Data_Sheet_1_Dual-Specificity Phosphatase CDC25B Was Inhibited by Natural Product HB-21 Through Covalently Binding to the Active Site.docx

Cysteine 473, within the active site of the enzyme, Cdc25B, is catalytically essential for substrate activation. The most well-reported inhibitors of Cdc25 phosphatases, especially quinone-type inhibitors, function by inducing irreversible oxidation at this active site of cysteine. Here, we identified a natural product, HB-21, having a sesquiterpene lactone skeleton that could irreversibly bind to cys473 through the formation of a covalent bond. This compound inhibited recombinant human Cdc25B phosphatase with an IC50 value of 24.25 μM. Molecular modeling predicted that HB-21 not only covalently binds to cys473 of Cdc25B but also forms six hydrogen bonds with residues at the active site. Moreover, HB-21 can dephosphorylate cyclin-dependent kinase (CDK1), the natural substrate of Cdc25b, and inhibit cell cycle progression. In summary, HB-21 is a new type of Cdc25B inhibitor with a novel molecular mechanism.</p

Occurrence and Bioaccumulation of Psychotropic Pharmaceuticals and Their Metabolites in Water and Fish in a Shallow Lake in China: Implications for Ecological and Human Health Risks

Psychotropic pharmaceuticalsand their metabolites are a growing concern for aquatic environments and may accumulate in aquatic organisms. In this study, 21 parent psychotropic pharmaceuticals and 8 metabolites from three categories of psychotropic drugs (anxiolytics, antiepileptics, and antidepressants) were evaluated in Gao–Bao–Shaobo lake (GBSL), a shallow lake in China. Among them, 18 psychotropic pharmaceuticals and 8 metabolites were detected in water samples from GBSL (0.2 up to ∼24.5 ng/L), and 13 psychotropic pharmaceuticals and 5 metabolites were identified in fish (1 up to ∼126.2 ng/g dw). In the wet season, concentrations of psychotropic pharmaceuticals and their metabolites showed an increase from the inflow to the discharge subarea. Carbamazepine and sertraline were the dominant pharmaceuticals detected in fish with bioaccumulation factors, exceeding 5000 L/kg. Physicochemical parameters (log Kow and MW) were negatively correlated with the pharmaceutical levels in fish. Carbamazepine posed a moderate risk to aquatic organisms in all subareas. Hazard quotient results showed that the consumption of fish from GBSL is unlikely to exhibit a direct adverse effect on humans. Our results indicated that a comprehensive understanding of psychotropic pharmaceutical contaminations in surface waters should consider not only the parent pharmaceuticals but also the subsequent accumulation of their metabolites in fish