On the Origin of Regio- and Stereo-Specific Catalysis by 8-Lipoxygenase

Lipoxygenases (lox’s) are a group of non-heme iron containing enzymes that catalyze oxygenation of polyunsaturated fatty acids with precise regio- and stereoselectivities. The origin of regio- and stereospecific catalysis by 8-lox is explored in its wild-type (wt) form and in three mutants (Arg185Ala, Ala592Met, and Ala623His). The catalytic action of this enzyme progresses in two steps, namely, hydrogen abstraction from one double allylic carbon atom of substrate followed by oxygen insertion at the resulting prochiral carbon radical of the substrate. It is shown that the positional specificity of the hydrogen abstraction is a result of conformational dynamics of the bound substrate. While the C10 atom of the substrate is found to be the most probable site of hydrogen abstraction in the wt-lox, hydrogen abstraction from C13 is more favorable in the mutants. The present study discovers the presence of an interconnected network of a three-channel migration pathway operating in the protein matrix for efficie...