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PubMed2000

The gene cloning and sequencing of Bm-12, a chlorotoxin-like peptide from the scorpion Buthus martensi Karsch.

According to the known amino acid sequence of Bm-12, a short chain insect neurotoxin from the venom of the scorpion Buthus martensi Karsch (BmK) with considerable primary sequence homology to chlorotoxin, the gene specific primers were designed and synthesized for 3' and 5'RACE (Rapid Amplification of cDNA Ends). The two partial cDNA fragments obtained by 3' and 5'RACE were cloned and sequenced, and the full length cDNA sequence of Bm-12 was then completed by overlapping these two partial cDNA sequences. The predicted amino acid sequence consists of 59 amino acid residues including a putative signal peptide of 24 residues and a mature toxin of 35 residues. The predicted amino acid sequence of Bm-12 was almost consistent with the determined, different only in one residue at position 27, Lys was replaced by Gly. Based on the determined cDNA sequence, and using the total DNA isolated from the scorpion venom glands as a template, the genomic DNA of Bm-12 was also amplified by PCR and sequenced. The genomic DNA sequence revealed an intron of 93 bp present within the signal peptide region.

Amino Acid Sequence↗
PubMed1999

Scorpion toxins as tools for studying potassium channels.

The search for peptidyl inhibitors of K+ channels is a very active area of investigation. In addition to scorpion venoms, other venom sources have been investigated; all of these sources have yielded novel peptides with interesting properties. For instance, spider venoms have provided peptides that block other families of K+ channels (e.g., Kv2 and Kv4) that act via mechanisms which modify the gating properties of these channels. Such inhibitors bind to a receptor on the channel that is different from the pore region in which the peptides discussed in this chapter bind. In fact, it is possible to have a channel occupied simultaneously by both inhibitor types. It is expected that many of the methodologies concerning peptidyl inhibitors from scorpion venom, which have been developed in the past and outlined above, will be extended to the new families of K+ channel blockers currently under development.

Amino Acid Sequence↗
PubMed1982

Diagnostic cardiac premonitory signs and symptoms of red scorpion sting.

The symptoms and signs of 51 patients with a history of scorpion sting were studied. Acute pulmonary oedema with peripheral circulatory failure due to myocarditis developed in 10. Pulmonary oedema appeared within thirty minutes to ten hours after the sting. 5 out of 7 male patients in whom pulmonary oedema subsequently developed presented with priapism. Profuse sweating, mydriasis, vomiting, and peripheral circulatory failure were also seen, and, in 1 patient, the clinical picture was suggestive on pancreatitis. The remaining 40 patients has severe local pain only and no subsequent cardiac manifestations. There appears to be a positive correlation between occurrence of priapism in a male and the later development of cardiac manifestations after a scorpion sting.

Acute Disease↗
PubMed2002

Molecular localization and crossreactivity of two epitopes of noxiustoxin from scorpion Centruroides noxius, identified by a panel of monoclonal antibodies and peptide mimotopes.

Mimotopes derived from peptide phage display libraries may reproduce basic functions of epitopes including their antigenicity. In case of toxins, this property makes phage displayed mimotopes highly specific vaccine components free of the toxicity. To explore the potential of mimotopes for vaccine development, their ability of substituting the whole toxin molecule deserves a detailed characterization. We used mimotopes of noxiustoxin (NTX), a neurotoxin from scorpion Centruroides noxius, for studying its epitopes recognized by a panel of six monoclonal antibodies (mAbs), as well as their crossreactivity with homologous toxins from other species of the Centruroides genus. Although competitive (displacement) immunoassay showed that all six mAbs inhibit each other for binding to whole NTX molecule, the mimotopes used as specific probes allowed separation of the mAbs into two functional groups recognizing distinct non-overlapping epitopes mapped on the opposite sites of the three-dimensional structure of the toxin. The use of mimotopes permitted a precise specificity analysis of a panel of antibodies raised against this toxin, that may be very important for immunological characterization of other scorpion toxins and for vaccine development.

