Molecular modelling of CYP2A enzymes: Application to metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

J. R. Jalas, M. Seetharaman, S. S. Hecht, S. E. Murphy

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

1. Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) is a lung carcinogen in a variety of animal models and a putative human lung carcinogen. Its tumorigenic potential is unmasked via cytochrome P450 (CYP)-mediated hydroxylation of the carbon atoms adjacent to the nitroso moiety (i.e. α-hydroxylation). Therefore, elucidation of enzyme-substrate interactions that facilitate α-hydroxylation is important to gain insight into the tumorigenic mechanism of NNK and to develop potent inhibitors of this detrimental reaction. 2. Molecular models of CYP2A enzymes from mice, rats and humans that are catalysts of NNK bioactivation were constructed and used, in conjunction with docking experiments, to identify active-site residues that make important substrate contacts. 3. Docking studies revealed that hydrophobic residues at positions 117, 209, 365 and 481, among others, play critical roles in orienting NNK in the active site to effect α-hydroxylation. These molecular models were then used to rationalize the stereo- and regioselectivity, as well as the efficiency, of CYP2A-mediated NNK metabolism.

Original languageEnglish (US)
Pages (from-to)515-533
Number of pages19
JournalXenobiotica
Volume34
Issue number6
DOIs
StatePublished - Jun 1 2004

Fingerprint Dive into the research topics of 'Molecular modelling of CYP2A enzymes: Application to metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)'. Together they form a unique fingerprint.

Cite this