Activation of molecular oxygen by cytochrome P450

Thomas M. Makris, Ilia Denisov, Ilme Schlichting, Stephen G. Sligar

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

4.5 Summary: The rich mechanistic enzymology of the cytochrome P450s has occupied chemists, biochemists, pharmacologists, and toxicologists for over three decades. Are we near to a detailed molecular understanding? We have attempted to convey in this chapter of Cytochrome P450 the recent discoveries that fill many of the lacunas in our understanding of P450-catalyzed substrate oxidations. We now have a precise three-dimensional structure of the ferrous-oxygenated state, and ample spectroscopic characterization of the ferric-peroxo anion and ferric-hydroperoxo intermediates. In the exogenous oxidant driven pathway, an archaeal P450 allowed facile observation of the formation and breakdown of the Compound I ferryl-oxo state. Yet much remains. Stabilization and characterization of the Compound I state in the dioxygen reaction has not yet been achieved. With the ability to separate, through time and temperature, the population of multiple active oxygen intermediates in P4 50 catalysis, it remains to precisely define the reactivity profiles of each state and thereby realize a mapping of observed in vivo metabolic profiles to specific states in the reaction cycle. An overriding revelation has been the subtle way in which Nature controls the reactivity of atmospheric dioxygen, electrons, and transition metal through delicate hydrogen-bonding interactions. Thus, in a Periclesian control of mechanism, the cytochromes P450 utilize a variety of proton pathways to finely tune this versatile catalyst for critical physiological processes.

Original languageEnglish (US)
Title of host publicationCytochrome P450
Subtitle of host publicationStructure, Mechanism, and Biochemistry: Third edition
PublisherSpringer US
Pages149-182
Number of pages34
ISBN (Print)9780306483240
DOIs
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Medicine(all)

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    Makris, T. M., Denisov, I., Schlichting, I., & Sligar, S. G. (2005). Activation of molecular oxygen by cytochrome P450. In Cytochrome P450: Structure, Mechanism, and Biochemistry: Third edition (pp. 149-182). Springer US. https://doi.org/10.1007/0-387-27447-2_5