Amino Acid Sequence↗
PubMed2000

The blocking effect of BmP02, one novel short-chain scorpion peptide on transient outward K(+) channel of adult rat ventricular myocyte.

Two components F-2-7-4 and F-2-7-5, each composed of 28 amino acid residues, were purified from the venom of Buthus martensi Karsch by an opportune procedure with cation-exchange column chromatography and repeated HPLC. Both components were totally accounted to about 0. 88% dry weight of the crude venom. The molecular weights of both components were determined to be 2950 and 2935 by mass spectrometry, which were fully coincidence with that of the known novel short-chain peptides BmP02 and BmP03, respectively [Romi-Lebrun R, Martin-Eauclaire M-F, Escoubas P, Wu FQ, Lebrun B, Hisada M, Nakajima T. Characterization of four toxins from Buthus martensi scorpion venom, which act on apamin-sensitive Ca(2+)-activated K(+) channels. Eur J Biochem 1997;145:457-464]. In addition, the sequence of component F-2-7-4 was analyzed to be the same as that of BmP02. The components F-2-7-4 and F-2-7-5 purified in this study were, thus, finally distinguished to be BmP02 and BmP03 from the same venom. Using whole cell patch-clamp recording, it was found that BmP02 diminished the current of transient outward K(+) channel in adult rat ventricular myocyte in a concentration-dependent manner. The inhibitory effect was reversible. Dynamic studies showed that the activation, inactivation and recovery processes of the transient outward K(+) channel were not changed significantly after applying of BmP02. In addition, when BmP02 was applied to guinea pig ventricular myocyte, both delayed and inward rectified K(+) currents showed no change compared with the control. The results suggest strongly that BmP02 or -like peptides from scorpion venom may provide a useful probe for the studying of transient outward K(+) channel in rat ventricular myocyte.

Amino Acid Sequence↗
PubMed2003

Isolation of scorpion (Androctonus amoreuxi) putative alpha neurotoxins and parallel cloning of their respective cDNAs from a single sample of venom.

The venoms of buthid scorpions are known to contain basic, single-chain protein toxins (alpha toxins) consisting of 60-70 amino acid residues that are tightly folded by four disulfide bridges. Here we describe isolation and sequencing of three novel putative alpha toxins (AamH1-3) from the venom of the North African scorpion, Androctonus amoreuxi, and subsequent cloning of their precursor cDNAs from the same sample of venom. This experimental approach can expedite functional genomic analyses of the protein toxins from this group of venomous animals and does not require specimen sacrifice for cloning of protein toxin precursor cDNAs.

Amino Acid Sequence↗
PubMed1999

Continuous intravenous midazolam infusion for Centruroides exilicauda scorpion envenomation.

STUDY OBJECTIVE: We sought to describe the effects of continuous intravenous midazolam infusion as therapy for severe bark scorpion (Centruroides exilicauda) envenomation. METHODS: A retrospective chart review from July 1, 1993, through January 1, 1998, identified all patients treated at a university hospital with International Classification of Diseases, Ninth Revision, codes 989.5 (toxic effect of venom) or E905.2 (scorpion sting causing poisoning). By using standardized collection forms, data were extracted from the medical record of every patient who had a grade III or IV envenomation and was treated with a continuous intravenous midazolam infusion. RESULTS: Our search identified 104 patients; 34 had grade III or IV envenomation. Of these, 33 were treated in the ICU with continuous intravenous midazolam infusion. Median patient age was 4 years (range, 1 to 68 years). Midazolam dosage was adjusted to induce a light sleep state to control agitation and involuntary motor activity. The median amount of midazolam resulting in the first recorded decrease in agitation and involuntary motor activity was 0.30 mg/kg (range, 0.03 to 1.76 mg/kg). This first evidence of clinical improvement was recorded as 1.00 hour (median), with a range of 0.00 to 3.75 hours. The initial midazolam infusion rate was 0.10 mg x kg(-1) x h(-1) (median), with a range of 0.01 to 0.31 mg x kg(-1) x h(-1). The maximal midazolam infusion rate was 0.30 mg x kg(-1) x h(-1) (median), with a range of 0.06 to 1.29 mg x kg(-1) x h(-1). The median time until the maximal midazolam infusion rate was 2.5 hours (range, 0.00 to 8.50 hours). The median duration of infusion was 9. 50 hours (range, 4.25 to 20.50 hours). The median length of stay in the ICU was 15.17 hours (range, 6.0 to 28.0 hours), and 85% of patients were discharged directly home. All patients had resolution of abnormal motor activity and agitation during their midazolam infusion. Transient hypoxemia without evidence of end-organ dysfunction was documented in 4 patients during midazolam therapy. CONCLUSION: A continuous intravenous midazolam infusion can be a safe, effective, and readily available treatment option for patients with grade III or IV C exilicauda envenomation.

