Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 19, Issue 7, Pages -Publisher
MDPI
DOI: 10.3390/ijms19071974
Keywords
enzyme mechanism; enzyme catalysis; heme; iron; hydrogen atom abstraction; density functional theory; QM/MM; inorganic reaction mechanism
Funding
- Ministerio de Economia y Competitividad of Spain [CTQ2017-85341-P, BES-2012-052801]
- Generalitat de Catalunya [2017SGR39]
- Generalitat de Catalunya (Xarxa de Referencia en Quimica Teorica i Computacional)
- European Fund for Regional Development (FEDER) [UNGI10-4E-801]
- Biological and Biotechnological Research Council (BBSRC) [BB/J014478/1]
- National Natural Science Foundation of China [21003116, 2187030441]
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The cytochromes P450 are drug metabolizing enzymes in the body that typically react with substrates through a monoxygenation reaction. During the catalytic cycle two reduction and protonation steps generate a high-valent iron (IV)-oxo heme cation radical species called Compound I. However, with sufficient reduction equivalents present, the catalytic cycle should be able to continue to the reduced species of Compound I, called Compound II, rather than a reaction of Compound I with substrate. In particular, since electron transfer is usually on faster timescales than atom transfer, we considered this process feasible and decided to investigate the reaction computationally. In this work we present a computational study using density functional theory methods on active site model complexes alongside quantum mechanics/molecular mechanics calculations on full enzyme structures of cytochrome P450 enzymes. Specifically, we focus on the relative reactivity of Compound I and II with a model substrate for O-H bond activation. We show that generally the barrier heights for hydrogen atom abstraction are higher in energy for Compound II than Compound I for O-H bond activation. Nevertheless, for the activation of such bonds, Compound II should still be an active oxidant under enzymatic conditions. As such, our computational modelling predicts that under high-reduction environments the cytochromes P450 can react with substrates via Compound II but the rates will be much slower.
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