Phospholipase A2s (PLA2s)
PLA2s are a superfamily of enzymes which can be divided into 15 groups based on their structure and source. They are commonly found in many types of organisms including fungi, bacteria, reptiles, and mammals, where they play an important role in many biological activities. These enzymes break apart phospholipid membranes found throughout the body by hydrolyzing them (breaking them apart by adding a water molecule). The PLA2s in snake venoms are classified in two of the PLA2 groups: group I (elapid enzymes) and group II (viperid venoms). The enzymatic activity of PLA2s on phospholipid membranes is responsible for the hemorrhaging associated with snake bites. The PLA2s in snake venom are also responsible for a large variety of pharmacological effects which do not depend on their enzymatic activity with phospholipids. PLA2s can be neurotoxic, hemotoxic, myotoxic, or cytotoxic.
The diversity of pharmacological effects caused by PLA2s is based on their ability to target specific tissues. Many snake venom PLA2s have molecular regions, called pharmacological sites, which are different from their catalytic sites (the part of an enzyme which performs any enzymatic activity). These pharmacological sites can bind with high specificity to membrane proteins on a target cell. Once they are bound to these proteins, the PLA2s can then cause further toxic activity which can be either dependent or independent of catalytic activity. The high affinity of PLA2s for membrane proteins on specific tissues allows PLA2s to target various tissues and organs throughout the body no matter where they were injected, giving PLA2s their diverse pharmacological effects.
The ability of each pharmacological site to bind with its specific membrane protein depends on the compatibility of the site to the protein’s active site. The two sites must have similar charges and hydrophobicity, qualities which are based on the structure of the proteins, especially their amino acid sequences. This makes the structure of each PLA2 very important to its function, and each enzymes structure must be very specific. This high degree of specificity is enabled by the accelerated evolution of snake venom proteins, including PLA2s.
Crotoxin
One very important type of PLA2 in snake venom is neurotoxic PLA2s. These proteins can be highly damaging to the human body, and the effects associated with neurotoxic PLA2s are more likely to kill a snakebite victim than the effects associated with other PLA2s. The best classified type of neurotoxic PLA2 is called crotoxin. Crotoxin was first isolated from Crotalus durisus terrificus (shown in the picture above) and is made up of two subunits, crotoxin A and crotoxin B. Crotoxin A is and acidic, non-neurotoxic PLA2, while crotoxin B is a basic, slightly neurotoxic PLA2. When the subunits interact, they amplify the neurotoxicity of crotoxin B, because crotoxin A prevents the nonspecific binding of crotoxin B to non-neuron proteins. Creating a complex between crotoxin A and crotoxin B can increase the neurotoxicity of crotxin B more than 30-fold. Most neurotoxic PLA2s highly resemble crotoxin in shape and structure, and they also have subunits which resemble crotoxin A and crotoxin B. It has also been noted that many neurotoxic PLA2s have asparagine (N) as their sixth amino acid, while non-neurotoxic PLA2s do not. Because of this, it is suspected that the amino acid N6 plays a large role in the neurotoxic function of PLA2s
The diversity of pharmacological effects caused by PLA2s is based on their ability to target specific tissues. Many snake venom PLA2s have molecular regions, called pharmacological sites, which are different from their catalytic sites (the part of an enzyme which performs any enzymatic activity). These pharmacological sites can bind with high specificity to membrane proteins on a target cell. Once they are bound to these proteins, the PLA2s can then cause further toxic activity which can be either dependent or independent of catalytic activity. The high affinity of PLA2s for membrane proteins on specific tissues allows PLA2s to target various tissues and organs throughout the body no matter where they were injected, giving PLA2s their diverse pharmacological effects.
The ability of each pharmacological site to bind with its specific membrane protein depends on the compatibility of the site to the protein’s active site. The two sites must have similar charges and hydrophobicity, qualities which are based on the structure of the proteins, especially their amino acid sequences. This makes the structure of each PLA2 very important to its function, and each enzymes structure must be very specific. This high degree of specificity is enabled by the accelerated evolution of snake venom proteins, including PLA2s.
Crotoxin
One very important type of PLA2 in snake venom is neurotoxic PLA2s. These proteins can be highly damaging to the human body, and the effects associated with neurotoxic PLA2s are more likely to kill a snakebite victim than the effects associated with other PLA2s. The best classified type of neurotoxic PLA2 is called crotoxin. Crotoxin was first isolated from Crotalus durisus terrificus (shown in the picture above) and is made up of two subunits, crotoxin A and crotoxin B. Crotoxin A is and acidic, non-neurotoxic PLA2, while crotoxin B is a basic, slightly neurotoxic PLA2. When the subunits interact, they amplify the neurotoxicity of crotoxin B, because crotoxin A prevents the nonspecific binding of crotoxin B to non-neuron proteins. Creating a complex between crotoxin A and crotoxin B can increase the neurotoxicity of crotxin B more than 30-fold. Most neurotoxic PLA2s highly resemble crotoxin in shape and structure, and they also have subunits which resemble crotoxin A and crotoxin B. It has also been noted that many neurotoxic PLA2s have asparagine (N) as their sixth amino acid, while non-neurotoxic PLA2s do not. Because of this, it is suspected that the amino acid N6 plays a large role in the neurotoxic function of PLA2s