Adolescent↗
PubMed1997

Isolation, characterization and comparison of a novel crustacean toxin with a mammalian toxin from the venom of the scorpion Centruroides noxius Hoffmann.

A novel crustacean-specific toxin, Cn5, containing 66 amino acid residues was isolated from the venom of the scorpion Centruroides noxius Hoffmann. It is stabilized by four disulfide bridges, formed between Cys12-Cys65, Cys16-Cys41, Cys25-Cys46 and Cys29-Cys48. Toxicity tests revealed that Cn5 is a toxin that affects arthropods but not mammals. However, at high concentrations, Cn5 does displace the mammal-specific toxin Cn2 from rat brain synaptosomes. The concentration of Cn5 that produces half-maximal inhibition (IC50) was estimated to be 100 microM. Sequence comparison of Cn5 with toxin Cn2, a mammal-specific toxin from the same scorpion, showed the presence of two sequence stretches, at positions 30 to 38 and 49 to 58, where the majority of the differences are concentrated. On the three-dimensional structure of Cn5 it is demonstrated that these two sequence stretches form a continuous surface region near the site thought to bind to the sodium channel. We assume that this region might be implicated in determining species specificity.

Amino Acid Sequence↗
PubMed1995

Promoter structure and intron-exon organization of a scorpion alpha-toxin gene.

The Androctonus australis scorpion venom contains alpha-toxins for which the complementary DNAs have been cloned [Bougis et al. (1989) J. Biol. Chem. 264, 19259-19265], targeting with high affinity the voltage-sensitive sodium channel. From a genomic library made of this species of scorpion, we have cloned and characterized the gene encoding the toxin AaH I'. The gene transcriptional unit is 793 base pairs long, and the gene has a single intron of 425 base pairs located near the end of the signal peptide of the toxin precursor. The transcription initiation site was determined by primer extension and corresponded to the nucleotide sequence AACAA. Upstream, a promoter region has been identified with positive acting sequence elements at consensus positions, such as a CCAAT box and a TATA box. In addition, putative elements for binding the transcriptional factors MAT-alpha 2, Pit-1, and IEF1 are also present. Analysis of DNA curvature by computer modeling revealed a strong bending centered around the transcription initiation site of the gene. The bending angle (61 degrees) estimated experimentally using polyacrylamide gel electrophoresis correlates well with the value predicted by computer modeling (66 degrees). Other minor deflections of the helix axis cooperate for an overall curvature of nearly 90 degrees, which is significantly stronger than similar structures already reported in eukaryotic cells. It is worth noting that the grooves relative to the CCAAT box and the TATA box lie along the inside of the DNA curve. This observation is in agreement with the previously reported correlation between DNA bending and promoter function.

Amino Acid Sequence↗
PubMed1995

Determination of the three-dimensional solution structure of noxiustoxin: analysis of structural differences with related short-chain scorpion toxins.

