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Mid-valent heme-oxygen intermediates are central to a medley of pivotal physiological transformations in humans, and such systems are increasingly becoming more relevant therapeutic targets for challenging disease conditions. Nonetheless, precise... 

Abstract Mammalian nitric oxide synthase (NOS) mediates the two‐step O₂‐dependent oxidative degradation of arginine, and has been linked to a medley of disease situations in humans. Nonetheless, its exact mechanism of action still remains unclear. This work presents the first NOS model system where biologically proposed heme superoxo and peroxo intermediates are assessed as active oxidants against oxime substrates. Markedly, heme peroxo intermediates engaged in a bioinspired oxime oxidation reaction pathway, converting oximes to ketones and nitroxyl anions (NO⁻). Detailed thermodynamic, kinetic, and mechanistic interrogations all evince a rate‐limiting step primarily driven by the nucleophilicity of the heme peroxo moiety. Coherent with other findings,¹⁸O and¹⁵N isotope substitution experiments herein suffice compelling evidence toward a detailed mechanism, which draw close parallels to one of the enzymatic proposals. Intriguingly, recent enzymatic studies also lend credence to these findings, and several relevant reaction intermediates have been observed during NOS turnover.