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(The FASEB Journal. 2008;22:919.4)
© 2008 FASEB
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(The FASEB Journal. 2008;22:919.4.)
© 2008 FASEB

919.4

Identification of active site residues essential for the metabolism of phenacetin to acetaminophen in human 2A cytochromes P450

Natasha M DeVore, Brian D. Smith, Michael J. Urban, Naseem Nikaeen, Linda C. Blake and Emily E. Scott

Medicinal Chemistry, The University of Kansas, Lawrence, KS

ABSTRACT

Human cytochromes P450 from the 2A subfamily have differing abilities to metabolize carcinogens and procarcinogens, including the nicotine-derived 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), aflatoxin B1, and 4-aminobiphenyl. Recently, Fukami et al. established that phenacetin, a hepatocarcinogen and known substrate for the CYP1A family, is even more efficiently metabolized by human lung cytochrome P450 2A13 (CYP2A13), while the human liver cytochrome P450 2A6 (CYP2A6) has almost no activity despite being 94% identical in amino acid sequence. To determine the basis for substrate specificity between these two closely related human 2A enzymes, site directed mutagenesis was used to construct eleven CYP2A13 single point mutants with mutations at positions in or near the active site where CYP2A13 and CYP2A6 wild type enzymes differ. Phenacetin metabolism kinetics were determined for the wild type enzymes CYP2A13 and CYP2A6, and eleven CYP2A13 mutants. Two CYP2A13 mutants, A117V and L366I, each increase phenacetin metabolism activity greater than four-fold. Four amino acid substitutions, S208I, F300I, A301G, and G369S, virtually abolished phenacetin metabolism in CYP2A13. The CYP2A6 enzyme is being modified by substitution of one or more 2A13 active site residues to determine those required to incorporate phenacetin metabolism into CYP2A6.

NIH GM76343





This Article
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Right arrow Articles by DeVore, N. M
Right arrow Articles by Scott, E. E.