Toxins

Toxins

Definition
A poisonous substance, especially a protein, that is produced by living cells or organisms and is capable of causing disease when introduced into the body tissues but is often also capable of inducing neutralizing antibodies or antitoxins.

Discovery
Kuch et al., in 2003 identified α-bungarotoxin (A31) as the major postsynaptic neurotoxin, and characterized the complete nucleotide identity of a genomic DNA of Bungarus candidus from Java with exons of the Bungarus multicinctus A31 gene 1. A. californica occurs Los Angeles embed the neurotoxic glucoside aesculin, which induces hemolysis of red blood cells 2. Grollman et al., in 2007 characterized the role of environmental toxins in endemic (Balkan) nephropathy 3. Epidemiologic findings suggest the involvement of an environmental toxin in both the nephropathy and urothelial cancer associated with endemic nephropathy. A variety of environmental factors have been explored during the past 50 yr, including heavy metals, polyaromatic hydrocarbons, viruses, and trace elements 4 with the mycotoxin, ochratoxin being the most recent focus of research 5.

Structural Characteristics
All scorpion toxins are disulphide-containing peptide neurotoxins, with three disulphide bonds in "short" and four in "long" neurotoxins. All scorpion venom toxins have a distinct structural motif, with a dense core of secondary structural elements comprising disulphide bonds stabilizing the structure 6. Leiurotoxin is 31-residue polypeptide chain reticulated by three disulfide bridges, i.e. Cys3-Cys21, Cys8-Cys26 and Cys12-Cys28. A proton NMR study at 500 MHz of leiurotoxin I in water was initially carried out to elucidate the secondary structure of toxin. It is inferred from a combination of short-range nuclear over hauser enhancements, scalar couplings and proton/deuteron exchange rates. Three disulfide bridges were found to locate near the N-terminal part (that is alpha-helical from residue 6 to 16) on one side of a C-terminal two stranded antiparallel beta sheet (from Leu18 to Val29). The latter features a tight turn at Gly23-Asp24 7.

The Malayan krait (Bungarus candidus) is one of the most medically significant snake species in Southeast Asia. Kuch et al., purified and identified the major postsynaptic toxin in the venom of B. candidus from Java. The toxin was indistinguishable from A31, a toxin originally isolated from Bungarus multicinctus, in its mass (7983.75 Da), LD50 (0.23 μg/g in mice i.p.), affinity to nicotinic acetylcholine receptors, and by its 40 N-terminal amino acid residues as determined by Edman degradation 1.

Mode of Action
A distinct class of small-conductance Ca2+-activated K+ channel is blocked by leiurotoxin-1. Leiurotoxin I completely inhibits 125I-apamin binding to rat brain synaptosomal membranes (Ki = 75 pM). Thus, it is 10-20-fold less potent than apamin. Leiurotoxin I is not a strictly competitive inhibitor of this binding reaction. Like apamin, leiurotoxin I blocks the epinephrine-induced relaxation of guinea pig teniae coli (ED50 = 6.5 nM), while having no effect on the rate or force of contraction in guinea pig atria or rabbit portal vein preparations 8. Ochratoxin A is nephrotoxic in rabbits, mice, and pigs; cytotoxic to cultured renal cells; and carcinogenic in rodents.5, 9 Oxidative DNA damage may account for some or all of these harmful effects. Fuchs and Peraica reported that levels of malondialdehyde and protein carbonyl were increased in renal tissue of male rats treated with low dosages (5 ng/kg) of ochratoxin A. Marin-Kuan and Schilter have used gene expression profiling to demonstrate ochratoxin A–induced disruption of pathways regulated by the transcription factor Nrf2, thereby reducing cellular defenses against oxidative stress 9.

Functions
Leiurotoxin blocks the apamin-sensitive K+ channel in guinea pig hepatocytes7- a potent inhibitor of apamin binding to rat brain synaptosomal membranes. This peptide, like apamin, blocks the epinephrine-induced relaxation of guinea pig 8.

Biochemical tools, toxins directed against a particular channel can still be useful in defining the physiological role of that channel in a particular tissue. In addition, for those K+ channels which are not yet successfully probed by molecular biology techniques, toxins can be used as biochemical tools with which to purify the target protein of interest 8.

Microbial pathogenicity, toxins produced by different microorganisms are the main cause of virulence determinants for microbial pathogenicity.

Biotoxins can be highly complex and relatively small proteins that target a specific nerve channel or receptor.

References
1. Kuch U, Molles BE, Omori-Satoh T, Chanhome L, Samejima Y, Mebs D (2003). Identification of alpha-bungarotoxin (A31) as the major postsynaptic neurotoxin, and complete nucleotide identity of a genomic DNA of Bungarus candidus from Java with exons of the Bungarus multicinctus alpha-bungarotoxin (A31) gene. Toxicon., 42(4):381-390.
2. Ratliff RD, Duncan DA and Westfall SE (1991). California oak-woodland overstory species affect herbage understory management implications. Journal of Range Management, 44(4):306-310.
3. Grollman AP, Jelakovi B (2007). Role of environmental toxins in endemic (balkan) nephropathy. J Am Soc Nephrol., 18:2817-2823.
4. Voice TC, Long DT, Radovanovic Z, Atkins JL, McElmurry SP, Niagolova ND, Dimitrov P, Petropoulos EA, Ganev VS (2006). Critical evaluation of environmental exposure agents suspected in the etiology of Balkan endemic nephropathy. Int J Occup Environ Health.,12:369-376.
5. Pfohl-Leszkowicz A, Manderville RA (2007). Ochratoxin: An overview on toxicity and carcinogenicity in animals and human. Mol Nutr Food Res., 51:61-99.
6. Narayanan P (1999). Common structural elements in 'scorpion-toxin' type proteins. J Postgrad Med., 45(1):23-27.
7. Martins JC, Zhang W, Tartar A (1990). Solution conformation of leiurotoxin I (Scyllatoxin) by 1H nuclear magnetic resonance: Resonance assignment and secondary structure. FEBS Lett., 260:249-253.
8. Zhu Q, Liang S, Martin L, Gasparini S, Me´nez A, Vita C (2002). Role of disulfide bonds in folding and activity of leiurotoxin i: just two disulfides suffice. Biochemistry. 41:11488-11494.
9। Cavin C, Delatour T, Marin-Kuan M, Holzhäuser D, Higgins L, Bezençon C, Guignard G, Junod S, Richoz-Payot J, Gremaud E, Hayes JD, Nestler S, Mantle P, Schilter B (2007). Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity. Toxicol Sci., 96:30-39.

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