Fasciculins are a class of toxic proteins found in certain snake venoms, notably some species of

mamba Mambas are fast moving highly venomous snakes of the genus ''Dendroaspis'' (which literally means "tree Asp (reptile), asp") in the family Elapidae. Four Neontology, extant species are recognised currently; three of those four species are essen ...

. Investigations have revealed distinct forms in some green mamba venoms, in particular FAS1 and FAS2 Fasciculins are so called because they cause intense

fasciculation A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as many as 70% of people experiencing them. They can be benign, or associated with more serio ...

muscle fascicle A muscle fascicle is a bundle of skeletal muscle fibers surrounded by perimysium, a type of connective tissue. Structure Muscle cells are grouped into muscle fascicles by enveloping perimysium connective tissue. Fascicles are bundled together b ...

s of susceptible organisms, such as the preferred prey of the snakes. This effect helps to incapacitate the muscles, either killing the prey, or paralysing it so that the snake can swallow it.

Fundamental mechanism of action

The mechanism of action of the FAS proteins is associated with their ability to attach to molecules of the

acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...

in the muscles and their

neuromuscular junction A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...

s, and thereby interfere with their necessary neuromodulatory inhibition.

Molecular nature and physiological effect

Fasciculins from mambas inhibit mammalian and fish acetylcholinesterases intensely, but are less active against the corresponding

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s in insects, reptiles and birds. As one might expect of fast-acting venoms, they are fairly small proteins of about 61 amino acid residues. Their three-dimensional shape is three-fingered, and is secured by four cross-linking

disulfide bridge In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...

Disruption of acetylcholine signalling

Venom disrupters of

acetylcholine Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

generally penetrate the neuromuscular junction, where they interfere with either the production or reception of acetylcholine, or the

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

of acetylcholine after it has achieved its function of neurotransmission; mamba fasciculins prevent the final stage of this process by binding to acetylcholinesterase and blocking its action on acetylcholine; the result is that after the acetylcholine has transmitted the required stimulus, it continues with the stimulus after it has become inappropriate. That mechanism is in some ways similar to the effect of the so-called

organophosphate In organic chemistry, organophosphates (also known as phosphate esters, or OPEs) are a class of organophosphorus compounds with the general structure , a central phosphate molecule with alkyl or aromatic substituents. They can be considered a ...

nerve agent Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (AChE), an enzyme that ...

s; the blockage of the acetylcholinesterase action is what causes the fasciculation that inspired the name ''fasciculin''.

Docking and activity

In mammalian acetylcholinesterase two conserved

peripheral A peripheral or peripheral device is an auxiliary device used to put information into and get information out of a computer. The term ''peripheral device'' refers to all hardware components that are attached to a computer and are controlled by the ...

anionic residues form part of the enzyme where the FAS molecule docks. Insect and avian acetylcholinesterases lack the two residues in those positions, and that drastically reduces their affinity for mamba fasciculins. However, there is a significant, though reduced, toxic effect, because several

basic BASIC (Beginners' All-purpose Symbolic Instruction Code) is a family of general-purpose, high-level programming languages designed for ease of use. The original version was created by John G. Kemeny and Thomas E. Kurtz at Dartmouth College ...

residues in the venom protein still establish and maintain contacts with the enzyme. This is unusual in protein complementarity, in that it involves attractions between multiple charged residues, but without any salt linkage between the molecules.

References

{{Acetylcholine metabolism and transport modulators Acetylcholinesterase inhibitors Neurotoxins Vertebrate toxins