STRUCTURE AND MECHANISM OF LIPOXYGENASES

In mammals, lipoxygenases catalyze the formation of hydroperoxides as the first step in the biosynthesis of several inflammatory mediators, The substrate of this reaction, arachidonic acid, is the key precursor of two families of potent physiological effecters. It is the branch p oint between two central pathways: one, involving the enzyme cyclooxyg enase, leads to the synthesis of prostaglandins and thromboxanes; the other, involving lipoxygenases, leads to the synthesis of leukotrienes and lipoxins, compounds that regulate important cellular responses in inflammation and immunity. While aspirin and other non-steroidal anti -inflammatory compounds are potent inhibitors of cyclooxygenase, no ef fective pharmacological inhibitor of lipoxygenase is presently availab le. Lipoxygenases are large non-heme, iron-containing enzymes that use molecular oxygen for the diooxygenation of arachidonic acid to form h ydroperoxides, the first step in the biosynthetic pathways leading to leukotrienes and lipoxins. Because of the importance of these compound s, lipoxygenases have been the subject of extensive study: from detail ed kinetic measurements to cloning, expression, and site-directed muta genesis. The sequences of over 50 lipoxy have been reported. In additi on, the structure of soybean lipoxygenase-1, determined by X-ray diffr action methods, has recently been reported. The structure revealed tha t the 839 amino acids in the protein are organized in two domains: a b eta-sheet N-terminal domain and a large, mostly helical C-terminal dom ain, The iron is present in the C-terminal domain facing two internal cavities that are probably the conduits through which the fatty acid a nd molecular oxygen gain access to the metal. Models of the mammalian lipoxygenases based on the soybean structure provide clues about the s tructural determinants of the positional specificity of the enzyme, an d can be used as targets for the design of more effective inhibitors.