Defensin


Defensin
Monomeric and dimeric structures of human beta-defensin HBD-2

Defensins are small cysteine-rich cationic proteins found in both vertebrates and invertebrates. They have also been reported in plants.[1][2] They are, and function as, host defense peptides. They are active against bacteria, fungi and many enveloped and nonenveloped viruses. They consist of 18-45 amino acids including six (in vertebrates) to eight conserved cysteine residues. Cells of the immune system contain these peptides to assist in killing phagocytized bacteria, for example in neutrophil granulocytes and almost all epithelial cells. Most defensins function by binding to the microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients.

Contents

Varieties

The underlying genes responsible for defensin production are highly polymorphic. Some aspects are conserved, however; the hallmarks of a β-defensin are its small size, high density of cationic charge, and six-cysteine-residue motif. In general, they are encoded by two-exon genes, wherein the first exon encodes for a hydrophobic leader sequence and the second for a peptide containing the cysteine motif.

Type Gene Symbol Gene Name Protein Name Description
α-defensins 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
β-defensins 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
DEFB103A Defensin, beta 103B Beta-defensin 103
... ... ...
DEFB107B Defensin, beta 107A Beta-defensin 107
DEFB110 Defensin, beta 110 Beta-defensin 110
... ... ...
DEFB136 Defensin, beta 136 Beta-defensin 136
θ-defensins 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[3] and the olive baboon, Papio anubis, being vestigial in humans and other primates.[4][5]

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.

Human genome contains theta-defensin genes, but they have a premature stop codon, hampering their expression. An artificial human theta-defensin,[6] retrocyclin, was created by `fixing' the pseudogene, and it was shown to be effective against HIV[7] 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.[8]

Defensin-like proteins are also a component of platypus venom.

Defensin-mimetics as antibiotics

Similar molecules (eg. PMX-30063) are being developed as antibiotics.[9]

Pathology

The alpha defensin peptides are increased in chronic inflammatory conditions.

Alpha defensin are increased in several cancers, including colorectal cancer.[10]

An imbalance of defensins in the skin may contribute to acne.[11]

A reduction of ileal defensins may predispose to Crohn's disease.[12][13]

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.[14]

Defensins are found in the human skin during inflammatory conditions like psoriasis[15] and also during wound healing.[16]

See also

References

  1. ^ Structure–activity studies of AtPep1, a plant peptide signal involved in the innate immune response Peptides Volume 29, Issue 12, December 2008, Pages 2083-2089
  2. ^ Planta. 2002 Dec;216(2):193-202. Epub 2002 Oct 8. Plant defensins.
  3. ^ Tran D, Tran P, Roberts K, Osapay G, Schaal J, Ouellette A, Selsted ME (March 2008). "Microbicidal properties and cytocidal selectivity of rhesus macaque theta defensins". Antimicrob. Agents Chemother. 52 (3): 944–53. doi:10.1128/AAC.01090-07. PMC 2258523. PMID 18160518. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2258523. 
  4. ^ Angie Eva Garcia and Michael Selsted Olive baboon theta-defensins FASEB J. 2008 22:673.11
  5. ^ Garcia AE, Osapay G, Tran PA, Yuan J, Selsted ME (December 2008). "Isolation, synthesis, and antimicrobial activities of naturally occurring theta-defensin isoforms from baboon leukocytes". Infect. Immun. 76 (12): 5883–91. doi:10.1128/IAI.01100-08. PMC 2583559. PMID 18852242. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2583559. 
  6. ^ MeSH retrocyclin
  7. ^ Münk C, Wei G, Yang OO, et al. (October 2003). "The theta-defensin, retrocyclin, inhibits HIV-1 entry". AIDS Res. Hum. Retroviruses 19 (10): 875–81. doi:10.1089/088922203322493049. PMID 14585219. 
  8. ^ Kim C, Gajendran N, Mittrücker H, Weiwad M, Song Y, Hurwitz R, Wilmanns M, Fischer G, Kaufmann S (2005). "Human alpha-defensins neutralize anthrax lethal toxin and protect against its fatal consequences". Proc Natl Acad Sci U S A 102 (13): 4830–5. doi:10.1073/pnas.0500508102. PMC 555714. PMID 15772169. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=555714. 
  9. ^ "PMX-30063 The First And Only Defensin Mimetic Systemic Antibiotic Drug In Human Clinical Trials". 2008. http://www.medicalnewstoday.com/releases/118978.php. 
  10. ^ Albrethsen J; Bøgebo, R; Gammeltoft, S; Olsen, J; Winther, B; Raskov, H (2005). "Upregulated expression of human neutrophil peptides 1, 2 and 3 (HNP 1-3) in colon cancer serum and tumours: a biomarker study". BMC cancer 19: 9. doi:http://www.biomedcentral.com/1471-2407/5/8. PMC 548152. PMID 15656915. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=548152. 
  11. ^ Philpott M (2003). "Defensins and acne". Mol Immunol 40 (7): 457–62. doi:10.1016/S0161-5890(03)00154-8. PMID 14568392. 
  12. ^ Genomics & Genetics Weekly, "Researchers discover a possible cause of chronic inflammations of Crohn Disease." August 11, 2006, page 72
  13. ^ Wehkamp J et al. (2005). "Reduced Paneth cell alpha-defensins in ileal Crohn's disease" (abstract). Proc Natl Acad Sci U S A 102 (50): 18129–34. doi:10.1073/pnas.0505256102. PMC 1306791. PMID 16330776. http://www.pnas.org/cgi/content/abstract/102/50/18129. 
  14. ^ Craddock RM, Huang JT, Jackson E, et al. (March 2008). "Increased alpha defensins as a blood marker for schizophrenia susceptibility". Mol. Cell Proteomics 7 (7): 1204–13. doi:10.1074/mcp.M700459-MCP200. PMID 18349140. http://www.mcponline.org/cgi/pmidlookup?view=long&pmid=18349140. 
  15. ^ Harder J, Bartels J, Christophers E, "et al." (1999). "A peptide antibiotic from human skin". Nature 387 (6636): 861. doi:10.1038/43088. PMID 9202117. 
  16. ^ Sorensen OE, Thapa, DR, Roupé KM, "et al." (2006). "Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor". J Clin Invest 116 (7): 1878–1885. doi:10.1172/JCI28422. PMC 1479426. PMID 16778986. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1479426. 

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  • defensin — (de fens sin) Specific peptides produced by neutrophils that permeabilize the outer and inner membranes of certain microorganisms, thus killing them …   Dictionary of microbiology

  • defensin — noun Any of a family of cysteine rich proteins that are active against bacteria, fungi and viruses …   Wiktionary

  • Defensin — De|fen|sin [lat. defendere, defensum = abwehren, verteidigen], das; s, e: aus Phagozyten isolierte Peptide aus ca. 30 Aminosäuren, die im Immungeschehen an der Abwehr von Bakterien, Pilzen u. Viren mitbeteiligt sind …   Universal-Lexikon

  • defensin — de·fen·sin di fen(t) sən n any of a class of peptides that are found in neutrophils and have antimicrobial and cytotoxic properties * * * de·fen·sin (de fenґsin) any of a group of small antimicrobial cationic peptides occurring in neutrophils and …   Medical dictionary

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