Issue 32, 2020

Coupled electron and proton transfer in the piperidine drug metabolism pathway by the active species of cytochromes P450

Abstract

Ring contraction of piperidine drugs by cytochrome P450 enzymes (P450s) is among the most important drug metabolisms for human beings. However, the underlying mechanism remains elusive and controversial even after decades of experimental study. Kohn–Sham density functional theory (KS-DFT) combined with multistate density functional theory (MSDFT) was used to explore the chemical nature of ring contraction of 2,2′,6,6′-tetramethylpiperidine (2,2′,6,6′-TMPi) mediated by the active species, Compound I of P450s. Our calculated results demonstrate that ring contraction is initiated by N–H bond activation. MSDFT combined with KS-DFT methods revealed that the N–H bond activation involves an initial tightly coupled electron–proton pair, essentially of hydrogen atom transfer (HAT) character prior to the diabatic crossing point, after which the mechanism is dominated by the concerted electron proton transfer (CEPT) product formation. The nascent N-centered radical intermediate undergoes electron tautomerism via rate-limiting homolytic C–C bond cleavage (ca. 21 kcal mol−1) to form a ring-opened, carbon-centered radical imine intermediate. The following barrierless C–N bond formation concomitant with hydroxyl rebound from the Fe–OH moiety forms the ring-contracted pyrrolidine product. To the best of our knowledge, this is the first application of MSDFT in P450 chemistry, and also the first comprehensive theoretical report on the ring contraction mediated by P450, in which the revealed new mechanism will undoubtedly promote relative rational drug design.

Graphical abstract: Coupled electron and proton transfer in the piperidine drug metabolism pathway by the active species of cytochromes P450

Supplementary files

Article information

Article type
Paper
Submitted
26 7 2019
Accepted
14 7 2020
First published
14 7 2020

Dalton Trans., 2020,49, 11099-11107

Coupled electron and proton transfer in the piperidine drug metabolism pathway by the active species of cytochromes P450

Z. Fu, L. Yang, D. Sun, Z. Qu, Y. Zhao, J. Gao and Y. Wang, Dalton Trans., 2020, 49, 11099 DOI: 10.1039/C9DT03056E

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements