Fasciculins

Bourne, Y., Taylor, P. and Marchot, P. Acetylcholinesterase inhibition by fasciculin. Crystal structure of the complex. Cell 83 503-512,1995. 

Fasciculins] (7 kDa proteins) Dendroaspis angusticeps (mamba snake) venom AChE (at pM-nM)... 

Onchidal and fasciculins are natural toxins, which produce their toxicity in mammalian systems by virtue of primarily acetylcholinesterase (AChE) inhibition. AChE hydrolyzes and inactivates acetylcholine, thereby regidating the concentration of the transmitter at the synapse. Termination of activation is normally dependent on dissociation of acetylcholine from the receptor and its subsequent diffusion and hydrolysis, except in diseases where acetylcholine levels are limiting or under AChE inhibition, conditions that increase the duration of receptor activation (Silver, 1963). 

Neurotoxins fi om snake venoms have proved to be valuable tools for the understanding of synaptic transmission mechanisms. Likewise, the powerful inhibitory action of fasciculins against mammalian AChE makes them potentially useful tools for pharmacological and neurochemical research. Studies of their biochemical and elec-trophysiological effects on the central nervous system and biochemical characterization are now being carried out. 

Toxins that facilitate neuromuscular transmission are a characteristic component of mamba venom. The four known fasciculins bind to a peripheral regulatory anionic site of AChE in a noncompetitive and irreversible manner... 

Fasciculins characterized From the mamha snake venoms (Elapidae family) Dendroaspis genus)... 

Fasciculin 4 Dendroaspis viridis (western green mamba)... 

The fasciculins are a family of closely related peptides that are isolated from the venom of mambas and exert their toxic action by inhibiting AChE. The crystal structure of fasciculin 2 from green mamba Dendroaspis angusticeps) snake venom was first resolved in 1992 (Le Du et al., 1992). The three-dimensional (3D) structure of fasciculin 1 obtained from the US National Library of Medicine, National Center for Biotechnology Information, MMDB database is illustrated in Figure 11.2. 

Other reversible inhibitors, such as propidium and the peptide toxin fasciculin, bind to the peripheral anionic site on AChE. This site resides at the lip of the gorge and is defined by tryptophan 286 and tyrosines 72 and 124 (Taylor, 2001). 

A large number of organic compounds reversibly or irreversibly inhibit AChE (Long, 1963), which bind either to the esteratic or the anionic subsite of AChE catalytic site or to the peripheral site of the enzyme. Most of them are synthetic substances, sometimes bearing insecticidal properties. Few natural inhibitors of AChE are known and, to date, fasciculins are the only known proteinic AChE... 

Fasciculins inhibit AChE from mammals, electric fish, and some snake venoms with Ki values in the pico- to nanomolar range in contrast, avian, insect, and some other snake venom AChEs are relatively resistant, and high micromolar concentrations are required to inhibit mammalian butyrylcholinesterases (BuChE) (Marchot et al, 1993). Dissociation constants of Fasl and Fas3 are two-fold and 60-fold lower, respectively, than that of Fas2 for synaptosomal rat brain. 

Fasciculin inhibition of AChE is prevented by chemical modification of the enzyme at a peripheral site (Duran et al, 1994). The specific interaction of fasciculin 2 with peripheral sites present in Electrophorus electricus AChE Ki, 0.04 nM fasciculin) was investigated by chemical modification with A,A-dimethyl-2-phenylaziridium (DPA) in the presence of active or peripheral anionic site protective agents. An enzyme was obtained that compared to the native AChE and was 10 times less sensitive to fasciculin 2. This enzyme was fully inhibited by edrophonium and tacrine, and was 25-170 times less sensitive to several peripheral site ligands. It seems fasciculin 2 binding to an AChE peripheral site partially overlaps the site of other peripheral site ligands including acetylcholine. 

There is limited information about the toxicity, toxicokinetics, and toxicological properties of onchidal and additional data are needed to make a health effects-based risk assessment of the natural compound. Although fasciculins are much better known, data on toxicological properties and toxicokinetics will be of interest and usefiil for risk assessments despite it being generally accepted that the toxicity of this proteinic toxin occurs at very low doses. 

Onchidal and fasciculins are interesting natural compounds and it is difficult to predict their toxicity. In the case of onchidal, in silico computational predictive modeling for toxic endpoints of interest may prove useful for risk assessment decision support. Likewise, it is a challenge to predict the mditary potential and human impact of these natural toxins since their affinity for enzyme inhibition depends upon the amount and duration of the human exposure. 

Cervenansky, C., Engstrom, A., Karlssom, E. (1994). Study of structure-activity relationship of fasciculin by acetylation of amino groups. Biochim. Biophys. Acta 1199 1-5. 

Duran, R., Cervenansky, C., Dajas, F., Tipton, K.F. (1994). Fasciculin inhibition of acetylcholinesterase is prevented by chemical modification of the enzyme at a peripheral site. Biochim. Biophys. Acta 1201 381-8. 

A Resolution stmcture of fasciculin 1, an antiacetylcholinesterase toxin from green mamha snake venom. J. Biol. Chem. 267 22122-30. 

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