Melittin is the main component of apitoxin (Apis mellifera venom), accounting for approximately 50% of its dry weight (Terra et al., 2006). The water-soluble, 26 amino acid-long polypeptide chain, weighing 2,840 Da, is largely composed of hydrophobic residues, with the exception of the cationic and hydrophilic carboxy-terminal sequence (Vogel et al., 1986). It is this amphiphilic nature that gives melittin its characteristic detergent-like properties (Maulet et al., 1980).
Using a range of techniques, including X-ray crystallography, NMR spectroscopy, and molecular dynamics simulations, melittin was found to adopt a variety of conformations, depending on factors including the pH and the type of aqueous medium. For instance, when dissolved in water, the hydrophilic residues 22-26 were shown to form a non-helical segment, whereas the remaining hydrophobic residues of melittin were reported to form a bent helix, composed of two smaller α-helical segments of residues 1-11 and 12-21. The concave side of the bent helix was found to be hydrophobic, while the convex side was shown to be hydrophilic (Vogel, et al., 1986). Additionally, melittin was found to be tetrameric at high pH, a random coil at pH 7.0, and monomeric in plasma (Terra, et al., 2006).
Mode of Action
In the bloodstream, melittin is able to rapidly bind to erythrocytes (red blood cells), inducing the release of haemoglobin and other cellular contents into the extracellular medium. Once melittin has penetrated the erythrocyte, it causes micellisation of phosphatidylcholine bilayers, ultimately leading to haemolysis and cell death (Dempsey, et al., 1990).
Apart from its ability to disrupt lipid bilayers, melittin can also inhibit transmembrane proteins, including Na+/K+-ATPase, leading to a rise in sodium concentration within cells (Yang, et al., 2001). The increase in sodium induces an increase in the concentration of intracellular calcium, which results in the increased contraction of cardiac and smooth muscle.
Potential Therapeutic Use
Melittin is currently one of the most extensively used peptides in the research on lipid-peptide and peptide-peptide interactions (Wessman, et al., 2010). The presence of a single tryptophan residue at position 19 allows for a facilitated interpretation of fluorescence data via the tryptophan fluorescence technique, whereby intrinsic fluorescence emissions can be measured via the excitation of tryptophan residues (Raghuraman, et al., 2004).
More recently, the peptide has been shown to possess a variety of therapeutic uses. For instance, melittin is currently being analysed as a potential treatment and preventative for HIV. In a study currently being conducted at Washington University School of Medicine in St. Louis, a melittin-nanoparticle complex was shown to effectively destroy the AIDS-causing virus by forming pores in its protective viral envelope, required for viral reproduction (Evangelou Strait, 2013).
Another use of melittin is in the treatment of cancer. A promising study, once again conducted by researchers at Washington University School of Medicine in St. Louis, involves the attaching of melittin to a different nanoparticle. The novel melittin-nanoparticle complex, named the “nanobee”, selectively targets tumour cells, thus avoiding healthy cells. Once attached to a tumour cell, melittin is able to break down the tumour by forming pores in the cell membrane (Loftus, 2009).
- Dempsey C.E., Sternberg B. 1991. Reversible disc-micellization of dimyristoylphosphatidylcholine bilayers induced by melittin and [Ala-14]melittin. Biochim. Biophys. Acta. 1061:175–184.
- Evangelou Strait J. (2013, March 7). Nanoparticles loaded with bee venom kill HIV. Newsroom. Retrieved June 19, 2013 from http://news.wustl.edu/news/Pages/25061.aspx
- Loftus P. (2009, September 28). The Buzz: Targeting cancer with bee venom in animal studies, tiny composite spheres deliver drug directly to tumor sites; 'It's Like an Injection'. The Wall Street Journal. Retrieved June 19, 2013 from http://online.wsj.com/article/SB10001424052970203803904574433382922095534.html?mod=WSJ_hpp_MIDDLENexttoWhatsNewsThird
- Maulet Y., Matthey-Prevot B., Kaiser G., Rüegg U.T., Fulpius B.W. 1980. Purification and chemical characterization of melittin and acetylated derivatives. Biochim. Biophys. Acta. 625:274-280
- Raghuraman H., Chattopadhyay A. 2004. Interaction of melittin with membrane cholesterol: a ﬂuorescence approach. Biophys J. 87:2419–2432.
- Terra R.M., Guimarães J.A., Verli H. 2006. Structural and functional behavior of biologically active monomeric melittin. Journal of Molecular Graphics and Modelling. 25:767–772.
- Vogel H., Jahnig F. 1986. The structure of melittin in membranes. Biophysical Journal. 50(4):573-582.
- Wessman P., Morin M., Reijmar K., Edwards K. 2010. Effect of a-helical peptides on liposome structure: A comparative study of melittin and alamethicin. Journal of Colloid and Interface Science 346:127–135.
- Yang S., Zhang X.M., Jiang M.H. 2001. Inhibitory effect of melittin on Na+,K+-ATPase from guinea pig myocardial mitochondria. Acta Pharmacologica Sinica. 22(3):279-282.
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