Oxidative and Hydrolytic HNO Formation from a Clinical Drug Hydroxyurea Catalyzed by Horseradish Peroxidase: Basic Mechanism, Active Site Effect, and Implications for Drug Design.

ABSTRACT: HNO plays an important role in many biological processes related to vasodilation, regulation of enzyme activities, and neurological functions. The understanding of enzymatic oxidative HNO-releasing pathways in biology remains scarce. We investigated HNO formation from a well-established small-molecule drug hydroxyurea catalyzed by horseradish peroxidase (HRP). Density functional theory results reveal two sequential proton-coupled electron transfers from hydroxyurea to HRP Compound I as the most favorable mechanism for HNO generation, which was found to be kinetically feasible and thermodynamically favorable. This is consistent with its experimentally observed reactivity. Moreover, the large active site model study uncovered interesting conformation changes involving HRP's amino acid H-bond

SUBMITTER: McCarthy E 

PROVIDER: S-EPMC12188405 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature