TY - JOUR T1 - β-Lactams SB 212047 and SB 216754 Are Irreversible, Time-Dependent Inhibitors of Coenzyme A-Independent Transacylase JF - Molecular Pharmacology JO - Mol Pharmacol SP - 322 LP - 329 DO - 10.1124/mol.53.2.322 VL - 53 IS - 2 AU - James D. Winkler AU - Chiu-Mei Sung AU - Marie Chabot-Flecher AU - Don E. Griswold AU - Lisa A. Marshall AU - Floyd H. Chilton AU - William Bondinell AU - Ruth J. Mayer Y1 - 1998/02/01 UR - http://molpharm.aspetjournals.org/content/53/2/322.abstract N2 - 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. ER -