Tachyplesin

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== Structural highlights ==
== Structural highlights ==
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Tachyplesine I is a 17-residue peptide containing six cationic residues with molecular weight - 2,269 and isoelectric point(pI) of 9.93. <ref name=Chen>Chen, Yixin, et al. "RGD-Tachyplesin inhibits tumor growth." Cancer research 61.6 (2001): 2434-2438.‏</ref>
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Tachyplesine I is a 17-residue peptide containing six cationic residues with molecular weight 2,269 and isoelectric point (pI) of 9.93. <ref name=Chen>Chen, Yixin, et al. "RGD-Tachyplesin inhibits tumor growth." Cancer research 61.6 (2001): 2434-2438.‏</ref>
The amino acid sequence of the TP-I is NH₂-Lys-Trp-Cys-Phe-Arg-Val-Cys-Tyr-Arg-Gly-Ile-Cys-Tyr-Arg-Arg-Cys-Arg-CONH₂.
The amino acid sequence of the TP-I is NH₂-Lys-Trp-Cys-Phe-Arg-Val-Cys-Tyr-Arg-Gly-Ile-Cys-Tyr-Arg-Arg-Cys-Arg-CONH₂.
[[Image:scheme.jpg|150px|left|thumb|<b>Figure 1: Simplefied model of Tachyplesin I.</b>]]
[[Image:scheme.jpg|150px|left|thumb|<b>Figure 1: Simplefied model of Tachyplesin I.</b>]]
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The sequence adapts antiparallel β-sheet (hairpin) conformation in solution stabilized by two cross-strand <scene name='67/671725/Disulfide_bonds/1'> disulfide bonds </scene> between Cys³-Cys¹⁶ and Cys⁷-Cys¹²<ref name=Nakamura>Nakamura, Takanori, et al. "Tachyplesin, a class of antimicrobial peptide from the hemocytes of the horseshoe crab (Tachypleus tridentatus). Isolation and chemical structure." Journal of Biological Chemistry 263.32 (1988): 16709-16713</ref>, and its [http://en.wikipedia.org/wiki/Protein_primary_structure C-terminus is amidated].<ref name=Laederach>PMID:12369825</ref><ref name=Kushibiki>PMID:24389234</ref>. Besides, there exists H-bond and aromatic ring stacking interactions which helps stabilizing the hairpin loop structure of the peptide.
The sequence adapts antiparallel β-sheet (hairpin) conformation in solution stabilized by two cross-strand <scene name='67/671725/Disulfide_bonds/1'> disulfide bonds </scene> between Cys³-Cys¹⁶ and Cys⁷-Cys¹²<ref name=Nakamura>Nakamura, Takanori, et al. "Tachyplesin, a class of antimicrobial peptide from the hemocytes of the horseshoe crab (Tachypleus tridentatus). Isolation and chemical structure." Journal of Biological Chemistry 263.32 (1988): 16709-16713</ref>, and its [http://en.wikipedia.org/wiki/Protein_primary_structure C-terminus is amidated].<ref name=Laederach>PMID:12369825</ref><ref name=Kushibiki>PMID:24389234</ref>. Besides, there exists H-bond and aromatic ring stacking interactions which helps stabilizing the hairpin loop structure of the peptide.
The β-hairpin structure is well characterized by a β-turn for the centrally located residues Tyr-Arg-Gly-Ile.<ref name=Saravanan>PMID:22464970</ref>
The β-hairpin structure is well characterized by a β-turn for the centrally located residues Tyr-Arg-Gly-Ile.<ref name=Saravanan>PMID:22464970</ref>
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== Mode of action ==
== Mode of action ==
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TP-I has affinity to LPS and also has ability to permeabilize the cell membrane of pathogens. Docking model suggests strong affinity to LPS gained by interaction between cationic residues of TP-I with phosphate group and sachharides of LPS. Furthermore, interaction between hydrophobic residues of TP-I with acyl chains of LPS strengthens the TP-I/LPS interaction. The binding of TPI to LPS neutralizes LPS, which is widely considered as endotoxin. In addition to LPS binding, footpriting analysis has revealed the binding of TP-I to DNA by interacting specifically in minor groove of DNA duplex. The interaction between TP-I and DNA is contributed by secondary structure of the peptide which contains an antiparallel beta-sheet constrained by two disulfide bridges and connected by β-turn <ref name=Yonezawa>PMID:1372516</ref>.
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TP-I has affinity to LPS and also has ability to permeabilize the cell membrane of pathogens. Docking model suggests strong affinity between TP-I and LPS; gained by interaction between cationic residues of TP-I with phosphate group and sachharides of LPS. Furthermore, interaction between hydrophobic residues of TP-I with acyl chains of LPS strengthens the TP-I/LPS interaction. The binding of TP-I/LPS neutralizes LPS, which is widely considered as endotoxin. In addition to LPS binding, footpriting analysis has revealed the binding of TP-I to DNA by interacting specifically in minor groove of DNA duplex. The interaction between TP-I and DNA is contributed by secondary structure of the peptide which contains an antiparallel beta-sheet constrained by two disulfide bridges and connected by β-turn <ref name=Yonezawa>PMID:1372516</ref>.
