A Predictive Pattern of Computed Barriers for C−H Hydroxylation by Compound I of Cytochrome P450

Abstract

The communication presents DFT calculations of 10 different C-H hydroxylation barriers by the active species of the enzyme cytochrome P450. The work demonstrates the existence of an excellent barrier-bond energy correlation. The so-obtained equation of the straight line is demonstrated to be useful for predicting barriers of related C-H activation processes, as well as for assessing barrier heights within the protein environment. This facility is demonstrated be estimating the barrier of camphor hydroxylation by P450cam.

Axial ligand tuning of a nonheme iron(IV)–oxo unit for hydrogen atom abstraction

“…Clearly, therefore, although the correlations found here are fundamentally important in the connection that they make with the ligand control of reactivity in heme enzymes, theory and spectroscopy suggest that the reactivity scenario might be more complex and more intriguing because of the availability of two closely lying spin states for all of the 1-X reagents (44). The two-state picture does not affect the correlations found here (49) but may provide rationale for other observations, such as the observed KIEs and the stereoselectivity of the reactions with substrates containing stereochemical probes.…”

The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monooxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation

“…As indicated earlier, hydrogen abstraction is generally disfavored for primary C-H bonds due to their higher bond strengths relative to adjacent secondary or tertiary C-H bonds or sites where functionalization reduces the bond strength, e.g. benzyl groups or allylic carbons (15)(16)(17). As a consequence, P450 4B1 must restrict access of the adjacent secondary C-H bonds to reactive intermediate to display a preference for hydroxylation of the primary C-H bond in P450 4B1 (46) as well as in other -hydroxylases (18).…”

“…Oxygenation of aliphatic C-H bonds is thought to proceed by abstraction of a hydrogen by the iron oxo intermediate followed by recombination of the resulting substrate radical with the transiently iron-bound hydroxyl radical (14). As the strength of primary C-H bonds is greater than that of secondary C-H bonds, oxygen addition at the -1 or -2 positions of fatty acids is typically seen for less specialized enzymes (15)(16)(17). These considerations suggest that the -hydroxylases have structural features that favor the approach to the reactive iron oxo species of the -carbon relative to the -1 carbon (18).…”

Recent density functional theory model calculations of drug metabolism by cytochrome P450

“…Later, the Yoshizawa group studied the kinetic isotope effect of the C H bond activation of alkane [26,27] and the mechanism of camphor hydroxylation by Cpd I [28]. Since then, P450-catalyzed substrate metabolism has been widely studied using the DFT method, including alkane hydroxylation [28,29], alkene epoxidation [30][31][32][33], aromatic hydroxylation [34][35][36][37][38], S-, N-, O-oxidation and dealkylation [39][40][41][42][43][44], dehalogenation of perhalogenated benzene [45], prostaglandin H 2 isomerization [46], and so on.…”