Beta-lactams SB 212047 and SB 216754 are irreversible, time-dependent inhibitors of coenzyme A-independent transacylase
| Autor: | Don E. Griswold, William E. Bondinell, Marie Chabot-Flecher, Floyd H. Chilton, Lisa A. Marshall, Ruth J. Mayer, James D. Winkler, Chiu-Mei Sung |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Lactams
Neutrophils Coenzyme A Anti-Inflammatory Agents Inflammation beta-Lactams Cell Line chemistry.chemical_compound Mice In vivo Acetyltransferases Microsomes medicine Animals Humans Enzyme Inhibitors Platelet Activating Factor IC50 Pharmacology chemistry.chemical_classification Mice Inbred BALB C Platelet-activating factor Lipid signaling Enzyme chemistry Biochemistry Phorbol Molecular Medicine Eicosanoids medicine.symptom Acyl-Carrier Protein S-Acetyltransferase |
| Zdroj: | Molecular pharmacology. 53(2) |
| ISSN: | 0026-895X |
| Popis: | 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 beta-lactam nucleus. beta-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 beta-lactams, SB 212047 and SB 216754, were shown to be specific, time-dependent inhibitors of CoA-IT activity (IC50 = 6 and 20 microM, 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 and in vivo and 2) the mechanism by which CoA-IT acts to transfer arachidonate is through an acyl-enzyme intermediate. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|