Single-electron reduction of quinone and nitroaromatic xenobiotics by recombinant rat neuronal nitric oxide synthase

• Autorzy: Anusevicius Z. , Nivinskas H. , Sarlauskas J. , Sari M.-A. , Boucher J.-L. , Cenas N.
• Języki publikacji: EN

Abstrakty

EN

 We examined the kinetics of single-electron reduction of a large number of structurally diverse quinones and nitroaromatic compounds, including a number of antitumour and antiparasitic drugs, and nitroaromatic explosives by recombinant rat neuronal nitric oxide synthase (nNOS, EC 1.14.13.39), aiming to characterize the role of nNOS in the oxidative stress-type cytotoxicity of the above compounds. The steady-state second-order rate constants (kcat/Km) of reduction of the quinones and nitroaromatics varied from 102 M-1s-1 to 106 M-1s-1, and increased with an increase in their single-electron reduction potentials (E17). The presence of Ca2+/calmodulin enhanced the reactivity of nNOS. These reactions were consistent with an "outer sphere" electron-transfer mechanism, considering the FMNH·/FMNH2 couple of nNOS as the most reactive reduced enzyme form. An analysis of the reactions of nNOS within the 'outer sphere' electron-transfer mechanism gave the approximate values of the distance of electron transfer, 0.39-0.47 nm, which are consistent with the crystal structure of the reductase domain of nNOS. On the other hand, at low oxygen concentrations ([O2] = 40-50 µM), nNOS performs a net two-electron reduction of quinones and nitroaromatics. This implies that NOS may in part be responsible for the bioreductive alkylation by two-electron reduced forms of antitumour aziridinyl-substituted quinones under a modest hypoxia.

Słowa kluczowe

EN

electron transfer mechanism; quinone; nitroaromatic xenobiotic; neuronal nitric oxide synthase; antitumour agent; oxidative stress

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2013
• Tom: 60
• Numer: 2
• Opis fizyczny: p.217-222,fig.,ref.

Twórcy

autor

Anusevicius Z.

• Institute of Biochemistry, Vilnius University, Vilnius, Lithuania

autor

Nivinskas H.

• Institute of Biochemistry, Vilnius University, Vilnius, Lithuania

autor

Sarlauskas J.

• Institute of Biochemistry, Vilnius University, Vilnius, Lithuania

autor

Sari M.-A.

• Laboratoire de Chimie and Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, Universite Paris Descartes, 45, Paris, France

autor

Boucher J.-L.

• Laboratoire de Chimie and Biochimie Pharmacologiques et Toxicologiques, CNRS UMR 8601, Universite Paris Descartes, 45, Paris, France

autor

Cenas N.

• Institute of Biochemistry, Vilnius University, Vilnius, Lithuania

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