Non-negligible inhibition effect of microcystin-LR biodegradation products target to protein phosphatase 2A

Abstract

Though biodegradation is an important regulation pathway for microcystins (MCs) pollution, more consideration needs to be given to the potential risk associated with related biodegradation products (MC-BDPs). In this work, typical MCLR-BDPs were prepared and their toxicity was evaluated by protein phosphatases (PPs) inhibition assay. Results showed the initial ring opening of MCLR played a crucial role in detoxification. However, partial MCLR-BDPs still retained the critical structures and thus exhibited certain toxicity (2.8-43.5% of MCLR). With the aid of molecular simulation, the mechanism for the potential toxicity of BDPs targeting PP2A was elucidated. The initial ring opening made the loss of hydrogen bond Leu²←Arg₈₉, and pi-H bond Adda⁵-His₁₉₁, which was responsible for the significant reduction in the toxicity of MCLR-BDP. However, the key hydrogen bonds MeAsp³←Arg₈₉, Glu⁶←Arg₈₉, Adda⁵←Asn₁₁₇, Adda⁵←His₁₁₈, Arg⁴→Pro₂₁₃, Arg⁴←Arg₂₁₄, Ala¹←Arg₂₆₈, and Mdha⁷←Arg₂₆₈, metal bond Glu⁶-Mn₁²⁺, and ionic bonds Glu⁶-Arg₈₉, and Glu⁶-Mn₂²⁺ were preserved in varying degrees. Above preserved interactions maintained the interactions between PP2A and Mn²⁺ ions (reducing the exposure of Mn²⁺ ions). Above preserved interactions also hindered the combination of phosphate groups to Arg₂₁₄ residual and thus exhibited potential toxicity.

Keywords: Biodegradation product; Homology modeling; Microcystin-LR; Molecular simulation; Toxicity regulation.