Koppenol Willem H
Institute of Inorganic Chemistry, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
J Am Chem Soc. 2007 Aug 8;129(31):9686-90. doi: 10.1021/ja071546p. Epub 2007 Jul 13.
Electrode potentials for every intermediate in the cytochrome P450 cycle were estimated and evaluated by means of an oxidation state diagram. By this approach, and within the uncertainties of the approximations, the superoxide complex of cytochrome P450 at pH 7 is oxidizing: E degrees ' (P450FeO(2)2+, H+/P450FeOOH2+) = +0.93 V, and the Gibbs energy for the reaction of the hydroperoxo complex of cytochrome P450 to form compound I and water, P450FeOOH2+ + H+ = P450FeO2+ por(+) + H2O, is 0 kJ/mol. Although cytochrome P450FeOOH2+ and cytochrome P450FeO2+ por(+) are approximately isoenergetic, they are likely to react at different rates with substrates and may yield different products. Homolysis of the hydroperoxo complex of cytochrome P450 to compound II and the hydroxyl radical, P450FeOOH2+ = P450FeO2+ + HO(*), is unfavorable (DeltaG degrees ' = +92 kJ/mol), as is the dissociation into HOO- and cytochrome P450Fe3+ (+73 kJ/mol). It is shown that the sum of the Gibbs energy of association for cytochrome P450Fe3+ with the hydroperoxo anion and the Gibbs energy for the one-electron reduction of cytochrome P450FeOOH2+, relative to NHE, is constant (-203 kJ/mol). While the estimated E degrees ' (P450FeO(2)2+, H+/P450FeOOH2+) = +0.93 V at pH 7 is larger than necessary to effect reduction of cytochrome P450FeO(2)2+, the magnitude of this electrode potential implies that the binding constant for cytochrome P450Fe3+ with hydrogen peroxide is ca. 3 x 106 M(-1) at pH 7. An association constant of this magnitude ensures that a fraction of cytochrome P450FeOOH2+ is available to form compound I or to react with substrates directly, while a larger one would imply that compound I is too weak an oxidant. In general, the energetics of the reduction of dioxygen to water determines the energetics of catalysis of hydroxylations by cytochrome P450. These results enable calibration of energy levels obtained for intermediates in the cytochrome P450 reaction cycle obtained by ab initio calculations and provide insights into the catalytic efficiency of cytochrome P450 and guidelines for the development of competent hydroxylation catalysts.
通过氧化态图估算并评估了细胞色素P450循环中每个中间体的电极电势。通过这种方法，并在近似值的不确定范围内，pH为7时细胞色素P450的超氧化物复合物具有氧化性：E°'（P450FeO₂²⁺，H⁺/P450FeOOH²⁺） = +0.93 V，并且细胞色素P450的氢过氧化物复合物反应形成化合物I和水的吉布斯自由能，P450FeOOH²⁺ + H⁺ = P450FeO₂⁺ por(⁺) + H₂O，为0 kJ/mol。尽管细胞色素P450FeOOH²⁺和细胞色素P450FeO₂⁺ por(⁺)的能量大致相等，但它们与底物反应的速率可能不同，并可能产生不同的产物。细胞色素P450的氢过氧化物复合物分解为化合物II和羟基自由基，P450FeOOH²⁺ = P450FeO₂⁺ + HO(*），是不利的（ΔG°' = +92 kJ/mol），分解为HOO⁻和细胞色素P450Fe³⁺也是如此（+73 kJ/mol）。结果表明，相对于标准氢电极（NHE），细胞色素P450Fe³⁺与氢过氧化物阴离子结合的吉布斯自由能和细胞色素P450FeOOH²⁺单电子还原的吉布斯自由能之和是恒定的（-203 kJ/mol）。虽然在pH为7时估计的E°'（P450FeO₂²⁺，H⁺/P450FeOOH²⁺） = +0.93 V大于实现细胞色素P450FeO₂²⁺还原所需的值，但该电极电势的大小意味着细胞色素P450Fe³⁺与过氧化氢的结合常数在pH为7时约为3×10⁶ M⁻¹。这种大小的缔合常数确保了一部分细胞色素P450FeOOH²⁺可用于形成化合物I或直接与底物反应，而更大的缔合常数则意味着化合物I作为氧化剂太弱。一般来说，将氧气还原为水的能量学决定了细胞色素P450催化羟基化反应的能量学。这些结果能够校准通过从头计算获得的细胞色素P450反应循环中中间体的能级，并为细胞色素P450的催化效率提供见解以及为开发有效的羟基化催化剂提供指导。
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