Do mammalian cytochrome P450s exhibit multiple ligand access pathways and ligand channelling?

Research output: Contribution to journalArticle

Authors

  • K Schleinkofer
  • S Sudarko
  • Peter Winn
  • SJ Luedemann
  • RC Wade

Colleges, School and Institutes

Abstract

Understanding substrate binding and product release in cytochrome P450 (CYP) enzymes is important for explaining their key role in drug metabolism, toxicity, xenobiotic degradation and biosynthesis. Here, molecular simulations of substrate and product exit from the buried active site of a mammalian P450, the microsomal CYP2C5, identified a dominant exit channel, termed pathway (pw) 2c. Previous simulations with soluble bacterial P450s showed a different dominant egress channel, pw2a. Combining these, we propose two mechanisms in CYP2C5: (i) a one-way route by which lipophilic substrates access the enzyme from the membrane by pw2a and hydroxylated products egress along pw2c; and (ii) a two-way route for access and egress, along pw2c, for soluble compounds. The proposed differences in substrate access and product egress routes between membrane-bound mammalian P450s and soluble bacterial P450s highlight the adaptability of the P450 fold to the requirements of differing cellular locations and substrate specificity profiles.

Details

Original languageEnglish
Pages (from-to)584-589
Number of pages6
JournalEMBO Reports
Volume6
Issue number6
Publication statusPublished - 1 Jun 2005