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First published on August 27, 2004; DOI: 10.1124/dmd.104.001370

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Received for publication July 7, 2004.
Revised August 24, 2004.
Accepted for publication August 27, 2004.

Identification of critical amino acid residues of human CYP2A13 for the metabolic activation of NNK, a tobacco-specific carcinogen

Xiao-Yang He 1, Jian Shen 2, Xinxin Ding 3, Anthony Y. H. Lu 4, Jun-Yan Hong 1*

1 School of Public Health, University of Medicine and Dentistry of New Jersey 2 Aventis Pharmaceuticals, Bridgewater, NJ 3 Wadsworth Center, New York State Department of Health, Albany, NY 4 College of Pharmacy, Rutgers University

* Address correspondence to: E-mail: jyhong{at}eohsi.rutgers.edu

Abstract

Among all the known human cytochrome P450 (CYP) enzymes, CYP2A13 has the highest efficiency in catalyzing the metabolic activation (keto aldehyde and keto alcohol formation) of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a potent lung carcinogen in animals and a suspected human lung carcinogen. As part of the structure-activity relationship (SAR) study, the present work was to identify the key amino acid residues that are responsible for this high catalytic efficiency by using a series of CYP2A13 mutants (Ala117Val, His164Gly, Ser208Ile, His372Arg and Pro465Ser). In these CYP2A13 mutants, the amino acid residues were substituted by the residues at the corresponding positions of CYP2A6, which shares 93.5% amino acid sequence identity with CYP2A13 but is significantly less active (<5%) than CYP2A13 in NNK {alpha}-hydroxylation. We demonstrated that, except for the His164Gly mutant, all the CYP2A13 mutant proteins showed a significant decrease in the catalytic efficiency (Vmax/Km) for NNK {alpha}-hydroxylation. The His372 to Arg substitution resulted in a 20-fold increase in the Km value and a 7-fold decrease in the Vmax value for keto aldehyde formation as well as a total loss of detectable keto alcohol formation. The Ala117 to Val substitution, however, only caused a selective decrease in the Vmax value for keto aldehyde formation. The role of these amino acid residues in CYP2A13-catalized reactions is clearly substrate-dependent, as the same Ala117Val and His372Arg mutants showed a 9-fold increase in the catalytic efficiency for coumarin 7-hydroxylation. Together with the computational substrate docking, our study provides new SAR information of human CYP2A13.


Key words: bioactivation, carcinogen metabolism, computational models, CYP2A, cytochrome P450, cytochrome P450 structure, enzyme kinetics, site-directed mutagenesis, structure-activity relationships


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