A Caltech Library Service

Hole Hopping through Cytochrome P450

Sørensen, Mette L. H. and Sanders, Brian C. and Hicks, L. Perry and Rasmussen, Maria H. and Vishart, Andreas L. and Kongsted, Jacob and Winkler, Jay R. and Gray, Harry B. and Hansen, Thorsten (2020) Hole Hopping through Cytochrome P450. Journal of Physical Chemistry B, 124 (15). pp. 3065-3073. ISSN 1520-6106.

[img] PDF - Accepted Version
See Usage Policy.

[img] PDF (Computational details) - Supplemental Material
See Usage Policy.


Use this Persistent URL to link to this item:


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 P450_(BM3), we identified Trp96 as a critical residue that could play such a protective role. This Trp is cation−π paired with Arg398 in 81% of mammalian P450s. Here we report on the effect of the Trp/Arg cation−π interaction 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.

Item Type:Article
Related URLs:
URLURL TypeDescription
Winkler, Jay R.0000-0002-4453-9716
Gray, Harry B.0000-0002-7937-7876
Additional Information:© 2020 American Chemical Society. Received: October 7, 2019; Revised: March 15, 2020; Published: March 16, 2020. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK019038. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. T.H. thanks the Lundbeck Foundation for generous financial support. B.C.S. was supported by the National Institutes of Health under Award Number F32GM123639-01 and in part by the U.S. Department of Energy (DOE), Oak Ridge National Laboratory Programmatic Fund, during manuscript preparation. Author Contributions: M.L.H.S. and B.C.S. contributed equally to this work. The authors declare no competing financial interest.
Funding AgencyGrant Number
Lundbeck FoundationUNSPECIFIED
NIH Postdoctoral FellowshipF32GM123639-01
Department of Energy (DOE)UNSPECIFIED
Oak Ridge National LaboratoryUNSPECIFIED
Issue or Number:15
Record Number:CaltechAUTHORS:20200316-150527143
Persistent URL:
Official Citation: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, and Thorsten Hansen. The Journal of Physical Chemistry B 2020 124 (15), 3065-3073; DOI: 10.1021/acs.jpcb.9b09414
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101922
Deposited By: George Porter
Deposited On:17 Mar 2020 14:13
Last Modified:16 Apr 2020 18:24

Repository Staff Only: item control page