# Biotransformation Is an Effective Mechanism for Modulating the Biological Toxicity of Nodularin (NODR)

## TL;DR

This study shows that biotransformation reduces the toxicity of nodularin by altering its interaction with protein phosphatase 1.

## Contribution

The study identifies specific biotransformation products and their molecular mechanisms in modulating nodularin toxicity.

## Key findings

- Biotransformation products of nodularin-R (NODR-BTPs) show reduced inhibitory effects on PP1 as molecular weight and polarity increase.
- Biothiol moieties enhance hydrogen bonding and interactions at key sites, affecting PP1's binding and Mn2+ ion exposure.
- These changes restore PP1 catalytic activity by disrupting conserved amino acid interactions.

## Abstract

The biotransformation of nodularin (NOD) is one of the critical strategies for regulating their biological toxicity. To investigate the effects and mechanisms of the biotransformation pathway, this study synthesized six biotransformation products of nodulein-R (NODR-BTPs) and evaluated their inhibitory effects on protein phosphatase 1 (PP1) through protein phosphatase inhibition assays. The inhibitory effects of NODR-BTPs diminished as the molecular weight and polarity of the introduced biological thiols increased, indicating that biotransformation is an efficient mechanism for modulating the biological toxicity of NODR. Through ligand replacement and molecular docking techniques, the potential regulatory mechanisms underlying the primary interaction processes between NODR-BTPs and PP1 were further elucidated. The introduced biological thiols improved the hydrogen bonding for Glu275 ← “Mdhb5”and enhanced the electropositive–electronegative interactions between “Mdhb5” and PP1. This resulted in an increase in the positive accessible surface area, negative accessible surface area, and polar surface area at the interface of “Mdhb5” and PP1. The biothiol moiety subsequently enhanced hydrogen bonds for Arg96 → MeAsp1 and Arg96 → Glu4, thereby affecting the binding of these key interaction sites to PP1. This further diminished interactions between conserved amino acids in PP1 and Mn2+ ions, including the ionic bond for Asp92-Mn12+ and metal bonds for Asp64-Mn12+ and His66-Mn12+, leading to increased exposure of Mn2+ ions. The regulatory mechanisms facilitated the restoration of PP1 catalytic activity.