Characterization of leukotriene A4 and B4 bioysnthesis |
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Authors: | Barbara A Jakschik Christine G Kuo |
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Institution: | Department of Pharmacology Washington University School of Medicine 660 South Euclid Avenue St. Louis, Missouri 63110, U.S.A. |
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Abstract: | We have studied LTA4 and LTB4 synthesis in a cell-free system from RBL-1 cells. All the enzymes leading to the formation of LTB4 from arachidonic acid are localized in the soluble fraction (100, 000 x g supernatant) of these cells. The formation of LTA4 and LTB4 is complete by 10 min. When we varied the arachidonic acid concentration from 1 to 300 μM, the synthesis of LTB4 leveled off at 30 μM and of LTA4 at 100 μM while 5-HETE had not reached a plateau at 300 μM. This enzyme system has the capacity to generate relatively large amounts of 5-HETE and LTA4 and only a relatively small amount of LTB4. Therefore, the rate limiting step is not the 5-lipoxygenase, the first step in the pathway, but the conversion of LTA4 to LTB4. This is in contrast to cyclooxygenase pathway where the first step is rate limiting. A second addition of arachidonic acid at submaximal concentration for LTA4 synthesis did not produce any additional LTA4 or LTB4. Further study of this phenomenon showed that the 5-lipoxygenase and LTA-synthase were inactivated with time by preincubation with arachidonic acid and that peroxy fatty acids seem to be the inactivating species. |
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Keywords: | Leukotrienes 5-hydroxyeicosatetraenoic acid 5-lipoxygenase LTA-synthase LTA-hydrolase peroxy fatty acids |
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