Association of cytochrome P450 enzymes is a determining factor in their catalytic activity

Eszter Hazai, Zsolt Bikádi, Miklós Simonyi, David Kupfer

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Previously, our laboratory demonstrated that one cytochrome P450 isoenzyme can influence the catalytic properties of another P450 isoenzyme when combined in a reconstituted system. Moreover, our data and that of other investigators indicate that P450 interaction is required for catalytic activity even when one isoenzyme is present. The goal of the current study was to examine the possible mechanism of these interactions in more detail. Analyzing recently published X-ray data of microsomal P450 enzymes and protein docking studies, four types of dimer formations of P450 enzymes were examined in more detail. In case of two dimer types, the aggregating partner was shown to contribute to NADPH cytochrome P450 reductase (CPR) binding-a flavoprotein whose interaction with P450 is required for expressing P450 functional activity of the neighboring P450 moiety. Thus, it was shown that dimerization of P450 enzymes might result in an altered affinity towards the CPR. Two dimer types were shown to exist only in the presence of a substrate, while the other two types exist also without a substrate present. The molecular basis was established for the fact that the presence of a substrate and other P450 enzymes simultaneously determine the catalytic activity. Furthermore, a kinetic model was improved describing the catalytic activity of P450 enzymes as a function of CPR concentration based on equilibrium between different supramolecular organizations of P450 enzymes. This model was successfully applied in order to explain our experimental data and that of other investigators.

Original languageEnglish
Pages (from-to)271-285
Number of pages15
JournalJournal of Computer-Aided Molecular Design
Volume19
Issue number4
DOIs
Publication statusPublished - Apr 1 2005

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Keywords

  • CPR
  • Kinetic modeling
  • P450 oligomers
  • P450-P450 interactions
  • Supramolecular structure

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

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