Structure and mechanism of lipoxygenases

• Published in: Biochimie Vol. 79; no. 11; pp. 629 - 636
• Main Authors: Prigge, S.T., Boyington, J.C., Faig, M., Doctor, K.S., Gaffney, B.J., Amzel, L.M.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-11-1997
• Subjects: Animals; arachidonic acid metabolism; dioxygenase; Humans; leukotrienes; lipoxins; Lipoxygenase - chemistry; Lipoxygenase - metabolism; Models, Molecular; non-heme iron; Protein Conformation; dioxygenase; non-heme iron; lipoxins; arachidonic acid metabolism; leukotrienes
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/S0300-9084(97)83495-5

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 effectors. It is the branch point between two central pathways: one, involving the enzyme cyclooxygenase, 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 effective pharmacological inhibitor of lipoxygenase is presently available. Lipoxygenases are large non-heme, iron-containing enzymes that use molecular oxygen for the diooxygenation of arachidonic acid to form hydroperoxides, the first step in the biosynthetic pathways leading to leukotrienes and lipoxins. Because of the importance of these compounds, lipoxygenases have been the subject of extensive study: from detailed kinetic measurements to cloning, expression, and site-directed mutagenesis. The sequences of over 50 lipoxygenases have been reported. In addition, the structure of soybean lipoxygenase-1, determined by X-ray diffraction methods, has recently been reported. The structure revealed that the 839 amino acids in the protein are organized in two domains: a β-sheet N-terminal domain and a large, mostly helical C-terminal domain. The iron is present in the C-terminal domain facing two internal cavities that are probably the conduits through which the fatty acid and molecular oxygen gain access to the metal. Models of the mammalian lipoxygenases based on the soybean structure provide clues about the structural determinants of the positional specificity of the enzyme, and can be used as targets for the design of more effective inhibitors.