Activation and execution of lipoxygenase catalysis

As noted in Gordon A. Hamilton's classic review "Chemical Models and Mechanisms for Oxygenases", the direct reaction of a triplet molecule (i.e. O₂) with a singlet to give singlet products is a spin-forbidden process (in Molecular Mechanisms of Oxygen Activation, O. Hayaishi (Ed), Academic Press, NY, pp. 405-451, 1974). As lipoxygenases are among the enzymes that do not activate molecular oxygen, activation of the fatty acid substrate is required. Furthermore, lipoxygenases do not bind the reacting O₂ molecule and it is free to travel wherever diffusion takes it. On top of all this, lipoxygenase enzymes are in a catalytically inactive state at rest. Within this set of limitations, here we consider lipoxygenase activation and the challenges overcome in execution of catalysis including activation of the catalytic metal, issues of substrate orientation, O₂ channels, hydrogen abstraction, and residues that affect regio- and stereo-specificity of the product hydroperoxides.