The 3D structure of noxiustoxin, the first identified scorpion toxin acting on K+ channels, has been elucidated by NMR and molecular modeling. Thirty-nine solution structures were calculated using 572 distance and 42 dihedral restraints. The average atomic rms deviation between the refined structures and the mean structure is 0.75 A for the backbone atoms. Noxiustoxin adopts a alpha/beta scaffold constituted of a three-stranded beta-sheet (residues 2-3, 25-30, 33-38) linked to a helix (residues 10-20) through two disulfide bridges. A comparison between the 3D structure of noxiustoxin and those of other structurally and functionally related scorpion toxins (charybdotoxin, PO5-NH2, kaliotoxin) revealed a bending capacity of the helix and a variability in the relative orientations between the helix and the beta-sheet. These two features highlight the plasticity of the alpha/beta scaffold and offer a structural explanation for the capacity of the fold to accommodate an additional alanine residue in the Gly-x-Cys pattern of a previously proposed consensus sequence [Bontems et al. (1991) Science 254, 1521-1523]. Our structural data also emphasize the possibility that the beta-sheet of NTX is implicated in the capacity of NTX to recognize voltage-dependent K+ channels.

Amino Acid Sequence↗
PubMed1994

Primary and NMR three-dimensional structure determination of a novel crustacean toxin from the venom of the scorpion Centruroides limpidus limpidus Karsch.

A crustacean-specific toxin from the Mexican scorpion Centruroides limpidus limpidus was purified, and its primary sequence was determined, including disulfide bonds. This toxin has 66 amino acid residues and is stabilized by four disulfide bridges (Cys12-Cys65, Cys16-Cys41, Cys25-Cys46, and Cys29-Cys48). A detailed nuclear magnetic resonance structure of this protein was obtained using a combination of two-dimensional proton NMR experiments. The NMR parameters that gave 69 dihedral restraints and 418 distance constraints were used in molecular dynamics calculations in order to determine the solution conformation of the toxin. It is composed of a short alpha-helix and a three-stranded antiparallel beta-sheet. Although the regular secondary structure of this crustacean toxin is common to the structural motif of other scorpion toxins, detailed conformational analysis was performed in order to highlight structural features that might be responsible for the differential modulation of the toxin on sodium channels of distinct tissues: mammalian versus crustacean.

Amino Acid Sequence↗
PubMed2005

Genetic polymorphism and expression of a highly potent scorpion depressant toxin enable refinement of the effects on insect Na channels and illuminate the key role of Asn-58.

We isolated from the venom of the scorpion Leiurus quinquestriatus hebraeus an extremely active anti-insect selective depressant toxin, Lqh-dprIT(3). Cloning of Lqh-dprIT(3) revealed a gene family encoding eight putative polypeptide variants (a-h) differing at three positions (37A/G, 50D/E, and 58N/D). All eight toxin variants were expressed in a functional form, and their toxicity to blowfly larvae, binding affinity for cockroach neuronal membranes, and CD spectra were compared. This analysis links Asn-58, which appears in variants a-d, to a toxin conformation associated with high binding affinity for insect sodium channels. Variants e-h, bearing Asp-58, exhibit a different conformation and are less potent. The importance of Asn-58, which is conserved in other depressant toxins, was further validated by construction and analysis of an N58D mutant of the well-characterized depressant toxin, LqhIT(2). Current and voltage clamp assays using the cockroach giant axon have shown that despite the vast difference in potency, the two types of Lqh-dprIT(3) variants (represented by Lqh-dprIT(3)-a and Lqh-dprIT(3)-e) are capable of blocking the action potentials (manifested as flaccid paralysis in blowfly larvae) and shift the voltage dependence of activation to more negative values, which typify the action of beta-toxins. Moreover, the stronger and faster shift in voltage dependence of activation and lack of tail currents observed in the presence of Lqh-dprIT(3)-a suggest an extremely efficient trapping of the voltage sensor compared to that of Lqh-dprIT(3)-e. The current clamp assays revealed that repetitive firing of the axon, which is reflected in contraction paralysis of blowfly larvae, can be obtained with either the less potent Lqh-dprIT(3)-e or the highly potent Lqh-dprIT(3)-a at more negative membrane potentials. Thus, the contraction symptoms in flies are likely to be dominated by the resting potential of neuronal membranes. This study clarifies the electrophysiological basis of the complex symptoms induced by scorpion depressant toxins in insects, and highlights for the first time molecular features involved in their activity.

Amino Acid Sequence↗
PubMed1997

Three-dimensional structure of toxin OSK1 from Orthochirus scrobiculosus scorpion venom.

