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Hainantoxin (HNTX) is a neurotoxic protein, part of the venom from the Chinese bird spider Ornithoctonus hainana, that specifically inhibits the tetrodotoxin-sensitive Voltage-gated sodium channels, thereby causing blockage of neuromuscular transmission which results in paralyzing its pray.[1][2]There are thirteen subgroups discovered (HNTX-I – HNTX-XIII), but only HNTX-I, -II, -III, -IV and -V are well described.[3]
Etymology
editThe hainantoxin is a toxin from the Chinese bird spider O. hainana. This spider lives in a province in southern China called Hainan.[2][4]
Source
editHNTX-I, HNTX-III, HNTX-IV and HNTX-V are isolated from the Chinese bird spider Ornithoctonus hainana.[1][2][4][5][6][7][8][9][10][11] HNTX-II is obtained from the spider Haplopelma hainanum.[12]
Chemistry
editStructure
editHNTX-I
editThere are 33 amino acid residues in HNTX-I, with a total molecular weight of 3605-3608 Da. HNTX-I further contains six cysteines, three disulfide bonds (Cys2 and Cys17, Cys9 and Cys22, and Cys16 and Cys29) and amidated c-terminal. HNTX-I is also part of the inhibitor cystine knot structural family and contains a short triple-stranded anti-parallel beta-sheet and four beta-turns.[4] The amino acid residues His28 and Asp26 are responsible for the bioactive part of HNTX-I.[13]
HNTX-II
editHNTX-II has a molecular weight of 4253 Da and contains 37 amino acid residues with six cysteines that form three disulfide bonds. The complete sequence of amino acids in HNTX-II is NH2-LFECSV SCEIEK EGNKD CKKKK CKGGW KCKFN MCVKV-COOH.[12]
HNTX-III
editThe structure of HNTX-III consists of 33-35 amino acid residues, which form a beta-sheet with connections between Asp7 and Cys9, Tyr21 and Ser23, and Lys27 and Val30.[6] The six cysteine amino acids form three disulfide bonds . Furthermore, an amidated c-terminal is present in HNTX-III. [6][8]
HNTX-IV
editHNTX-IV has 35 amino acid residues with a total molecular weight of 3989 Da and the first strand consists of an antiparallel beta-sheet.[11] Furthermore HNTX-IV contains three disulfide bonds arranged in a cystine knot motif.[10] The complete sequence of amino acids in HNTX-IV is NH2-ECLGFG KGCNPS NDQCCK SSNLVC SRKHRW CKYEI-CONH2.[11] Lys 27, His28, Arg29 and Lys 32 are the neuroactive amino acid residues.[1][5][10]
HNTX-V
editHNTX-V consists of 35 amino acid residues, six cysteines and three disulfide bonds.[2] The whole amino acid residue sequence of HNTX-V is NH2-ECLGFG KGCNPS NDQCCK SANLVC SRKHRW CKYEI-COOH. At the active binding site of HNTX-V, Lys27 and Arg 29 are the most important.[2]
Family
editHNTX-III and HNTX-IV are part of the Huwentoxin-I family.[3][8] Toxins from the Huwentoxin-I family bind to site 1 on the sodium channels. Other subgroups of the Hainantoxin showed to bind at site 3 of the sodium channels.
Homology
editThe main component of the venom of O. hainana is HNTX-I.[12] HNTX-I – HNTX-V all contain three disulfide bonds. HNTX-I, HNTX-II and HNTX-V have six cysteines. The cystine knot motif is present in HNTX-I and HNTX-IV. Amidated c-terminals are present in HNTX-I and HNTX-III.
Table 1: Homology between five subtypes of the Hainantoxin
| Three disulfide bonds | Cystine knot motif | Amidated c-terminals | |
|---|---|---|---|
| HNTX-I | X | X | X |
| HNTX-II | X | ||
| HNTX-III | X | X | |
| HNTX-IV | X | X | |
| HNTX-V | X |
Target
editChannel
editThe Hainantoxin inhibits selectively the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channels (VGSCs).[1][5][6][9] Voltage-gated Ca2+ channels (VGCCs), tetrodotoxin-resistant (TTX-R) VGSCs and rectifier-delayed potassium channels are not affected by the Hainantoxin.[8] HNTX-I specifically blocks Nav1.2 and para/tipE channels expressed in Xenopus laevis oocytes, the African clawed frog. HNTX-I is a weak antagonist of the vertebrate TTX-S VGSCs, but it is more potent on insect VGSCs.[4][10]
Affinity
editFor the blockage of sodium channels, electrostatic interactions or hydrogen bonds are needed. Important for the electrostatic interaction is the presence of a positively charged region in the toxin, because the receptor site of the sodium channel contains a lot of negatively charged residues.[1][2] In HNTX-I, the positively charged residues and a vicinal hydrophobic patch have most influence on the binding to the sodium channels.[4] HNTX-IV has a positively charged patch containing the amino acids Arg26, Lys27, His28, Arg29 and Lys32, of which Lys27, Arg29 and Lys32 are the most important for interaction with the TTX-S VGSCs.[10][14] Also HNTX-V shows an interface of positively charged amino acids that are responsible for the binding with the TTX-S VGSCs, where also Lys27 and Arg29 are the most important. Subtle differences in the positively charged patch can result in altered electro-static properties, causing altered pharmacological effects.[4]
