STRUCTURE CONSERVATION IN LIPOXYGENASES - STRUCTURAL-ANALYSIS OF SOYBEAN LIPOXYGENASE-1 AND MODELING OF HUMAN LIPOXYGENASES

Lipoxygenases are a class of non-heme iron dioxygenases which catalyze the hydroperoxidation of fatty acids for the biosynthesis of leukotri enes and lipoxins, The structure of the 839-residue soybean lipoxygena se-1 was used as a template to model human 5-, 12-, and 15-lipoxygenas es, A distance-based algorithm for placing side chains in a low homolo gy environment (only the four iron ligands were fixed during side chai n placement) was devised. Twenty-six of the 56 conserved lipoxygenase residues were grouped in four distinct regions of the enzyme. These re gions were analyzed to discern whether the side chain interactions cou ld be duplicated in the models or whether alternate conformers should be considered. The effects of site directed mutagenesis variants were rationalized using the models of the human lipoxygenases. In particula r, variants which shifted positional specificity between 12- and 15-li poxygenase activity were analyzed. Analysis of active site residues pr oduced a model which accounts for observed lipoxygenase positional spe cificity and stereospecificity. (C) 1996 Wiley-Liss, Inc.