A DFT Study of the Heme Role in the N-Demethylation of Theophylline Mediated by Compound I of Cytochrome P450

Abstract

Using accurate DFT calculations we have examined the role that Compound I of cytochrome P450 plays as a catalyst in the conversion of theophylline to 1-methylxanthine. This reaction proceeds in two steps according to the characteristics of the oxygen rebound mechanism. In this study we found that the activation energy for the transition state corresponding to the abstraction of the H atom at the C13 in theophylline is 9.3 kcal/mol. This H atom abstraction is the rate-determining step in this reaction which takes place via a single electron transfer (SET) mechanism and leads to an intermediate containing theophylline cationic and iron-hydroxo species. The rebounding step between the reaction intermediate and the product alcohol complex is a barrierless step. The alcohol complex is then separated from the heme moiety and yields 1-methylxanthine by intramolecular rearrangement.

Quantum chemical studies for oxidation of morpholine by Cytochrome P450

“…There exist two possible mechanisms for the conversion of amine to 2-hydroxyamine, namely, hydrogen atom transfer (HAT) and single electron transfer (SET). Although there is no direct experimental evidence for either the SET or HAT mechanism for the hydroxylation of morpholine, SET mechanism is excluded based on previous studies on N-demethylation of N,N-dimethylanilines [23,24] and theophyllin [25]. The SET mechanism [21,22], would involve an initial one-electron oxidation of the amine, followed by deprotonation of the cation radical to produce an a-amino radical, whereas model electrochemical-mass spectrometric studies by Jurva et al [26] showed that amino radical cations were unlikely to be intermediates in the CYP catalyzed oxidations of N-cyclopropyl cyclic tertiary allylamines.…”

Quantum-Mechanical Studies of Reactions Performed by Cytochrome P450 Enzymes

“…If the reactive carbon atom is not in an alcohol group, the reorganization results in an O-or N-dealkylation ( Figure 1). 71,74,76 Consequently, from a theoretical perspective, this reaction is identical to the aliphatic hydroxylation, described in the previous section, i.e. with hydrogen-abstraction and rebound steps, of which the first is rate limiting.…”

“…with hydrogen-abstraction and rebound steps, of which the first is rate limiting. Because of the importance of understanding these reaction types in drug degradation, a number of theoretical studies have been performed, in several cases including the non-enzymatic reaction, 62,71,72,[74][75][76][77] as are summarized in Figure 5.…”