In the world of nature's pharmacy, few substances are as intriguing and polarizing as bee venom. For centuries, bee venom, along with other bee products, have held a significant place in traditional medicine. Its usage dates back thousands of years to ancient Egypt, Greece, and China. The ancient Greek physician Hippocrates was known to employ bee venom for therapeutic purposes, particularly in the treatment of arthritis. This historical use has left a lasting impression and even today, the belief persists that bee stings possess beneficial properties, particularly in treating rheumatoid arthritis, as it is often stated that few beekeepers suffer from this disease.
Bee venom therapy consists of either indirect application of bee venom by injection into the body or direct application via bee sting. Despite the discomfort and fear often associated with bee stings, researchers are deeply intrigued by the therapeutic potential of bee venom, drawn to its complex array of bioactive compounds and their potential applications in modern medicine. However, it is important to acknowledge that while bee venom offers promise for health benefits, it also carries the risk of triggering allergic reactions in certain individuals, which can even be fatal.
Bee venom
Bee venom, also known as apitoxin, is a clear, colourless liquid that is produced by worker honeybees (Apis mellifera). It is primarily used as a defensive mechanism against threats to the hive, such as predators.
The composition of bee venom is complex. It is a mixture of peptides: melittin, apamin, mast cell degranulating peptides, adolapin and proteins with enzymatic properties: phospholipase A2, hyaluronidase. These molecules exhibit antimicrobial, anti-inflammatory, and analgesic properties, which lead to investigations into venom’s potential application for conditions such as arthritis, gout, multiple sclerosis, chronic pain, and skin disorders. In addition, bee venom contains many low molecular mass compounds, such as sugars, amino acids, phospholipids, and pheromones.
Melittin
The main component of bee venom is melittin, representing 40-60% of the dry weight. Melittin is synthesized by secretory cells associated with the bee venom glands as an inactive precursor known as prepromelittin. The activation of this 70 amino acid long precursor is a multistep process. Firstly, the N-terminal signal peptide, that directs the protein to secretory pathways, is cleaved. The remaining proprotein has an N-terminal domain composed of multiple anionic residues, interspersed with proline and alanine at every other residue. The proline and alanine residues in the proprotein enable the proprotein to become a mature melittin peptide through the sequential action of dipeptidyl peptidase IV on the N-terminal residues. Finally, the C-terminal glutamine-glycine dipeptide is enzymatically converted to a terminal glutamine-amide to give the native 26-residue peptide amide – Melittin (Fig. 1A).
Figure 1. The amino acid sequence of prepromelitin (A) and melittin (B) from Apis mellifera. (C) The helical wheel diagram of melittin - hydrophobic residues are black, hydrophilic residues are orange, and charged residues are blue. (The helical wheel diagram was created using CPT Galaxy Tools. https://github.com/tamu-cpt/galaxy-tools/).
Structurally, melittin typically adopts an alpha-helical conformation, characterized by a coiled shape. Its amphipathic nature manifests in both primary and secondary structures. In its primary sequence, melittin exhibits amphipathicity, where the first 20 amino acids (from the N-terminus) are mostly hydrophobic while the C-terminus is hydrophilic. In the secondary structure, one surface of the alpha-helix presents a continuous hydrophobic face while the opposite surface displays a polar face (Fig. 1C). Under physiological conditions, melitin molecules are monomeric and have a random coil structure at low concentration transforming into a monomeric α-helix upon binding with the cell membrane. At high concentration, melittin folds into alpha-helical tetramers (Fig. 2), in which the hydrophobic surfaces of the amphipathic helices are buried, and the polar surfaces are exposed.
Figure 2. The 3D structure of melittin. (A) The helical monomer consists of two helical segments joined by a coiled region (PDB ID 2MW6). (B) Tetrameric assembly of melittin (PDB ID 2MLT).
