theta defensin

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| header = Structure of human retrocyclin-2 θ-defensin

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| caption1 = Secondary structure - Beta sheets in blue, loops in white, disulfides in yellow.

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| caption2 = Chemical structure - Peptide backbone in black, side chains in white, disulfides in yellow.

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| caption3 = Monomers - Each half contributed by each of the two monomer precursors before cyclisation are indicated in red and blue.

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θ-defensins are cyclic peptides of 18 amino acids (~2 kDa), possessing antimicrobial activity against a range of Gram-positive and Gram-negative bacteria, fungi, and some retroviruses.{{cite journal | vauthors = Tang YQ, Yuan J, Osapay G, Osapay K, Tran D, Miller CJ, Ouellette AJ, Selsted ME | title = A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins | journal = Science | volume = 286 | issue = 5439 | pages = 498–502 | date = October 1999 | pmid = 10521339 | doi = 10.1126/science.286.5439.498 | url = https://zenodo.org/record/1064174 }}{{cite journal | vauthors = Leonova L, Kokryakov VN, Aleshina G, Hong T, Nguyen T, Zhao C, Waring AJ, Lehrer RI | title = Circular minidefensins and posttranslational generation of molecular diversity | journal = J. Leukoc. Biol. | volume = 70 | issue = 3 | pages = 461–4 | date = September 2001 | doi = 10.1189/jlb.70.3.461 | pmid = 11527997 | s2cid = 19334630 }}{{cite journal | vauthors = Tran D, Tran PA, Tang YQ, Yuan J, Cole T, Selsted ME | title = Homodimeric θ-defensins from rhesus macaque leukocytes: isolation, synthesis, antimicrobial activities, and bacterial binding properties of the cyclic peptides | journal = J. Biol. Chem. | volume = 277 | issue = 5 | pages = 3079–3084 | date = February 2002 | pmid = 11675394 | doi = 10.1074/jbc.M109117200 | doi-access = free }}{{cite journal | vauthors = Garcia AE, Osapay G, Tran PA, Yuan J, Selsted ME | title = Isolation, synthesis, and antimicrobial activities of naturally occurring θ-defensin isoforms from baboon leukocytes | journal = Infect. Immun. | volume = 76 | issue = 12 | pages = 5883–5891 | date = December 2008 | pmid = 18852242 | pmc = 2583559 | doi = 10.1128/IAI.01100-08 }} They consist of a pair of antiparallel β-sheets linked by three disulfide bonds arranged as a ladder along the sheets to form an extremely stable structure. Additionally, the peptides may self-associate into trimers.{{cite journal | vauthors = Daly NL, Chen YK, Rosengren KJ, Marx UC, Phillips ML, Waring AJ, Wang W, Lehrer RI, Craik DJ | title = Retrocyclin-2: structural analysis of a potent anti-HIV theta-defensin | journal = Biochemistry | volume = 46 | issue = 35 | pages = 9920–8 | date = Sep 4, 2007 | pmid = 17685559 | doi = 10.1021/bi700720e }}

In rhesus macaque (Macaca mulatta) and olive baboon (Papio anubis), θ-defensins are produced from precursor proteins with 76 amino acids each. A single nine amino acid peptide is derived from each precursor. Two of these nine amino acid peptides are spliced together to form the circular 18 amino acid defensin. Since there are two precursor genes (rhesus theta defensin RTD-1 and RTD-2) they can form 3 different mature θ-defensins: the homodimer of processed RTD-1, The homodimer of processed RTD-2 or the heterodimer composed of both precursors. The heterodimeric form is the most abundant.

In the olive baboon, four θ-defensin precursor genes have been isolated: BTD-a, BTD-b, BTD-c and BTD-d, which encode subunits A, B, C and D. These four subunits could theoretically combine to produce 10 different processed defensins. However, only five have been observed: consisting of subunits A+A, A+B, A+C, A+D and B+B (Referred to as BTD-3, BTD-1, BTD-4, BTD7 and BTD-2 respectively). Finally, orangutan genomes encode 4 θ-defensin precursor genes and gibbon genomes encode 2.

Antimicrobial activity has been reported against bacteria, fungi, enveloped viruses, and protozoa. Antimicrobial activity is generally through binding to and disrupting the cell membrane. Antiviral activity appears to derive from their binding to the sugar component of glycoproteins and blocking the entry of viruses into the cell.{{cite journal | vauthors = Cascales L, Craik DJ | title = Naturally occurring circular proteins: distribution, biosynthesis and evolution. | journal = Organic & Biomolecular Chemistry | volume = 8 | issue = 22 | pages = 5035–47 | date = Nov 21, 2010 | pmid = 20835453 | doi=10.1039/c0ob00139b}}

θ-defensins are extremely divergent members of the defensin protein superfamily which includes alpha-, beta- and big-defensins. The θ-defensins appear to have evolved from α-defensin genes around 40 million years ago in Old World monkeys. Compared to their α-defensin ancestors, θ-defensin genes are truncated into two halves.

Although New World monkeys and great apes do not produce θ-defensin proteins, their genomes do encode θ-defensin genes which are transcribed to mRNA but not translated due to a premature stop codon.{{cite journal | vauthors = Venkataraman N, Cole AL, Ruchala P, Waring AJ, Lehrer RI, Stuchlik O, Pohl J, Cole AM | title = Reawakening retrocyclins: ancestral human defensins active against HIV-1. | journal = PLOS Biology | volume = 7 | issue = 4 | pages = e95 | date = Apr 28, 2009 | pmid = 19402752 | doi=10.1371/journal.pbio.1000095 | pmc=2672613 | doi-access = free }} When the mature defensin that would be expressed is chemically synthesised in a laboratory, it shows antimicrobial activity (including anti-retrovirus, leading to the name "retrocyclin").{{cite journal | vauthors = Cole AM, Hong T, Boo LM, Nguyen T, Zhao C, Bristol G, Zack JA, Waring AJ, Yang OO, Lehrer RI | title = Retrocyclin: a primate peptide that protects cells from infection by T- and M-tropic strains of HIV-1. | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 4 | pages = 1813–8 | date = Feb 19, 2002 | pmid = 11854483 | doi=10.1073/pnas.052706399 | pmc=122276| bibcode = 2002PNAS...99.1813C | doi-access = free }} It is unknown whether this pseudogenisation gave a selective advantage or was due to genetic drift. The anti-HIV activity of retrocyclins has been further enhanced by protein engineering efforts with the aim of generating a viable treatment.

• Defensin
• α-defensin
• β-defensin
• Cyclic peptide

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Category:Defensins

Category:Pseudogenes