact with anionic phospholipid head groups and water. Subsequently, some defensins can aggregate to form 'channel-like' pores; others might bind to and cover the microbial membrane in a 'carpet-like' manner. The net outcome is the disruption of membrane integrity and function, which ultimately leads to the lysis of microorganisms. Some defensins are synthesized as propeptides which may be relevant to this process. Alpha defensins of the mouse bowel were historically called when first discovered.
Like other alpha-defensins, cryptdins are small, 32-36 amino acid long cationic peptides. They possess 6 conserved cysteines that form a tridisulfide array with an arrangement of cysteine pairings that typify alpha-defensins. Cryptdins also display a secondary and tertiary structure that is dominated by a three-stranded beta-sheet. The topology that arises from this structure is an amphipathic globular form in which the termini are paired opposite a pole including a cluster of cationic residues.
Sequences of major human α-defensins: (2025). 9783540299158 ISBN 9783540299158
| ACYCRIPACIAGERRYGTCIYQGRLWAFCC |
| CYCRIPACIAGERRYGTCIYQGRLWAFCC |
| DCYCRIPACIAGERRYGTCIYQGRLWAFCC |
| VCSCRLVFCRRTELRVGNCLIGGVSFTYCCTRV |
| ATCYCRHGRCATRESLSGVCEISGRLYRLCCR |
| AFTCHCRRSCYSTEYSYGTCTVMGINHRFCCL |
Genes encoding cryptdins are located on the proximal arm of mouse chromosome 8. They are similar to other enteric alpha-defensins genes in that they involve a two exon structure. The first exon encodes an N-terminal canonical signal peptide and proregion that is present in the cryptdin precursor. The processed, mature peptide is encoded by the second exon which is separated from the first exon by a ~500 bp intron.
Biosynthesized as precursors possessing an anionic, N-terminal proregion, cryptdins are packaged into the apically directed secretory granules of Paneth cells. During this process and perhaps succeeding it, the precursors are cleaved by matrix metalloproteinase-7 (matrilysin; MMP-7). As a result of this proteolysis, the C-terminal mature form is released from the proregion.
Human neutrophil-derived alpha-defensins (HNPs) are capable of enhancing phagocytosis by mouse macrophages. HNP1-3 have been reported to increase the production of tumor necrosis factor (TNF) and IL-1, while decreasing the production of IL-10 by monocytes. Increased levels of proinflammatory factors (e.g., IL-1, TNF, histamine and prostaglandin D2) and suppressed levels of IL-10 at the site of microbial infection are likely to amplify local inflammatory responses. This might be further reinforced by the capacity of some human and rabbit alpha-defensins to inhibit the production of immunosuppressive glucocorticoids by competing for the binding of adrenocorticotropic hormone to its receptor. Moreover, human alpha-defensins can enhance or suppress the activation of the classical pathway of complement in vitro by binding to solid-phase or fluid-phase complement C1q, respectively. The capacity of defensins to enhance phagocytosis, promote neutrophil recruitment, enhance the production of proinflammatory cytokines, suppress anti-inflammatory mediators and regulate complement activation argues that defensins upregulate innate host inflammatory defenses against microbial invasion.
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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 Virtual Colony Count antibacterial assay was originally developed to measure the activity of all six human alpha defensins on the same microplate.
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