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76862-65-2,芋螺毒素,H2N-Glu-Cys-Cys-Asn-Pro-Ala-Cys-Gly-Arg-His-Tyr-Ser-Cys-NH2(Disulfide Bridge:Cys2-Cys7 & Cys3-Cys13),H2N-ECCNPACGRHYSC-NH2(Disulfide Bridge:C2-C7 & C3-C13),杭州专肽生物的产品

芋螺毒素

编号:134039

CAS号:76862-65-2

单字母:H2N-ECCNPACGRHYSC-NH2(Disulfide Bridge:C2-C7 & C3-C13)

纠错
  • 编号:134039
    中文名称:芋螺毒素
    英文名:alpha-ConotoxinGI
    CAS号:76862-65-2
    单字母:H2N-ECCNPACGRHYSC-NH2(Disulfide Bridge:C2-C7 & C3-C13)
    三字母:H2N-Glu-Cys-Cys-Asn-Pro-Ala-Cys-Gly-Arg-His-Tyr-Ser-Cys-NH2(Disulfide Bridge:Cys2-Cys7 & Cys3-Cys13)
    氨基酸个数:13
    分子式:C55H80N20O18S4
    平均分子量:1437.61
    精确分子量:1436.48
    等电点(PI):11.34
    pH=7.0时的净电荷数:6.09
    平均亲水性:-0.17272727272727
    疏水性值:-0.51
    外观与性状:白色粉末状固体
    消光系数:1490
    来源:人工化学合成,仅限科学研究使用,不得用于人体。
    纯度:95%、98%
    盐体系:可选TFA、HAc、HCl或其它
    生成周期:2-3周
    储存条件:负80℃至负20℃
    标签:二硫键环肽    芋螺毒素(Conotoxins)   

  • 二硫键广泛存在与蛋白结构中,对稳定蛋白结构具有非常重要的意义,二硫键一般是通过序列中的2个Cys的巯基,经氧化形成。
     

    形成二硫键的方法很多:空气氧化法,DMSO氧化法,过氧化氢氧化法等。
     

    二硫键的合成过程,  可以通过Ellman检测以及HPLC检测方法对其反应进程进行监测。  
       

    如果多肽中只含有1对Cys,那二硫键的形成是简单的。多肽经固相或液相合成,然后在pH8-9的溶液中进行氧化。      
     

    当需要形成2对或2对以上的二硫键时,合成过程则相对复杂。尽管二硫键的形成通常是在合成方案的最后阶段完成,但有时引入预先形成的二硫化物是有利于连合或延长肽链的。通常采用的巯基保护基有trt, Acm, Mmt, tBu, Bzl, Mob, Tmob等多种基团。我们分别列出两种以2-Cl树脂和Rink树脂为载体合成的多肽上多对二硫键形成路线:
     

    二硫键反应条件选择    
     

     二硫键即为蛋白质或多肽分子中两个不同位点Cys的巯基(-SH)被氧化形成的S-S共价键。 一条肽链上不同位置的氨基酸之间形成的二硫键,可以将肽链折叠成特定的空间结构。多肽分 子通常分子量较大,空间结构复杂,结构中形成二硫键时要求两个半胱氨酸在空间距离上接近。 此外,多肽结构中还原态的巯基化学性质活泼,容易发生其他的副反应,而且肽链上其他侧链 也可能会发生一系列修饰,因此,肽链进行修饰所选取的氧化剂和氧化条件是反应的关键因素, 反应机理也比较复杂,既可能是自由基反应,也可能是离子反应。      

    反应条件有多种选择,比如空气氧化,DMSO氧化等温和的氧化过程,也可以采用H2O2,I2, 汞盐等激烈的反应条件。
     

    空气氧化法: 空气氧化法形成二硫键是多肽合成中最经典的方法,通常是将巯基处于还原态的多肽溶于水中,在近中性或弱碱性条件下(PH值6.5-10),反应24小时以上。为了降低分子之间二硫键形成的可能,该方法通常需要在低浓度条件下进行。
     

    碘氧化法:将多肽溶于25%的甲醇水溶液或30%的醋酸水溶液中,逐滴滴加10-15mol/L的碘进行氧化,反应15-40min。当肽链中含有对碘比较敏感的Tyr、Trp、Met和His的残基时,氧化条件要控制的更精确,氧化完后,立即加入维生素C或硫代硫酸钠除去过量的碘。 当序列中有两对或多对二硫键需要成环时,通常有两种情况:
     

    自然随机成环:       序列中的Cys之间随机成环,与一对二硫键成环条件相似;
     

    定点成环:       定点成环即序列中的Cys按照设计要求形成二硫键,反应过程相对复杂。在 固相合成多肽之前,需要提前设计几对二硫键形成的顺序和方法路线,选择不同的侧链 巯基保护基,利用其性质差异,分步氧化形成两对或多对二硫键。       通常采用的巯基保护 基有trt, Acm, Mmt, tBu, Bzl, Mob, Tmob等多种基团。

    Definition
    The conotoxins are paralytic poisons from Pacific cone snails that block the transmission of a nerve impulse from the nerve to the muscle at the neuromuscular junction.

    Discovery
    Kohn in 1976 studied cone snails, the venomous predators. Most Conus use their venoms for multiple purposes, including prey capture and defense. All 500 living species of cone snails have a highly sophisticated venom production apparatus and delivery system. They have specialized teeth, which in effect serve both as harpoon and disposable hypodermic needle for venom delivery 1,2,3.

