Defining the structural consequences of mechanism-based inactivation of mammalian cytochrome P450 2B4 using resonance Raman spectroscopy. J Am Chem Soc 2010 Feb 10;132(5):1494-5
Date
01/19/2010Pubmed ID
20078059Pubmed Central ID
PMC2820406DOI
10.1021/ja910276sScopus ID
2-s2.0-76149134076 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
In view of the potent oxidizing strength of cytochrome P450 intermediates, it is not surprising that certain substrates can give rise to reactive species capable of attacking the heme or critical distal-pocket protein residues to irreversibly modify the enzyme in a process known as mechanism-based (MB) inactivation, a result that can have serious physiological consequences leading to adverse drug-drug interactions and toxicity. While methods exist to document the attachment of these substrate fragments, it is more difficult to gain insight into the structural basis for the altered functional properties of these modified enzymes. In response to this pressing need to better understand MB inhibition, we here report the first application of resonance Raman spectroscopy to study the inactivation of a truncated form of mammalian CYP2B4 by the acetylenic inhibitor 4-(tert-butyl)phenylacetylene, whose activated form is known to attach to the distal-pocket T302 residue of CYP2B4.
Author List
Mak PJ, Zhang H, Hollenberg PF, Kincaid JRAuthor
James Kincaid PhD Department Chair and Professor, Biophysical Chemistry in the Chemistry department at Marquette UniversityMESH terms used to index this publication - Major topics in bold
AcetyleneAnimals
Aryl Hydrocarbon Hydroxylases
Catalytic Domain
Cytochrome P450 Family 2
Protein Conformation
Spectrum Analysis, Raman
