Zong Wansong, Wang Xiaoning, Du Yonggang, Zhang Shuhan, Zhang Ying, Teng Yue
College of Geography and Environment, Shandong Normal University, 88 East Wenhua Road, Jinan, Shandong 250014, China.
School of Environmental and Civil Engineering, Jiangnan University, 1800 Lihu Avenue, Wuxi, Jiangsu 214122, China.
Biomed Res Int. 2017;2017:9676504. doi: 10.1155/2017/9676504. Epub 2017 Feb 27.
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 (Mdha to Cys), the hydrophobic interaction (Adda with PP1), the hydrogen bonds (especially for Lys-Arg and Glu-Tyr), the covalent combination (between Mdha and Cys), and the ion bonds (between Mn and Asn/His/Asp/His) of MCLR/MCRR-PP1 complexes weakened to a certain extent, while the ion bonds between Mn and His/Asp 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.
谷胱甘肽（GSH）结合是调节微囊藻毒素（MCs）对蛋白磷酸酶毒性的重要途径。为探索GSH解毒的具体分子机制，根据先前研究合成、制备并纯化了两种典型的MC-GSHs（源自MCLR和MCRR）。然后，通过与原始毒素比较，验证了MC-GSHs对蛋白磷酸酶1的抑制作用减弱。为进一步阐明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引入到MCs中时，MCLR/MCRR-PP1复合物的共价结合（Mdha与Cys）、疏水相互作用（Adda与PP1）、氢键（尤其是Lys-Arg和Glu-Tyr）、共价组合（Mdha与Cys之间）以及离子键（Mn与Asn/His/Asp/His之间）在一定程度上减弱，而Mn与His/Asp残基之间的离子键增加。不难发现，MCs的毒性与上述位点/相互作用以及MCs-PP1的上述关键信息密切相关；MC-GSHs-PP1复合物对于阐明MC-GSHs途径的解毒机制很重要。本研究提供了对MCs毒性调节的全面认识，并为控制其潜在风险提供了有效的理论支持。
