RT Journal Article SR Electronic T1 β-Lactams SB 212047 and SB 216754 Are Irreversible, Time-Dependent Inhibitors of Coenzyme A-Independent Transacylase JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 322 OP 329 DO 10.1124/mol.53.2.322 VO 53 IS 2 A1 James D. Winkler A1 Chiu-Mei Sung A1 Marie Chabot-Flecher A1 Don E. Griswold A1 Lisa A. Marshall A1 Floyd H. Chilton A1 William Bondinell A1 Ruth J. Mayer YR 1998 UL http://molpharm.aspetjournals.org/content/53/2/322.abstract AB The enzyme coenzyme A-independent transacylase (CoA-IT) has been demonstrated to be the key mediator of arachidonate remodeling, a process that moves arachidonate into 1-ether-containing phospholipids. Blockade of CoA-IT by reversible inhibitors has been shown to block the release of arachidonate in stimulated neutrophils and inhibit the production of eicosanoids and platelet-activating factor. We describe novel inhibitors of CoA-IT activity that contain a β-lactam nucleus. β-Lactams were investigated as potential mechanism-based inhibitors of CoA-IT on the basis of the expected formation of an acyl-enzyme intermediate complex. Two β-lactams, SB 212047 and SB 216754, were shown to be specific, time-dependent inhibitors of CoA-IT activity (IC50 = 6 and 20 μm, respectively, with a 10-min pretreatment time). Extensive washing and dilution could not remove the inhibition, suggesting it was irreversible. In stimulated human monocytes, SB 216754 decreased the production of eicosanoids in a time-dependent manner. In an in vivo model of phorbol ester-induced ear inflammation, SB 216754 was able to inhibit indices of both edema and cell infiltration. Taken together, the results support two hypotheses: 1) CoA-IT activity is important for the production of inflammatory lipid mediators in stimulated cells andin vivo and 2) the mechanism by which CoA-IT acts to transfer arachidonate is through an acyl-enzyme intermediate.