Constituents and Biological Activities of Bee Venom

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This entry is adapted from the peer-reviewed paper 10.3390/vetsci10020119

Bee products consist of many substances that have long been known for their medicinal and health-beneficial properties. Venom is the one that has attracted the most interest due to the complexity of its chemical composition. Several types of research have been conducted utilizing biological (cellular) systems to figure out the properties of bee venom in vitro.

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1. Venom Source

Bee venom is produced by the venom gland located in the abdominal cavity of female honeybees ^[1]. The gland is connected to a containment sac. The veliniferous apparatus of social insects belonging to the genus Apis is an essential defence mechanism. Bees sting in the vicinity of the apiary in an attitude of colony defence ^[2]. The queen, on the other hand, stings to kill rivals ^[3]. Each hive can only have one queen, and when several queens are born at once, either some of them escape along with a specific number of bees, a born queen kills the unborn queens who are still within their cell, or two queens engage in a death battle ^[4]. The protein concentration of queen bee venom is highest in the first (0–3) days of life and diminishes after 7 days (a necessary condition shortly after emergence to kill the eldest queen and twin queens in competition for hive domination). As the gland degenerates, the protein content of the venom in honeybees diminishes during the following days. In contrast, the venom is not detectable at the time of emergence in the female honeybees. Instead, it increases quickly over the following two days, remains constant for the first 14 days, and then drops. Therefore, older honeybees produce less poison than younger ones ^[2]. The venom’s composition changes throughout time with age. For instance, melittin is released in an inactive precursor form, which transforms into an active form with growth and the passage into the guardian stage, which happens about day 20 of age ^[2].

Honeybees have a pointed stinger that is extracted from the abdomen during stinging along with the venom sac. Unlike wasps and hornets, they can only sting once before dying ^[5]. When a bee stings a person or a mammal in general, the stinger remains embedded in the skin, and the bee dies as a result of ripping out its intestines, muscles, and nerve center in an effort to detach. The bee dies because such a large amount of its body is lost. The stinger’s pointed end features tiny hooks that keep it from being removed without damage. Once embedded, it uses a separate piston mechanism to push the venom into the wound ^[6]. The stinger self-incorporates into the tissue and there is a simultaneous release of the contents of the venom sac, which is usually expelled completely within a few minutes ^[5]. Additionally, the alarm pheromone message conveyed by bee venom activates other bees to defend the hive. The alarm pheromone is made up of the mandibular gland’s 2-heptanone molecule and other substances, such as isopentyl acetate, released by the gland connected to the stinging apparatus. ^[5]^[7]. Bee venom cause localized inflammation with symptoms like pain, heat, and itching to systemic allergic reactions that can end in anaphylactic shock and, in extreme cases of hypersensitivity, can be fatal. ^[8]^[9]. In popular culture, bee venom is frequently connected to these phenomena. However, it is one of the most priceless gifts the beehive has given us. It can be helpful in the treatment of a wide range of illnesses when used in tiny dosages. Its use in the treatment of many illnesses states is intriguing due to its complex composition of chemicals with significant pharmacological and biochemical activity.

Freshly secreted bee venom is a clear, colourless liquid that forms a light yellow powder when it dries ^[10]. It has the pungent aromatic odour of honey and is acidic (between 4.5 and 5.5). The water content in bee venom varies between 55 and 70 percent ^[11]. The active components of the venom of various hymenoptera are peptides, proteins, enzymes, low molecular weight substances, and aliphatic constituents in varying quantities ^[2]^[12]. No exemption applies to bee venom. It is a very complicated composition that is largely (80%) made up of proteins. These latter compounds have high (proteins) or low (peptide) molecular weights. Biogenic amines are the most important low-molecular-weight substances. The peptides in bee venom adolapine, melittin, apamin, and peptide 401 have undergone extensive research ^[13] Table 1 summarises the composition of bee venom.

Table 1. Composition of bee venom: dry matter data according to Dotimas and Hider (1987) ^[11].