Table 2: IC50 values of five subgroups of the Hainantoxin
| IC50 | |
|---|---|
| HNTX-I | 6.8 mM on Nav1.2[10] |
| HNTX-III | 1.1 nM[8] |
| HNTX-IV | 44.6 nM[8] |
| HNTX-V | 42.3 nM[2] |
Mode of action
editThe Hainantoxin has a mode of action similar to α-scorpion toxins.[9] These toxins bind to site 3 on sodium channels and slow or block the inactivation of the sodium channels to prolong the time course of an action potential.[1][9] HNTX-II, HNTX-III and HNTX-V bind to site 3 and show to reduce the peak amplitude of sodium currents, but did not change the activation and inactivation kinetics of the VGSCs or the voltage threshold of inward currents.[2][8][14] HNTX-III and HNTX-IV cause a hyperpolarizing shift during steady-state and differ the rate of recovery from inactivation.[8] HNTX-I and HNTX-IV bind to site 1, similar to TTX, and thereby blocking the channel conductance. They do not alter the activation and inactivation kinetics.[1][4] Ion selectivity of the VGSCs is not changed by the hainantoxin.[8][9]
Toxicity
editSymptoms
editThe Hainantoxin causes symptoms in mice, rats and cockroaches. HNTX-I has no significant effect on insects or rats.[2][12] HNTX-III and HNTX-IV cause spontaneous contractions of the diaphragm muscle and the vas deferens smooth muscle of the rat.[8][9] HNTX-III and HNTX-IV are able to paralyze cockroaches, and HNTX-IV can even paralyze rats.[14]
LD50
editIntracerebroventricular injection in mice with HNTX-II has a LD50 of 1.41 μg/g. The intraperitoneal LD50 value of HNTX-IV in mice is 0.2mg/kg.[8][9] HNTX-III is 40 times more potent that HNTX-IV.[8]
Therapeutic use
editHNTX-III and HNTX-IV have an antagonistic effect on the toxin BMK-I, a toxic protein in the venom of the scorpion Buthus martensii.[8]
References
edit- ^ a b c d e f g Li D et al. Structure--activity relationships of hainantoxin-IV and structure determination of active and inactive sodium channel blockers. J Biol Chem. 2004 Sep 3;279(36):37734-40. Epub 2004 Jun 16.
- ^ a b c d e f g h i Xiao YC, Liang SP. Purification and characterization of Hainantoxin-V, a tetrodotoxin-sensitive sodium channel inhibitor from the venom of the spider Selenocosmia hainana. Toxicon. 2003 May;41(6):643-50.
- ^ a b http://www.uniprot.org/uniprot/?query=family:%22huwentoxin-1+family%22
- ^ a b c d e f g Li D, et al. Function and solution structure of hainantoxin-I, a novel insect sodium channel inhibitor from the Chinese bird spider Selenocosmia hainana. FEBS Lett. 2003 Dec 18;555(3):616-22.
- ^ a b c Xu X et al. Solid-phase synthesis and biological characterization of S12A-HNTX-IV and R29A-HNTX-IV: two mutants of hainantoxin-IV. Sheng Wu Gong Cheng Xue Bao. 2005 Jan;21(1):92-6.
- ^ a b c d Zeng XZ et al. Sequence-specific assignment of 1H-NMR resonance and determination of the secondary structure of Jingzhaotoxin-I. Acta Biochim Biophys Sin (Shanghai). 2005 Aug;37(8):567-72.
- ^ Honma T et al. Novel peptide toxins from acrorhagi, aggressive organs of the sea anemone Actinia equina. Toxicon. 2005 Dec 1;46(7):768-74. Epub 2005 Sep 23.
- ^ a b c d e f g h i j k l m Xiao Y, Liang S. Inhibition of neuronal tetrodotoxin-sensitive Na+ channels by two spider toxins: hainantoxin-III and hainantoxin-IV. Eur J Pharmacol. 2003 Sep 5;477(1):1-7.
- ^ a b c d e f g Xiao YC, Liang SP. Inhibition of sodium channels in rat dorsal root ganglion neurons by Hainantoxin-IV, a novel spider toxin. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2003 Jan;35(1):82-5.
- ^ a b c d e f Liu Y et al. A positively charged surface patch is important for hainantoxin-IV binding to voltage-gated sodium channels. J Pept Sci. 2012 Oct;18(10):643-9. doi: 10.1002/psc.2451. Epub 2012 Aug 27.
- ^ a b c XIONG Xia et al. Effects of Arg26 and Lys27 mutation on the bioactivity of HNTX-IV
- ^ a b c d Liu Z et al. Isolation and characterization of hainantoxin-IV, a novel antagonist of tetrodotoxin-sensitive sodium channels from the Chinese bird spider Selenocosmia hainana. Cell Mol Life Sci. 2003 May;60(5):972-8.
- ^ Nicholson GM. Insect-selective spider toxins targeting voltage-gated sodium channels. Toxicon. 2007 Mar 15;49(4):490-512. Epub 2006 Dec 5.
- ^ a b c Wang RL et al. Mechanism of action of two insect toxins huwentoxin-III and hainantoxin-VI on voltage-gated sodium channels. J Zhejiang Univ Sci B. 2010 Jun;11(6):451-7.