Hole Hopping through Cytochrome P450

Mette L.H. Sørensen, Brian C. Sanders, L. Perry Hicks, Maria H. Rasmussen, Andreas L. Vishart, Jacob Kongsted, Jay R. Winkler, Harry B. Gray, Thorsten Hansen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

High-potential iron-oxo species are intermediates in the catalytic cycles of oxygenase enzymes. They can cause heme degradation and irreversible oxidation of nearby amino acids. We have proposed that there are protective mechanisms in which hole hopping from oxidized hemes through tryptophan/tyrosine chains generates a surface-exposed amino-acid oxidant that could be rapidly disarmed by reaction with cellular reductants. In investigations of cytochrome P450BM3, we identified Trp96 as a critical residue that could play such a protective role. This Trp is cation-πpaired with Arg398 in 81% of mammalian P450s. Here we report on the effect of the Trp/Arg cation-πinteraction on Trp96 formal potentials as well as on electronic coupling strengths between Trp96 and the heme both for wild type cytochrome P450 and selected mutants. Mutation of Arg398 to His, which decreases the Trp96 formal potential, increases Trp-heme electronic coupling; however, surprisingly, the rate of phototriggered electron transfer from a Ru-sensitizer (through Trp96) to the P450BM3 heme was unaffected by the Arg398His mutation. We conclude that Trp96 has moved away from Arg398, suggesting that the protective mechanism for P450s with this Trp-Arg pair is conformationally gated.

Original languageEnglish
JournalJournal of Physical Chemistry B
Volume124
Issue number15
Pages (from-to)3065-3073
ISSN1520-6106
DOIs
Publication statusPublished - 2020

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