Research on the discrepant inhibition mechanism of microcystin-LR disinfectant by-products target to protein phosphatase 1.

The secondary contamination for microcystin disinfection by-products (MC-DBPs) is of concern due to the residual toxic structure similar to their original toxins. To evaluate the toxicity of MC-DBPs, the discrepant inhibition mechanisms target to protein phosphatase 1 (PP1) were evaluated. Five typical MCLR-DBPs related to the oxidation of Adda5 were identified as C49H75N10O13Cl (+1Cl1OH, P1/P2), C34H54N10O12 (+2OH, P3/P4), and C49H76N10O14 (P5). Toxicity inhibition experiment on PP1 showed that the toxicity was in the sequence of MCLR > P3 > P1 > P4 > P2 > P5. Base on MOE molecular simulation, the discrepant inhibition mechanisms for MCLR and MCLR-DBPs target to PP1 were further clarified. The combination of MCLR/MCLR-DBPs to PP1 was mainly restrained by residues Adda5 and Arg4. Above key sites promoted the binding of MCLR/MCLR-DBPs to PP1 through the hydrogen bonds (H2O ← Adda5, Tyr134 → Adda5, H2O ← Arg4, Tyr134 → Arg4, Glu275 ← Arg4), ionic bonds (Asp197-Adda5, Glu275-Arg4, Asp220 → Arg4), and H-pi bonds (Trp206 ↔ Adda5, Ser129 ↔ Adda5). The oxidation of Adda5 also affected Mdha7 participated ionic bond Glu275-Mdha7 and Glu6 participated hydrogen bond H2O → Glu6. Besides, the "integral hydrogen bonds and ionic bonds" between toxin and PP1 also had important effects on the toxin toxicity. In this way, the inhibition of "Adda5 destroyed" MC-DBPs target to PP1 was regulated.