DOI: 10.1073/pnas.94.6.2133. Identification of a functional water channel in cytochrome P450 enzymes

Identification of a functional water channel in cytochrome P450 enzymes

10.1073/pnas.94.6.2133

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Cytochrome P450 enzymes are monooxygenases that contain a functional heme b group linked to a conserved cysteine with a thiolate bond. In the native state, the central iron atom is hexacoordinated with a covalently bound water molecule. The exclusion of solvent molecules from the active site is essential for efficient enzymatic function. Upon substrate binding, water has to be displaced from the active site to prevent electron uncoupling that results in hydrogen peroxide or water. In contrast to typical hemoproteins, the protein surface is not directly accessible from the heme of cytochromes P450. We postulate a two-state model in which a conserved arginine, stabilizing the heme propionate in all known cytochrome P450 crystal structures, changes from the initial, stable side-chain conformation to another rotamer (metastable). In this new state, a functional water channel (aqueduct) is formed from the active site to a water cluster located on the thiolate side of the heme, close to the protein surface. This water cluster communicates with the surface in the closed state and is partly replaced by the flipping arginine side chain in the open state, allowing water molecules to exit to the surface or to reaccess the active site. This two-state model suggests the presence of an exit pathway for water between the active site and the protein surface.

Bibliography

Oprea, T. I., Hummer, G., & GarcÃa, A. E. (1997). Identification of a functional water channel in cytochromeâP450âenzymes. Proceedings of the National Academy of Sciences, 94(6), 2133â2138.

Authors 3

Tudor I. Oprea (first)
Gerhard Hummer (additional)
Angel E. García (additional)

References 45 Referenced 109

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:43 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 3:15 p.m.)
Indexed	1 month, 1 week ago (July 28, 2025, 2:32 a.m.)
Issued	28 years, 5 months ago (March 18, 1997)
Published	28 years, 5 months ago (March 18, 1997)
Published Online	28 years, 5 months ago (March 18, 1997)
Published Print	28 years, 5 months ago (March 18, 1997)

Funders 0

None

BibTeX

@article{Oprea_1997, title={Identification of a functional water channel in cytochrome P450 enzymes}, volume={94}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.94.6.2133}, DOI={10.1073/pnas.94.6.2133}, number={6}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Oprea, Tudor I. and Hummer, Gerhard and García, Angel E.}, year={1997}, month=mar, pages={2133–2138} }

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