Additionally, the amphipathic nature of melittin contributes to its ability to interact with membranes by inserting itself into the lipid bilayer. This leads to pore formation and disruption of membrane integrity. As a result, water, ions, metabolites and other molecules can leak out of the cell, causing cell lysis and tissue damage.
Melittin is considered the major pain-inducing component of bee venom. Following the sting, melittin’s presence prompts an immune response, leading to the activation of inflammatory mediators like histamine, prostaglandins, and cytokines. These mediators cause the typical symptoms of inflammation, including redness, swelling, and pain, observed at the site of the bee sting. At the cellular level, melittin activates nociceptors, or pain receptors, through direct actions such as membrane depolarization and modulation of ion channels, as well as indirect effects like the release of inflammatory mediators from surrounding damaged tissues. Together, these mechanisms facilitate the transmission of pain signals to the brain, intensifying the sensation of pain following a bee sting.
Beyond the pain
The primary role of melittin is to lyse cell membranes and disrupt tissue to cause immediate pain and discomfort in creatures which might threaten the bees and their hive. However, beyond the antipredatory defence, melittin exhibits a wide range of interesting and potentially valuable biological activities. Many studies explore these diverse effects under conditions where melittin is not uniformly toxic to all cells or to the host organism. These conditions include melittin at low concentrations, conjugated to proteins, loaded on nanoparticles, liposomes, or other carriers that reduce its undesirable effects. It has been tested against host and pathogen cells from all branches of life and it has shown a potential in treating infectious diseases and cancer.
While research into bee venom therapy continues to expand, there are still uncertainties and controversies surrounding its effectiveness and safety. Allergic reactions to bee venom, ranging from mild to severe, pose a significant risk, particularly for individuals with known allergies. Furthermore, the lack of standardized protocols and regulatory oversight in bee venom therapy raises concerns about consistency and quality control. Nonetheless, the promising therapeutic potential of bee venom motivates ongoing scientific exploration and clinical investigation. Researchers are actively working to better understand the mechanisms of action underlying bee venom's effects and to evaluate its efficacy in well-controlled clinical trials.
Did you know?
- The gene for melittin is only found in bees.
- Over 80% of bee venom comprises water, and only about 0.1 μg of dry venom can be extracted from a single bee.
- Various factors such as bee age, seasonal changes, and the strain of honeybee have an impact on the quantitative composition of bee venom. For example, melittin content rises steadily from eclosion until reaching a peak at four weeks of age, after which it declines gradually. Additionally, melittin levels peak in March and May, then decrease to their lowest levels in January. African bees typically contain less venom than European bees.
- The queen bee has a smooth stinger allowing multiple stings without losing it and dying in the process of stinging. The queen does not leave the hive under normal conditions, so her sting is not for defence of the hive, but for eliminating rival queens within the hive, ideally before they can finish pupating.
- Insects capable of stinging belong to the order Hymenoptera, comprising ants, wasps, and bees. It's believed that the sting evolved from the egg-laying apparatus of ancestral hymenopteran species, limiting this ability to females.
Romana Gáborová
About the artwork
Faith Okeke, a year 12 student at The Leys School in Cambridge, found inspiration in the structure of melittin, a component of bee venom. She used printmaking and sewing techniques to create her artwork, aiming to achieve a specific effect. This involved using etching to produce darker and harsher lines, complemented by sewing soft textiles to achieve a smoother, gentler finish. Faith enjoys maths and art at school. During her leisure time, she enjoys acting, netball, and reading crime novels.
View the artwork in the virtual 2023 PDB Art exhibition
Structures mentioned in this article
Sources:
Bee Venom Composition: From Chemistry to Biological Activity
Bee Venom: Overview of Main Compounds and Bioactivities for Therapeutic Interests
Melittin, the Major Pain-Producing Substance of Bee Venom
Applications and evolution of melittin, the quintessential membrane active peptide
Melittin Aggregation in Aqueous Solutions: Insight from Molecular Dynamics Simulations
