Mechanism-based inactivation and reversibility: is there a new trend in the inactivation of cytochrome p450 enzymes?
Recent studies with cytochrome P450 (P450) enzymes from the 2E and 2B subfamilies have shed light on what may be a new trend in the mechanism-based inactivation of P450s: reversibility. The reversible inactivation of P450-type enzymes was first reported in the mid-1990s by Dexter and Hager [Dexter AF and Hager LP (1995) J Am Chem Soc 117:817-818], who studied the transient heme N-alkylation of chloroperoxidase by allylbenzene and 1-hexyne. While characterizing small tert-butyl acetylenes as mechanism-based inactivators of P450s 2E1 and 2B4, Hollenberg and coworkers observed the reversible inactivation of an acetylene-inactivated T303A mutant of P450 2E1. The mechanism of reversibility was a combined product of the structure of the inactivator and the positioning of conserved amino acid residues, threonine 303 (alanine in the mutant) and glutamate 302, in the enzyme active site. Reversibility was also observed with both wild-type P450 2B4 and the T302A mutant of 2B4, although this inactivation and reversibility did not seem to depend on the T302 residue. Subsequent studies have attempted to elucidate the chemical/structural requirements of the inactivator in determining reversibility and have shown that both the size and the chemical nature of functional groups play an important role. At this time, reversibility has only been observed with P450 2E and 2B enzymes during their mechanism-based inactivation by terminal alkynes. Future studies with P450s from other subfamilies and structurally distinct inactivators will greatly aid our understanding of the molecular and chemical determinants of reversibility.
Blobaum
Anna L
AL
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA. anna.l.blobaum@vanderbilt.edu
D000114:Acetylene / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D012106:Research / Q000639:trends; D012107:Research Design
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000114:Acetylene