Regulation Effectiveness and Mechanism of Biotransformation Pathway on the Toxicity of Microcystin-LR Target to Protein Phosphatase 2A

Biotransformation is recognized as a potential pathway to regulate the environmental risk of microcystins (MCs). To explore the regulation effectiveness and mechanism of the biotransformation pathway, six typical MCLR-biotransformation products (MCLR-BTPs) were prepared, and their inhibition effects on protein phosphatase 2A (PP2A) were evaluated. The inhibition effects of the MCLR-BTPs generally decreased with the increase in biothiol molecular weights and polarity, indicating that biotransformation was an effective pathway through which to regulate MCLR toxicity. To further explore the regulation mechanism, the key interaction processes between the MCLR/MCLR-BTPs and the PP2A were explored by homology modeling and molecular docking. The introduced biothiols blocked the covalent binding of Mdha 7 to Cys 269 but strengthened the hydrogen bond “Mdha 7 ”→Arg 268 . The changed “Mdha 7 ” intervened the combination of MCLR-BTPs to PP2A by weakening the hydrogen bonds Arg 4 ←Arg 214 , Arg 4 →Pro 213 , Adda 5 ←His 118 , and Ala 1 ←Arg 268 , and the ionic bond Glu 6 -Mn 1 2+ . The weakening combination of the MCLR-BTPs to PP2A further attenuated the interactions between the conserved domain and the Mn 2+ ions (including the ionic bonds Asp 57 -Mn 1 2+ and Asp 85 -Mn 1 2+ and the metal bonds Asp 57 -Mn 1 2+ and Asn 117 -Mn 1 2+ ) and increased the exposure of the Mn 2+ ions. Meanwhile, the weakened hydrogen bond Arg 4 ←Arg 214 facilitated the combination of the phosphate group to Arg 214 (with increased exposure). In this way, the catalytic activity of the PP2A was restored.