A 600 MHz 1H NMR study of toxin OSK1, blocker of small-conductance Ca2+-activated K+ channels, is presented. The unambiguous sequential assignment of all the protons of the toxin was obtained using TOCSY, DQF-COSY, and NOESY experiments at pH 3.0 (10, 30, and 45 degrees C) in aqueous solution. 3J(N alpha), 3J(alphabeta) vicinal spin coupling constants were determined in high-resolution spectra. The cross-peak volumes in NOESY spectra and the coupling constants were used to define the local structure of the protein by the program HABAS and to generate torsion angle and interproton distance constraints for the program DIANA. Hydrogen-deuterium exchange rates of amide protons showed possible locations of hydrogen bonds. The hydrogen bond acceptors and disulfide bridges between residues 8-28, 14-33, and 18-35 were determined when analyzing distance distribution in preliminary DIANA structures. All constraints were used to obtain a set of 30 structures by DIANA. The resulting rms deviations over 30 structures are 1.30 A for the heavy atoms and 0.42 A for the backbone heavy atoms. The structures were refined by constrained energy minimization using the SYBYL program. Their analysis indicated the existence of the alpha-helix (residues 10-21) slightly distorted at the Cys14 residue, two main strands of the antiparallel beta-sheet (24-29, 32-38), and the extended fragment (2-6). The motif is stabilized by the disulfide bridges in the way, common to all known scorpion toxins. Using the fine spatial toxin structure, alignment of the homologues, mutagenesis analysis, and comparison of scorpion toxin family functions, we delineate some differences significant for the toxin specificity.

Amino Acid Sequence↗
PubMed2001

A new insect neurotoxin AngP1 with analgesic effect from the scorpion Buthus martensii Karsch: purification and characterization.

An insect toxin named BmK AngP1 was purified from the venom of the scorpion Buthus martensii Karsch (BmK). It also shows an evident analgesic effect on mice, but is interestingly devoid of mammalian toxicity. Bioassay showed that the CPU value of AngP1 was 0.01 microg/body ( approximately 30 mg) for the excitatory insect toxicity and 43.0% inhibition efficiency for analgesia at a dose of 5 mg/kg. However, even at the dosage of 10 mg/kg no detectable toxicity on mice could be found. The isoelectric point (pI) value for AngP1 was 4.0, and its molecular mass analyzed by MALDI-TOF MS was 8141.0. The first 15 N-terminal residues of AngP1 were determined by Edman degradation and showed high similarity to that of other excitatory scorpion insect toxins. The circular dichroism spectroscopy measured on a JASCO J-720 system showed that there were 10.4% alpha-helix, 46.2% beta-strand and 14.1% turn structure in this peptide. Under two conditions single crystals of AngP1 were obtained.

Amino Acid Sequence↗
PubMed2003

Purification of two depressant insect neurotoxins and their gene cloning from the scorpion Buthus martensi Karsch.

Insect-specific neurotoxins are important components of scorpion venoms. In this study, two toxins from the scorpion Buthus martensi Karsch (BmK) were purified. They shared high sequence homology with other depressant insect toxins and were designated BmK ITa and BmK ITb, respectively. They were able to suppress the action potential of cockroach isolated axon, which is due to a decrease in the peak sodium current. Furthermore, the effect of BmK ITb was lower than that of BmK ITa, and some of the electrophysiological characteristics of BmK ITb even resemble that of excitatory insect toxins. Their primary structures were determined by N-terminal partial sequence determination and cDNA cloning. The differences in their structures, especially the 31st residues, may result in the unique activity of BmK ITb.

Amino Acid Sequence↗
PubMed2005

A new type of scorpion Na+-channel-toxin-like polypeptide active on K+ channels.

