Leukotriene B4 omega-hydroxylase in human polymorphonuclear leukocytes. Suicidal inactivation by acetylenic fatty acids
| Autor: | P R Ortiz de Montellano, Norbert O. Reich, S Shak, I M Goldstein |
|---|---|
| Rok vydání: | 1985 |
| Předmět: |
chemistry.chemical_classification
Cytochrome biology Leukotriene B4 Catabolism Stereochemistry Fatty acid hemic and immune systems Inflammation Cell Biology Biochemistry chemistry.chemical_compound Mediator Enzyme chemistry medicine biology.protein Moiety lipids (amino acids peptides and proteins) medicine.symptom Molecular Biology |
| Zdroj: | Journal of Biological Chemistry. 260:13023-13028 |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/s0021-9258(17)38832-4 |
| Popis: | Human polymorphonuclear leukocytes (PMN) not only generate and respond to leukotriene B4 (LTB4), but also catabolize this mediator of inflammation rapidly and specifically by omega-oxidation (probably due to the action of a cytochrome P-450 enzyme). To develop pharmacologically useful inhibitors of the LTB4 omega-hydroxylase in human PMN, we devised a general scheme for synthesizing terminal acetylenic fatty acids based on the "acetylenic zipper" reaction. We found that the LTB4 omega-hydroxylase in intact PMN and in PMN sonicates is inactivated in a concentration-dependent fashion by terminal acetylenic analogues of lauric, palmitic, and stearic acids (i.e. 11-dodecynoic, 15-hexadecynoic, and 17-octadecynoic acids). Consistent with a suicidal process, inactivation of the LTB4 omega-hydroxylase requires molecular oxygen and NADPH, is time-dependent, and follows pseudo-first-order kinetics. Inactivation of the omega-hydroxylase by acetylenic fatty acids also is dependent on the terminal acetylenic moiety and the carbon chain length. Saturated fatty acids lacking a terminal acetylenic moiety do not inactivate the omega-hydroxylase. In addition, the two long-chain (C16, C18) acetylenic fatty acids inactivate the omega-hydroxylase at much lower concentrations (less than 5.0 microM) than those required for inactivation by the short-chain (C12) terminal acetylenic fatty acid (100 microM). Potent suicidal inhibitors of the LTB4 omega-hydroxylase in human PMN will help elucidate the roles played by LTB4 and its omega-oxidation products in regulating PMN function and in mediating inflammation. |
| Databáze: | OpenAIRE |
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