== Importance and relevance ==
== Importance and relevance ==
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<scene name='67/671725/Cdt/1'>CDT</scene> is a linear mutant lacking the cysteines and therfor also lacking the disulfide bonds (NH₂-Lys-Trp-Phe-Arg-Val-Tyr-Arg-Gly-Ile-Tyr-Arg-Arg-Arg-CONH₂). It contains a broad spectrum of bactericidal activity with a reduced hemolytic property that stems from selective interactions with the negatively charged lipids including LPS.
<scene name='67/671725/Cdt/1'>CDT</scene> is a linear mutant lacking the cysteines and therfor also lacking the disulfide bonds (NH₂-Lys-Trp-Phe-Arg-Val-Tyr-Arg-Gly-Ile-Tyr-Arg-Arg-Arg-CONH₂). It contains a broad spectrum of bactericidal activity with a reduced hemolytic property that stems from selective interactions with the negatively charged lipids including LPS.
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CDT demonstrated a marked inhibition of growth of Gram negative and Gram positive bacterial strains akin to TP-1.
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CDT demonstrated a marked inhibition of growth of Gram negative and Gram positive bacterial strains akin to TP-I.
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Its MIC values were found to be lower agains <i>E. Coli</i> and <i>Listeria monocytogenes</i> in comperison to the native TP-1 peptide.
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Its MIC values were found to be lower agains <i>E. Coli</i> and <i>Listeria monocytogenes</i> in comperison to the native TP-I peptide.
<ref name=Saravanan>PMID:22464970</ref>
<ref name=Saravanan>PMID:22464970</ref>
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The cationic nature of tachyplesin allows it to interact with anionic phospholipids present in the bacterial membrane and thereby disrupt membrane function.
The cationic nature of tachyplesin allows it to interact with anionic phospholipids present in the bacterial membrane and thereby disrupt membrane function.
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The structural nature of Tachyplesin suggested that it might also posses antitumor properties. Since it can interact with the membrance of prokaryotic cell, it is likely that TP I can also interact with the mitochondrial membrane of eukaryotic cells due to the structure similarity of these membranes because mitochondria are widely belived to have evolved from prokaryotic cells that have established a symbiotic relationship with the promitive eukaryotic cell.
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The structural nature of Tachyplesin suggested that it might also posses antitumor properties. Since it can interact with the membrance of prokaryotic cell, it is likely that TP-I can also interact with the mitochondrial membrane of eukaryotic cells due to the structure similarity of these membranes because mitochondria are widely belived to have evolved from prokaryotic cells that have established a symbiotic relationship with the promitive eukaryotic cell.
It was found that the synthetic RGD-Tachyplesin can inhibit the [http://en.wikipedia.org/wiki/Cell_growth proliferation] of TSU [http://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells and B16 [http://en.wikipedia.org/wiki/Melanoma melanoma] cells as well as [http://en.wikipedia.org/wiki/Endothelium endothelial cells] in a dose-dependent mannar <i>in vitro</i> and reduce tumor growth <i>in vivo</i> by inducing [http://en.wikipedia.org/wiki/Apoptosis apoptosis].<ref name=Chen>Chen, Yixin, et al. "RGD-Tachyplesin inhibits tumor growth." Cancer research 61.6 (2001): 2434-2438.‏</ref>
It was found that the synthetic RGD-Tachyplesin can inhibit the [http://en.wikipedia.org/wiki/Cell_growth proliferation] of TSU [http://en.wikipedia.org/wiki/Prostate_cancer prostate cancer] cells and B16 [http://en.wikipedia.org/wiki/Melanoma melanoma] cells as well as [http://en.wikipedia.org/wiki/Endothelium endothelial cells] in a dose-dependent mannar <i>in vitro</i> and reduce tumor growth <i>in vivo</i> by inducing [http://en.wikipedia.org/wiki/Apoptosis apoptosis].<ref name=Chen>Chen, Yixin, et al. "RGD-Tachyplesin inhibits tumor growth." Cancer research 61.6 (2001): 2434-2438.‏</ref>

