The sequence of events in the biosynthesis of leukotrienes from arachidonic acid is inaugurated by the enzyme lipoxygenase. Like their counterparts, the prostaglandins in the cyclooxygenase pathway, the leukotrienes display a variety of medically relevant physiological effects. For example, low doses of these compounds evoke an inflammatory response in vivo. A group of leukotrienes has been identified as the agent responsible for the biological effects of slow reacting substance of anaphylaxis. In this capacity, they have a constricting effect on smooth muscle that is more powerful than that of histamine. Another leukotriene causes neutrophils to migrate to the site of its secretion. The accumulation of neutrophils in this way is a characteristic phenomenon in rheumatoid arthritis. Taken together, these findings firmly establish the involvement of these arachidonic acid metabolites in several health related physiological processes. The amount of information currently available on the enzymology of leukotriene biosynthesis is limited. It is the long term objective of this research to develop new diagnostic tools and therapeutic strategies based on an understanding of the biochemistry of leukotriene formation. The basic approach utilized will be the application of fundamental chemical principles for the solution of biochemical problems. Many areas of chemistry will be called upon to provide pertinent information. The concepts of electroanalytical chemistry, spectroscopy, synthetic organic chemistry, and chemical kinetics will be particularly useful. More specifically, the method of high performance liquid chromatography with electrochemical detection will be developed for the purpose of analyzing lipoxygenase (and cyclooxygenase) products in physiological fluids. This will provide biomedical researchers with a technique for the quantification of peroxides in a variety of experimental situations. This may prove to be of diagnostic value in the many deleterious processes associated with peroxide formation. Also, new derivatives of lipoxygenase products and substrates will be synthesized. These compounds are designated to provide direct information about the catalysis of lipoxygenase and the associated peroxidase. By studying the effects of such substances on these enzymes, it may be possible to provide information that will lead to new therapeutic strategies for diseases in which lipoxygenase metabolites are involved.
| Funk, M O; Whitney, M A; Hausknecht, E C et al. (1985) Resolution of the isoenzymes of soybean lipoxygenase using isoelectric focusing and chromatofocusing. Anal Biochem 146:246-51 |