We have purified and characterized two peptides, named KAaH1 and KAaH2 (AaH polypeptides 1 and 2 active on K+ channels, where AaH stands for Androctonus australis Hector), from the venom of A. australis Hector scorpions. Their sequences contain 58 amino acids including six half-cysteines and differ only at positions 26 (Phe/Ser) and 29 (Lys/Gln). Although KAaH1 and KAaH2 show important sequence similarity with anti-mammal beta toxins specific for voltage-gated Na+ channels, only weak beta-like effects were observed when KAaH1 or KAaH2 (1 microM) were tested on brain Nav1.2 channels. In contrast, KAaH1 blocks Kv1.1 and Kv1.3 channels expressed in Xenopus oocytes with IC50 values of 5 and 50 nM respectively, whereas KAaH2 blocks only 20% of the current on Kv1.1 and is not active on Kv1.3 channels at a 100 nM concentration. KAaH1 is thus the first member of a new subfamily of long-chain toxins mainly active on voltage-gated K+ channels. NMR spectra of KAaH1 and KAaH2 show good dispersion of signals but broad lines and poor quality. Self-diffusion NMR experiments indicate that lines are broadened due to a conformational exchange on the millisecond time scale. NMR and CD indicate that both polypeptides adopt a similar fold with alpha-helical and b-sheet structures. Homology-based molecular models generated for KAaH1 and KAaH2 are in accordance with CD and NMR data. In the model of KAaH1, the functionally important residues Phe26 and Lys29 are close to each other and are located in the alpha-helix. These residues may constitute the so-called functional dyad observed for short alpha-KTx scorpion toxins in the beta-sheet.

Amino Acid Sequence↗
PubMed2005

An unusual fold for potassium channel blockers: NMR structure of three toxins from the scorpion Opisthacanthus madagascariensis.

The Om-toxins are short peptides (23-27 amino acids) purified from the venom of the scorpion Opisthacanthus madagascariensis. Their pharmacological targets are thought to be potassium channels. Like Csalpha/beta (cystine-stabilized alpha/beta) toxins, the Om-toxins alter the electrophysiological properties of these channels; however, they do not share any sequence similarity with other scorpion toxins. We herein demonstrate by electrophysiological experiments that Om-toxins decrease the amplitude of the K+ current of the rat channels Kv1.1 and Kv1.2, as well as human Kv1.3. We also determine the solution structure of three of the toxins by use of two-dimensional proton NMR techniques followed by distance geometry and molecular dynamics. The structures of these three peptides display an uncommon fold for ion-channel blockers, Csalpha/alpha (cystine-stabilized alpha-helix-loop-helix), i.e. two alpha-helices connected by a loop and stabilized by two disulphide bridges. We compare the structures obtained and the dipole moments resulting from the electrostatic anisotropy of these peptides with those of the only other toxin known to share the same fold, namely kappa-hefutoxin1.

Amino Acid Sequence↗
PubMed1996

Toxic peptides and genes encoding toxin gamma of the Brazilian scorpions Tityus bahiensis and Tityus stigmurus.

Seven toxic peptides from the venom of Tityus bahiensis and Tityus stigmurus was isolated and sequenced, five of them to completion. The most abundant peptide from each of these two species of scorpion was 95% identical with that of toxin gamma from the venom of Tityus serrulatus. They were consequently named gamma-b and gamma-st respectively. The genes encoding these new gamma-like peptides were cloned and sequenced by utilizing oligonucleotides synthesized according to known cDNA sequences of toxin gamma, and amplified by PCR on templates of DNA purified from both T. bahiensis and T. stigmurus. They contain an intron of approx. 470 bp. Possible mechanisms of processing and expressing these peptides are discussed, in view of the fact that glycine is the first residue of the N-terminal sequence of T. stigmurus, whereas lysine is the residue at position 1 of toxin gamma from T. serrulatus and T. bahiensis. In addition, chemical characterization of the less abundant toxic peptides showed the presence of at least four distinct families of peptides in all three species of the genus Tityus studied. There is a large degree of similarity among peptides from different venoms of the same family. By using specific horse and rabbit antisera, the venoms of T. bahiensis, T. serrulatus and T. stigmurus were compared. They showed an extended degree of cross-reactivity. Thus these three species of scorpion have similar toxic components, the genes of which are similarly organized, processed and expressed.

Amino Acid Sequence↗