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Fasciculin - Wikipedia

From Wikipedia, the free encyclopedia

Fasciculin 1, Dendroaspis angusticeps (green mamba).

Fasciculins are a class of toxic proteins found in certain snake venoms, notably some species of mamba. Investigations have revealed distinct forms in some green mamba venoms, in particular FAS1 and FAS2^[1] Fasciculins are so called because they cause intense fasciculation in muscle fascicles 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 in the muscles and their neuromuscular junctions, and thereby interfere with their necessary neuromodulatory inhibition.^[2]

Molecular nature and physiological effect

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

Disruption of acetylcholine signalling

Venom disrupters of acetylcholine neurotransmission generally penetrate the neuromuscular junction, where they interfere with either the production or reception of acetylcholine, or the hydrolysis 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.^[2] That mechanism is in some ways similar to the effect of the so-called organophosphate nerve agents; 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 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 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.^[3]

References

^ "Fasciculin". Proteopedia, life in 3D. January 2016. Retrieved 2016-06-29.
^ ^a ^b Reed, Tim; Eaton, Katie; Peng, Cathy; Doern, BettyLou (2002). "Neurotoxins in Snake Venom". Elements of Bioinformatics. California State University Stanislaus. Retrieved 2016-06-29.^{[permanent dead link‍]}
^ Harel, Michal; Kleywegt, Gerard J; Ravelli, Raimond BG; Silman, Israel; Sussman, Joel L (December 1995). "Crystal structure of an acetylcholinesterase–fasciculin complex: interaction of a three-fingered toxin from snake venom with its target". Structure. 3 (12): 1355–1366. doi:10.1016/S0969-2126(01)00273-8. ISSN 0969-2126. PMID 8747462.

Acetylcholine metabolism and transport modulators

Enzyme
(modulators)

ChATTooltip Choline acetyltransferase	Inhibitors: 1-(-Benzoylethyl)pyridinium 2-(α-Naphthoyl)ethyltrimethylammonium 3-Chloro-4-stillbazole 4-(1-Naphthylvinyl)pyridine Acetylseco hemicholinium-3 Acryloylcholine AF64A B115 BETA CM-54,903 N,N-Dimethylaminoethylacrylate N,N-Dimethylaminoethylchloroacetate
AChETooltip Acetylcholinesterase	Inhibitors: Reversible: Carbamates: Aldicarb Aminocarb Bendiocarb Bufencarb Carbaryl Carbendazim Carbetamide Carbofuran Carbosulfan Chlorbufam Chloropropham Dimetilan Ethienocarb Ethiofencarb Fenobucarb Formetanate Formparanate Methiocarb Methomyl Metolcarb Miotine Oxamyl Phenmedipham Pinmicarb Pirimicarb Promecarb Propamocarb Propham Propoxur Thiodicarb Thiofanox; Stigmines: Distigmine Eptastigmine Ganstigmine Neostigmine +glycopyrronium bromide Phenserine Physostigmine Pyridostigmine Quilostigmine Rivastigmine Terestigmine; Others: Acotiamide Ambenonium Caffeine Donepezil EA-3990 EA-4056 Edrophonium Galantamine Huperzine A Huprine W Huprine X Huprine Y Ipidacrine Itopride Ladostigil Minaprine Octamethylene-bis(5-dimethylcarbamoxyisoquinolinium bromide) T-1123 T-1152 T-1194 TL-599 TL-1238 Tacrine Zanapezil Irreversible: Organophosphates: 2-Ethoxycarbonyl-1-methylvinyl cyclohexyl methylphosphonate Acephate Armine Azinphos-ethyl Azinphos-methyl BAY-29952 Bensulide Cadusafos Carbophenothion Chlorethoxyfos Chlorfenvinphos Chlorpyrifos Chlorpyrifos-methyl Coumaphos Crotylsarin Cyanophos Cyclosarin (GF) Demephion Demeton Demeton-S-methyl Dialifor Diazinon Dichlorvos Dicrotophos Dicyclohexyl phosphorofluoridate Diisopropylphosphate Diisopropyl fluorophosphate Dimefox Dimethoate Dimethyl 4-(methylthio)phenyl phosphate Dioxathion Disulfoton EA-2012 EA-2054 EA-2098 EA-2192 EA-2613 EA-3148 EA-4352 Echothiophate Ethylsarin (GE) Endothion EPN Ethion Ethoprop Fenamiphos Fenitrothion Fenthion Fluorotabun Fonofos Formothion Fosthiazate GD-42 GH GT-45 GV Guanitoxin Hexaethyl tetraphosphate (HETP) Isofluorophate Isoxathion Leptophos Malaoxon Malathion Mazidox Methamidophos Methidathion Methyl phenkapton Methylfluorophosphonylcholine (MFPCh) Metrifonate Mevinphos Mipafox Monocrotophos MSPI Naled Novichok agent Omethoate Oxydemeton-methyl Paraoxon Parathion Parathion-methyl Phorate Phosalone Phosfolan Phosmet Phosphamidon Phoxim Pirimiphos-methyl Profenofos Prothoate R-16661 Ro 3-0340 Ro 3-0346 Ro 3-0347 Ro 3-0351 Ro 3-0352 Ro 3-0397 Ro 3-0411 Ro 3-0412 Ro 3-0417 Ro 3-0419 Ro 3-0422 Ro 3-0433 Ronnel Sarin (GB) Schradan Soman (GD) Sulfotep (TEDP) Tabun (GA) Tebupirimfos Temefos Terbufos Tetrachlorvinphos Tetraethyl pyrophosphate (TEPP) Triazofos Tribufos Trichlorfon Trichloronate Tricresyl phosphate VE VG VM VP VS VR VX; Others: Demecarium Fasciculins (green mamba toxins) (1, 2, 3, 4) Onchidal (Onchidella binneyi) Methanesulfonyl fluoride Unsorted: α-Pinene α-Viniferin Affinine Affinisine Arisugacin A Bulbocapnine Conodurine Coronaridine Corydaline Corynoline Crimidine Cyclanoline Cymserine Harmaline Kobophenol A Lactucopicrin Lycorine Phosacetim Rosmarinic acid Stercuronium iodide Taspine Tetrahydrocannabinol Ungeremine Ungiminorine Dimethylcarbamoyl fluoride BW284C51 TMTFA 3152 CT Reactivators: Asoxime chloride Methoxime Obidoxime Pralidoxime Trimedoxime bromide
BChETooltip Butyrylcholinesterase	Inhibitors: Affinine Affinisine Conodurine Cymserine Ladostigil Profenamine (ethopropazine) Rivastigmine Tacrine ZINC-12613047 Many of the other AChE inhibitors listed above

Transporter
(modulators)

CHTTooltip Choline transporter	Inhibitors: Hemicholinium-3 (hemicholine) Triethylcholine Enhancers: Coluracetam
VAChTTooltip Vesicular acetylcholine transporter	Inhibitors: Vesamicol

Release
(modulators)

Inhibitors	SNAP-25Tooltip Synaptosomal-associated protein 25 inactivators: Botulinum toxin (A, C, E) VAMPTooltip Vesicle-associated membrane protein inactivators: Botulinum toxin (B, D, F, G) Others: Bungarotoxins (β-bungarotoxin, γ-bungarotoxin)
Enhancers	LPHNTooltip Latrophilin agonists: α-Latrotoxin Others: Atracotoxins (e.g., robustoxin, versutoxin) Crotoxin

See also: Receptor/signaling modulators; Muscarinic acetylcholine receptor modulators; Nicotinic acetylcholine receptor modulators

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