Substance	%	Substance	%
Enzymes		Biogenic amines
Phospholipase A2	10–12	Histamine	0.5–2
Hyaluronidase	1.5–2	Dopamine	0.2–1
Phosphatase, glucosidase	1-2	Noradrenaline	0.1–0.5
Proteins		Carbohydrates
Mast cell degranulating Peptide	1–2	Sugar (glucose, fructose)	2
Melittin	40–50	Phospholipids	5
		Amino acids
Secapine	0.5	Aminobutyric acid and α-amino acids	0.4
Tertiapine, apamin, procamine	2–5	Volatile substances (pheromones)	4–8
Other small peptides	13–15	Mineral substances	3–4

The right collection is the crucial element in obtaining the best quality bee venom. Pollen, honey, and other colony products must be free of impurities. As pointed out by Krell ^[14], there are no official quality standards, as bee venom is not recognised as an official drug or foodstuff. A quantitative study of its more stable or readily quantifiable components, such as melittin, dopamine, histamine, noradrenaline, or those for which contamination is suspected, can be used to determine a substance’s degree of purity. Standardization and quality control techniques for the efficacy and purity of hymenoptera venom, particularly those of bees, were discussed by Guralnick et al. in 1986 ^[15].

2. Venom Constituents and Their Biological Activities

2.1. Melittin

The more abundant element is melittin. It makes up roughly 50% of the peptides in the venom and consequently 50% of the dry BV ^[16]. The sequencing of the peptide by Habermann and Jentsch (1967) revealed that it included 26 amino acid residues ^[17].

The carboxy-terminal region (residues 21–26) is hydrophilic due to the presence of a positively charged amino acid stretch, whereas the amino-terminal region (residues 1–20) is hydrophobic ^[18]^[19]. Melittin is soluble in water as a monomer or tetramer due to its amphoteric nature. The polypeptide spontaneously integrates into the phospholipid bilayer of cell membranes, damaging them ^[20]^[21]^[22]. Thus, the molecule’s primary structure resembles the fundamental form of a detergent-type molecule. By changing the phospholipid composition of the cell membrane, melittin accumulation leads to cell lysis. Neumann and Habermann (1953) discovered that it was a haemolytic factor for the first time ^[23]. Melittin is a member of the class of compounds known as amphiphilic due to its distinctive structure. Each melittin chain has two α-helical segments and resembles a bent rod overall. Melittin is monomeric at the lowest concentrations necessary for cell lysis and tetrameric at the amounts found in the bee venom sac ^[24]. To describe the precise steps involved in membrane permeation by amphipathic α-helical lytic peptides, two different pathways were put forth. They are theoretically quite different from one another.

The first one, known as the “barrel-stave” model, is characterized by the insertion of amphipathic α-helices into the membrane’s hydrophobic core to create transmembrane holes. In the second, known as the “carpet” model, the peptides are in touch with the lipid head group during the whole process of membrane permeation and do not integrate into the hydrophobic core of the membrane, even if they are not required to acquire an amphipathic α-helical structure ^[25]. The cytotoxic and anti-inflammatory actions of melittin on tumor cells may be significantly influenced by these structural characteristics. By facilitating an enhanced Ca²⁺ ion influx, melittin also activates phospholipase A2 and adenylate cyclase ^[26]. All of the above characteristics make melittin interesting due to its currently known anti-cancer, anti-inflammatory, antiviral, antibacterial, and neuroprotective properties ^[27]^[28]^[29]^[30].

2.2. Apamin

Eighteen amino acids make up the polypeptide apamin, which also has two disulfide bridges in it. It is the smallest neurotoxin in bee venom and makes up less than 2% of the weight of dry venom ^[31]. Apamin functions as an allosteric inhibitor since it has long been recognized as a highly selective blocker of small-conductance Ca²⁺ -activated K⁺ (SK) channels ^[32]. These channels help control the ionic balance in the cell membrane, which regulates the resting and action potentials in vital cells as well as signal transmission through neurons and muscle contraction. Through this route, apamin produces a neurotoxic impact by mediating long-term after-hyperpolarization in neurons and muscle cells. This polypeptide can also pass the blood–brain barrier and affect how the central nervous system functions through a variety of mechanisms. For instance, it has been shown in rats to have neurotoxic effects that result in hyperactivity and convulsions ^[33]. Apamin also affects the permeability of the cell membrane to potassium (K+) ions by inhibiting calcium-activated K+ channels. Through the Akt and Erk signaling pathways, the toxin can prevent vascular smooth muscle cells from proliferating and migrating ^[34]. This finding emphasizes apamin’s potential for use in atherosclerosis treatment plans. Generally speaking, pathophysiological responses, including atherosclerosis and Parkinson’s disease involve a significant function for apamin target channels.

