Molecular Mechanism for the Regulation of Microcystin Toxicity to Protein Phosphatase 1 by Glutathione Conjugation Pathway.
Molecular Mechanism for the Regulation of Microcystin Toxicity to Protein Phosphatase 1 by Glutathione Conjugation Pathway.
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谷胱甘肽缀合途径调节微囊藻毒素对蛋白磷酸酶 1 毒性的分子机制
DOI：
10.1155/2017/9676504
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发表时间：
2017
影响因子：
--
通讯作者：
Teng Y
中科院分区：
文献类型：
--
作者：
Zong W;Wang X;Du Y;Zhang S;Zhang Y;Teng Y
谷胱甘肽（GSH）缀合是调节针对蛋白磷酸酶的微囊藻毒素（MC）毒性的重要途径。为了探索GSH解毒的具体分子机制，根据前期研究合成、制备和纯化了两种典型的MC-GSH（来源于MCLR和MCRR）。然后，通过与原始毒素的比较，验证了MC-GSH对蛋白磷酸酶1的抑制作用降低。为了进一步阐明MC-GSHs解毒的分子机制，我们借助MOE分子模拟评估了MCs/MC-GSHs与PP1之间的相互作用。当 GSH 引入 MC 时，共价结合（Mdha7 与 Cys273）、疏水相互作用（Adda5 与 PP1）、氢键（尤其是 Lys2-Arg96 和 Glu6-Tyr272）、共价结合（Mdha7 和 Cys273 之间）以及离子键（Mn2+ 和 Asn124/His248/Asp64/His66 之间） MCLR/MCRR-PP1复合物的结合力有一定程度减弱，而Mn2+与His173/Asp92残基之间的离子键增加。不难发现，MCs的毒性与MCs-PP1的上述位点/相互作用以及上述关键信息密切相关； MC-GSHs-PP1复合物对于阐明MC-GSHs途径的解毒机制具有重要意义。该研究为MCs毒性调控提供了全面的认识，为控制其潜在风险提供了有效的理论支持。
Glutathione (GSH) conjugation was an important pathway to regulate the toxicity of microcystins (MCs) targeted to protein phosphatases. To explore the specific molecular mechanism for GSH detoxification, two typical MC-GSHs (derived from MCLR and MCRR) were synthesized, prepared, and purified according to previous research. Then, the reduced inhibition effect for MC-GSHs on protein phosphatase 1 was verified by comparing with their original toxins. To further clarify the molecular mechanism for MC-GSHs detoxification, we evaluated the interactions between MCs/MC-GSHs and PP1 with the assistance of MOE molecule simulation. When GSH was introduced to MCs, the covalent binding (Mdha7 to Cys273), the hydrophobic interaction (Adda5 with PP1), the hydrogen bonds (especially for Lys2-Arg96 and Glu6-Tyr272), the covalent combination (between Mdha7 and Cys273), and the ion bonds (between Mn2+ and Asn124/His248/Asp64/His66) of MCLR/MCRR-PP1 complexes weakened to a certain extent, while the ion bonds between Mn2+ and His173/Asp92 residues increased. It was not difficult to find that the toxicity of MCs was closely related to the above sites/interactions and the above key information for MCs-PP1; MC-GSHs-PP1 complexes were important for clarifying the detoxification mechanism of MC-GSHs pathway. This study offers a comprehensive cognition on MCs toxicity regulation and provides valid theoretical support to control their potential risk.