Identification of critical amino acid residues of human CYP2A13 for the metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco-specific carcinogen

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Xiao-Yang HeJun-Yan Hong

Abstract

Among all the known human cytochrome P450 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 done to identify the key amino acid residues in CYP2A13 that are responsible for this high catalytic efficiency by using a series of 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 detectab...Continue Reading

References

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Citations

Apr 26, 2012·Chemical Research in Toxicology·Slobodan Rendic, F Peter Guengerich
Jun 1, 2011·Carcinogenesis·M Christine HollanderPhillip A Dennis
Jul 26, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Hong WuXinxin Ding
Sep 10, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Natasha M DeVoreEmily E Scott
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Dec 31, 2005·International Journal of Cancer. Journal International Du Cancer·Xiao-Yang HeJun-Yan Hong
Aug 28, 2010·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tatsushi GotoHiromasa Imaishi
Jan 30, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jing-Fen HanJun-Yan Hong
Feb 25, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Zhihua LiuXinxin Ding
Aug 2, 2008·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jaime D'AgostinoXinxin Ding
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