Neurotoxin Mamba snake Why Fasciculin Mambas have only

Neurotoxin Mamba snake

Why Fasciculin? • Mambas have only Fasciculin • Fasciculins : a family of closely related peptides isolated from Mamba venom toxins (FAS-I, FAS-II, and FAS-III) • Function : Inhibits ACETYLCHOLINESTERASE (ACh. E), which is an enzyme to degrade neurotransmitter ACh. In skeletal muscle, fasciculations are observed initially, followed by flaccid paralysis.

About Fasciculin • Small protein (61 amino acids) • 3 -finger shaped • Cross-linked by 4 disulfide bridges (S atoms are in Cystine amino acid)

Mode of Action The snake neurotoxins act on the neuromuscular junction and block neuromuscular transmission. • Fasciculin interferes with this process by binding to Acetylcholinesterase (ACh. E). • Result: “Death by respiratory paralysis”.

Receptors as Targets • Antagonists: prevent receptor activation • Agonists: stimulate then inactivate • Acetylcholinesterase inhibitors: prevent degradation Mechanism: By inhibiting acetylcholinesterase and pseudocholinesterase, this neurotoxin allows ACh to build up at its receptors. Thus, they result in enhancement of both muscarinic and nicotinic agonist effect

Neuromuscular Junction Vesicles containing Acetylcholine (ACh) ACh receptors Acetylcholinesterase (ACh. E)

ACh Receptor Channel Opens

Mechanism of Enzyme Action • Lock and Key Theory states that “a substrate has a shape fitting that of the enzyme’s active side, as a key fits a lock”. “The lock is the enzyme and the key is the substrate” (Mechanism of Enzyme Action) • Induced-Fit Theory states that “the conformation of an enzyme changes to accommodate an incoming substrate”.

Lock and Key Theory vs. Induced-Fit Theory Lock and Key Induced-Fit

Acetylcholinesterase • Enzyme which breaks down acetylcholine neurotransmitter – acetylcholinesterase inhibitors = neurotoxins active site in red acetylcholinesterase neurotoxin in green snake toxin blocking acetylcholinesterase active site

Acetycholinesterase Cleans Up • ACh. E hydrolizes ACh, so that the process can start again.

Mechanism of ACh Hydrolysis by ACh. E

Binding site

Irreversible Inhibitors • Bind to the active site of the enzyme. • Exhibit concentration-dependent inhibition: the more inhibitor, the greater the inhibition of the enzyme. • Inhibition cannot be reversed by adding more substrate. • Usually resemble the substrate in chemical structure somewhat.

Example of Inhibitors

Structure/Function of Fasciculin Acetylcholinesterase with Acetylcholine bound. Red = ACh. E active site Yellow = ACh molecule Fasciculin (yellow) docked with ACh. E. • One loop covers the ACh. E active site. • Two other loops fit into a crevice and surround a protrusion.