2.3. Mast Cell Degranulation Peptide

It also is known as “peptide 401”. It is a polypeptide with 22 amino acid residues and a molecular structure that resembles an apamin with two disulfide bridges ^[35]. It only makes up a small portion of the venom, roughly 2–3% of the dry matter volume. The name MCD refers to the physiologic process by which mast cells release histamine; the peptide promotes mast cell degranulation and sets off inflammatory responses. In animal trials, MCD has been proven to significantly lower blood pressure ^[36]. In this context, it is the component considered responsible for the hypotension observed in BV intoxication ^[37].

2.4. Adolapin

It is a polypeptide of 103 amino acids and makes up around 1% of dry BV. By inhibiting prostaglandin synthesis and cyclooxygenase activity, adolapin exerts anti-inflammatory, analgesic, antinociceptive, and antipyretic effects ^[38]^[39]. Because naloxone has been shown to partially suppress the analgesic effect of adolapin, a central mechanism may be involved in the drug’s action ^[40]. According to Koburova (1985), adolapin, like aspirin and other comparable substances, has antipyretic actions, most likely via inhibiting the synthesis of cerebral prostaglandins ^[41].

2.5. Phospholipase A2

The enzyme that is most prevalent in bee venom is phospholipase A2. It is an alkaline component that makes up 12–15% of the dry BV. It has four disulfide bridges and 128 amino acid residues ^[42]. It is highly aggressive against the cell membrane, resulting in cytolysis, together with melittin and lysolecithin, which are produced when phospholipase acts. Furthermore, phospholipase is the most significant allergen and hence the most toxic element of bee venom. Phospholipases A2 (PLA2) are enzymes capable of hydrolysing the ester linkage of glycerophospholipids leading to the liberation of free fatty acids and lysophospolipids, including arachidonic acid, a precursor necessary for the biosynthesis of eicosanoids through the intervention of cyclooxygenase, molecules involved in the inflammatory cascade. Phospholipase A2 is therefore involved in the synthesis of prostaglandins and leukotrienes. Pure phospholipase A2 is not poisonous, but when it is near melittin, it becomes a haemolytic factor. ^[5]. It works in concert with melittin to lyse erythrocytes by causing breaches in the cell membrane that let melittin flow through. Melittin does this by dissolving the phospholipid layers that make up the majority of the cell membranes. This haemolytic effect of bee venom is inhibited by heparin ^[43]. Additionally, it has been demonstrated that phospholipase A2 has anti-inflammatory, anti-tumor, and anti-parasitic properties ^[44]^[45].

2.6. Hyaluronidase

Hyaluronidase is a 350 amino acid residue polypeptide that makes up 1% to 2% of the BV. Human hyaluronidase, which is involved in the turnover of hyaluronic acid, and bee venom hyaluronidase share a 30% sequence identity ^[46]. Hyaluronidase acts as an adjuvant to venom diffusion. Certain acidic mucopolysaccharides in connective tissues have intrinsic glycolide linkages that the enzyme hyaluronidase breaks down, decreasing the viscosity of the tissue and allowing the venom to enter the tissues ^[47]. Additionally, because hydrolyzed hyaluronic acid particles have pro-inflammatory, pro-angiogenic, and immune-stimulating capabilities, they accelerate systemic poisoning ^[5]. It is known to promote blood vessel dilatation, increasing permeability and hence, blood circulation, which in turn enhances BV circulation ^[45].

The Table 2 below summarizes the key characteristics of the bee venom’s constituent parts and the associated biological effects.

Table 2. Biological effects of bee venom and its components.

Components	Effect
Melittin	Peptide with biological activity. Melittin prevents blood from clotting, works well against germs, shields against radiation. Melittin works as an anti-inflammatory in small dosages. It has a haemolytic action and is clearly cytotoxic.
Phospholipase A2	Phospholipase is the most important allergen and therefore the most harmful component of bee venom.
Hyaluronidase	It is an enzyme that allows venom to enter tissues and causes blood vessels to widen and tissues to become more permeable, increasing blood flow.
Acid phosphatase	Allergen.
Apamin	Biologically active peptide; a neurotoxin.
Mast cell degranulating peptide	Peptide that degranulates mast cells by releasing biogenic amines.
Protease inhibitor	It has anti-inflammatory and hemorrhagic properties and inhibits the action of various proteases, including trypsin, chymotrypsin, plasmin, and thrombin.
Adolapin	Anti-inflammatory, anti-rheumatic, and analgesic.
Histamine	It dilates blood vessels and increases capillary permeability. It is an allergen.
Dopamine, noradrenaline	Neurotransmitters that affect the behaviour and physiology of the senses.
Alarm pheromone	It puts the colony on high alert.

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