    Bulaj G et al., in 2003 demonstrated that the correct folding of a Conus peptide is facilitated by a posttranslationally modified amino acid, γ-carboxyglutamate. In addition, they showed that multiple isoforms of protein disulfide isomerase are major soluble proteins in Conus venom duct extracts. The results provided evidence for the type of adaptations required before cone snails could systematically explore the specialized biochemical world of ‘‘microproteins’’ that other organisms have not been able to systematically access 4.  

    Structural Characteristics
    Most conotoxin protein genes initially produce a translation product that is 100 amino acids in length, a size sufficient to allow conventional folding by multiple intramolecular interactions. Toxin proteins found in venoms are generally smaller (50–100 aa), with additional stability provided by disulfide bonds. In effect, the cone snails have extended this tendency one step further, with some venom peptide superfamilies being the smallest highly structured but functionally diverse classes of gene products known (12–20 aa with two to three disulfide bonds). Conopeptide evolution has resulted in a large diversity of biological function being generated in each conotoxin superfamily. Thus, Conus peptide superfamilies are like other major classes of proteins produced through gene translation: structural and functional novelty can evolve, and thus, conotoxins are in many respects ‘‘microproteins’’ and differ from more conventional unstructured peptides. Each conotoxin superfamily has a characteristic arrangement of cysteine residues, which is assembled into a particular disulfide bonding configuration (the ‘‘disulfide framework’’). The latter is the primary determinant of polypeptide backbone structure. Despite hypermutation of the amino acids between Cys residues, the disulfide framework generally remains conserved within a superfamily, generating a characteristic scaffold. In principle, for peptides with six Cys residues (characteristic of at least four conotoxin superfamilies) there are 15 different of Conus peptides could have evolved: (i) specialized intramolecular interactions may stabilize conformation, and (ii) intermolecular interactions with extrinsic factors, perhaps within the endoplasmic reticulum (ER), may promote appropriate folding pathways within the ER  4.  Conotoxins (or conopeptides) are named in a reasonably systemic manner: A Greek letter prefix denoting the structural class (α,μ,ω,δ,κ). Naturally occurring conotoxins include conotoxin GI, GIA and GII. In conotoxin GI, U is Glu, V4 is Asn, V5 is Pro, V6 is Ala, W is Gly, X is Arg, Y is His, Z is Tyr, V12 is Ser and R is --NH2.

    Mode of Action
    Many conotoxin have been found to be highly selective for a diverse range of mammalian ion channels and receptors associated with pain signaling pathways. All of these conotoxins act by preventing neuronal communication, but each targets a different aspect of the process to achieve this. The α-conotoxins target nicotinic ligand gated channels, the μ-conotoxins target the voltage-gated sodium channels and the ω-conotoxins target the voltage-gated calcium channels. α-conotoxin acts on nicotinic acetylcholine receptors. The effect is a paralysis similar to that seen with curare. δ-conontoxins acts on sodium channels. Unlike μ-conotoxins, they slow the inactivation of the sodium channel. μ-conotoxin acts on sodium channels. This is also the target for saxitoxin and tetrodotoxin and the effects are similar. κ-conotoxin acts on potassium channels. They are also known as shaker peptides because they block a potassium channel known as "Shaker" and as a result they induce tremors. ω-conotoxin acts on calcium channels associated with nerve impulse transmission at the neuromuscular junction. Conantonkins acts on NMDA glutamate receptors. This blocks nerve impulses that use glutamic acid rather than acetylcholine as the neurotransmitter.

    Functions

    Individual conotoxins vary greatly in lethality towards mammals. Some of the tremor inducing omega conotoxins is not lethal, whereas others of the same group are lethal at low levels.

    The toxicity in rats and mice is usually reported for the toxins administered intracranially (into the brain). Some α-conotoxins have lethal doses as low as 25 μgrams/kg for mouse.

    Synergistic interaction, the toxicity of the complex mixture of peptides that is cone snail venom may be much greater than the sum of its parts because of the synergistic interaction between toxins acting on different aspects of neural function 5.

    At neuromuscular junction, conotoxins were found to act at the neuromuscular junction to inhibit the passage of an excitatory impulse across the junction, but which had no effect on muscle action potential.

    Pharmacologic agents, their small size, structural stability, and target specificity make them attractive pharmacologic agents 6.

    References

    1.     Kohn AJ, Nybakken JW, Mool V (1972). Radula tooth structure of the gastropod Conus imperialis. Science, 176:49-51.

    2.     Kohn AJ, Saunders PR, Wiener S (1960). Preliminary studies on the venom of the marine snail. Conus. Ann NY Acad Sci., 90:706-725.

    3.     Kohn AJ (1976). Chronological analysis of the species of Conus described during the 18 century. Zool J Linn Soc Lond., 58:39-59.

    4.     Bulaj G, Buczek O, Goodsell I, Jimenez EC, Kranski J, Nielsen JS, Garrett JE, Olivera BM (2003). Efficient oxidative folding of conotoxins and the radiation of venomous cone snails. PNAS., 100(2):14562–14568.

    5.     Terlau H, Olivera BM (2004). Conus venoms: a rich source of novel ion channels-targeted peptides. Physiol. Rev., 84:41-68.

    6.     Jones RM, Cartier GE. McIntosh JM, Bulaj G, Farrar VE, Olivera BM (2001). Composition and therapeutic utility of conotoxins from genus Conus. Expert Opinion on Therapeutic Patents, 11(4):603-623.

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