Molecular basis for the differences in lidocaine binding and regioselectivity of oxidation by cytochromes P450 2B1 and 2B2

Biochemistry
Imad H HannaPaul F Hollenberg

Abstract

The interactions of lidocaine (LIDO) with two closely related P450s, 2B1 and 2B2, were investigated using chimeric enzymes and single-point mutants derived from the two proteins. P450 2B1 exclusively catalyzed the N-deethylation of LIDO to generate monoethylglycinexylidide (MEGX) and 2B2 catalyzed both N-deethylation and hydroxylation reactions to generate MEGX and omega-diethylamino-2-hydroxymethyl-6-methylacetanilide. The addition of LIDO to 2B2 evoked a type I binding spectral change with a measured Ks of approximately 20 microM. The magnitude of the change in the absorbance obtained following the binding of LIDO to 2B2 was indicative of an approximately 30% switch of the heme iron to the high-spin form. In contrast, the addition of LIDO to 2B1 resulted in less than a 1% shift to the high-spin form even at LIDO concentrations as high as 10 mM. P450 2B2 exhibited a low Km value for LIDO (62 microM), whereas 2B1 had an approximately 10-fold higher Km value. However, the rates of LIDO oxidation by 2B1 were approximately 200-fold those exhibited by 2B2. Substitution of 2B2 residues by 2B1-derived amino acids influenced the spectral binding, regioselectivity of LIDO oxidation, and the kinetic properties of the enzyme. With the 2B...Continue Reading

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Citations

Jan 11, 2001·Biochimica Et Biophysica Acta·C S MilesS K Chapman
Apr 30, 2011·Chemical Reviews·Daniela MontiSergio Riva
Oct 26, 2000·Proceedings of the National Academy of Sciences of the United States of America·M Schalk, R Croteau
May 20, 2005·American Journal of Veterinary Research·Bruno H Pypendop, Jan E Ilkiw
Jan 26, 2010·Journal of Inorganic Biochemistry·Namandjé N Bumpus, Paul F Hollenberg
Aug 13, 2011·Journal of Veterinary Pharmacology and Therapeutics·S CoxT Doherty
Sep 15, 2005·Biochemical and Biophysical Research Communications·Chitra SridarPaul F Hollenberg
May 3, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Diane M CalinskiPaul F Hollenberg
Jun 21, 2006·The Journal of Pharmacology and Experimental Therapeutics·Ute M KentPaul F Hollenberg
Apr 14, 2006·The Journal of Pharmacology and Experimental Therapeutics·Namandjé N BumpusPaul F Hollenberg
May 4, 2004·The Journal of Pharmacology and Experimental Therapeutics·Erin HarletonPaul F Hollenberg
Mar 17, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Namandjé N BumpusPaul F Hollenberg

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