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Melittins is a toxic protein in bee venom that causes localized pain and inflammation but also has a moderate antibacterial and antifungal effect

It was first identified as a ‘direct lytic factor’ since it induced haemolysis in the absence of added lecithin1,2. The active peptide melittin is released from its precursor, promelittin, during its biosynthesis in honey bee and later gets formylated2.



Structural Characteristics
It is a small linear peptide composed of 26 amino acid residues (NH2- GIGAVLKVLTTGLPALISWIKRKRQQ-CONH2) in which the amino-terminal region (residues 1–20) is predominantly hydrophobic whereas the carboxy-terminal region (residues 21–26) is hydrophilic due to the presence of a stretch of positively charged amino acids. The amphiphilic property of this peptide makes it water-soluble and yet it spontaneously associates with natural and artificial membranes 3. There is an asymmetric distribution of polar and non-polar amino acids which makes melittin amphipathic when the peptide is aligned in a a-helical configurations a helical wheel diagram3.



Mode of Action
The characteristic action of melittin is its hemolytic activity, since the target for the action of melittin is the erythrocyte membrane. At sub-micromolar concentrations and higher, melittin binds rapidly to erythrocytes (within seconds) and induces the release of haemoglobin into the extracellular medium. Melittin-induced haemolysis follows reproducible, temperature-dependent biphasic kinetics with characteristic fast and slow phases which dominate lysis at 4 and 37 0C, respectively. The fast phase is interpreted as resulting from the perturbation of membrane structure and organization due to the rapid accumulation of melittin in the outer leaflet of the erythrocyte membrane and its decay into a slow phase is a result of the reorganization of peptide and membrane lipids to recover favourable packing geometry. It has been proposed that the internalization of the melittin dimer underlies the slow phase of haemoglobin release because of the second order dependence of the rate on peptide concentration 4,5.



Voltage-gated Channel Formation- Melittin disrupts the barrier function of cell membranes and has been shown to form channels in planar bilayers. In the presence of a trans-negative membrane potential, melittin has been reported to induce increased permeability of ions in planar lipid membranes. This observed change in conductance, under high ionic strength conditions, exhibits discrete multilevel conductances3.

Micellization and Fusion of Bilayers-
Melittin-induced permeabilization of membranes is known to cause the breakdown of membranes into micelles at high peptide concentration. This is similar to the solubilisation of membranes by detergents3.

Melittin and Pore Formation-
It is commonly believed that multimeric pore formation is the mode of action of many naturally produced peptides such as antimicrobial peptides and toxins.  Under certain conditions, melittin molecules insert into the lipid bilayer and form multiple aggregated forms that are controlled by temperature, pH, ionic strength, lipid composition and lipid-to-peptide


Cellular Activities of Melittin-
Action of Melittin on Membrane Proteins Apart from its ability to disrupt lipid bilayers, melittin affects the dynamics of membrane proteins. For instance, it has been shown that lytic concentrations of melittin dramatically reduce the rotational mobility of band 3 proteins in human erythrocyte membranes and of bacteriorhodopsin in lipid vesicles3.

Melittin and Cell Transformation-
Oncogenes play an important role in the initiation and progression of the neoplastic phenotype. The ras oncogene is especially important with respect to human cancer since at least one-third of all human colorectal tumours analyzed express an activated ras oncogene. Interestingly, it has been demonstrated that melittin specifically selects against cells in culture that express high levels of the ras oncogene. Melittin therefore exerts its anti-transformation effect(s) by specifically eliminating cells that express the oncoprotein3.

Melittin and Signal Transduction-
It is known that cationic amphiphilic peptides such as mastoparan and melittin directly stimulate nucleotide exchange by heterotrimeric GTP-binding proteins (G-proteins) in a manner similar to that of G-protein coupled receptors3.

Leishmanicidal Activity of Melittin-
Melittin induces membrane permeabilization and lyses prokaryotic as well as eukaryotic cells in a non-selective manner. This mode of action is responsible for its hemolytic, anti-microbial, anti-fungal, anti-tumour and leishmanicidal activities of melittin3.

Anti-viral Activity of Melittin-
It has been shown that melittin reduces HIV-1 production in a dose-dependent manner. The reduction in viral infectivity is proposed to be due to the affinity of melittin for the gag/pol precursor, thereby preventing the processing of gag/ pol by the HIV protease3.




1.     Neumann W, Habermann E, Hansen H (1953). Differentiation of two hemolytic factors in bee venom. Naunyn-Schmiedebergs Arch Exp Path Pharma., 217(2):130-143.

2.     Habermann E (1972). Bee and wasp venoms. Science, 177(43): 314-322.

3.     Raghuraman   H, Chattopadhyay A (2007). Melittin: a Membrane-active Peptide with Diverse Functions. Biosci Rep., 27:189-223.

4.     Dathe M, Wieprecht T (1999). Structural features of helical antimicrobial peptides: their potential to modulate activity on model membranes and biological cells. Biochim Biophys Acta., 1432:71-87.

5.     Dempsey CE (1990). The actions of melittin on membranes. Biochim Biophys Acta., 1031(2):143-131.

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