TY - JOUR
T1 - The Role of Heme Peroxo Oxidants in the Rational Mechanistic Modeling of Nitric Oxide Synthase
T2 - Characterization of Key Intermediates and Elucidation of the Mechanism
AU - Mondal, Pritam
AU - Ishigami, Izumi
AU - Yeh, Syun Ru
AU - Wijeratne, Gayan B.
N1 - Publisher Copyright:
© 2022 Wiley-VCH GmbH.
PY - 2022/11/25
Y1 - 2022/11/25
N2 - 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 and 15N 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.
AB - 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 and 15N 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.
KW - Bioinorganic Chemistry
KW - Enzyme Models
KW - Heme Peroxo Complexes
KW - Heme Proteins
KW - Structure–Activity Relationships
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U2 - 10.1002/anie.202211521
DO - 10.1002/anie.202211521
M3 - Article
C2 - 36169890
AN - SCOPUS:85140385341
SN - 1433-7851
VL - 61
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 48
M1 - e202211521
ER -