Revision as of 11:07, 31 December 2014

Introduction

1MA2

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References

  1. ↑ 1.0 1.1 1.2 Laederach A, Andreotti AH, Fulton DB. Solution and micelle-bound structures of tachyplesin I and its active aromatic linear derivatives. Biochemistry. 2002 Oct 15;41(41):12359-68. PMID:12369825
  2. ↑ 2.0 2.1 Chen, Yixin, et al. "RGD-Tachyplesin inhibits tumor growth." Cancer research 61.6 (2001): 2434-2438.‏
  3. ↑ Nakamura, Takanori, et al. "Tachyplesin, a class of antimicrobial peptide from the hemocytes of the horseshoe crab (Tachypleus tridentatus). Isolation and chemical structure." Journal of Biological Chemistry 263.32 (1988): 16709-16713
  4. ↑ Kushibiki T, Kamiya M, Aizawa T, Kumaki Y, Kikukawa T, Mizuguchi M, Demura M, Kawabata SI, Kawano K. Interaction between tachyplesin I, an antimicrobial peptide derived from horseshoe crab, and lipopolysaccharide. Biochim Biophys Acta. 2014 Jan 2;1844(3):527-534. doi:, 10.1016/j.bbapap.2013.12.017. PMID:24389234 doi:http://dx.doi.org/10.1016/j.bbapap.2013.12.017
  5. ↑ 5.0 5.1 Saravanan R, Mohanram H, Joshi M, Domadia PN, Torres J, Ruedl C, Bhattacharjya S. Structure, activity and interactions of the cysteine deleted analog of tachyplesin-1 with lipopolysaccharide micelle: Mechanistic insights into outer-membrane permeabilization and endotoxin neutralization. Biochim Biophys Acta. 2012 Mar 23;1818(7):1613-1624. PMID:22464970 doi:10.1016/j.bbamem.2012.03.015
  6. ↑ Yonezawa A, Kuwahara J, Fujii N, Sugiura Y. Binding of tachyplesin I to DNA revealed by footprinting analysis: significant contribution of secondary structure to DNA binding and implication for biological action. Biochemistry. 1992 Mar 24;31(11):2998-3004. PMID:1372516
  7. ↑ Lipsky A, Cohen A, Ion A, Yedidia I. Genetic transformation of Ornithogalum via particle bombardment and generation of Pectobacterium carotovorum-resistant plants. Plant Sci. 2014 Nov;228:150-8. doi: 10.1016/j.plantsci.2014.02.002. Epub 2014 Feb, 12. PMID:25438795 doi:http://dx.doi.org/10.1016/j.plantsci.2014.02.002
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