Hydroperoxidation of Docosahexaenoic Acid by Human ALOX12 and pigALOX15-mini-LOX

Abstract

Human lipoxygenase 12 (hALOX12) catalyzes the conversion of docosahexaenoic acid (DHA) into mainly 14S-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-docosahexaenoic acid (14S-H(p)DHA). This hydroperoxidation reaction is followed by an epoxidation and hydrolysis process that finally leads to maresin 1 (MaR1), a potent bioactive specialized pro-resolving mediator (SPM) in chronic inflammation resolution. By combining docking, molecular dynamics simulations, and quantum mechanics/molecular mechanics calculations, we have computed the potential energy profile of DHA hydroperoxidation in the active site of hALOX12. Our results describe the structural evolution of the molecular system at each step of this catalytic reaction pathway. Noteworthy, the required stereospecificity of the reaction leading to MaR1 is explained by the configurations adopted by DHA bound to hALOX12, along with the stereochemistry of the pentadienyl radical formed after the first step of the mechanism. In pig lipoxygenase 15 (pigALOX15-mini-LOX), our calculations suggest that 14S-H(p)DHA can be formed, but with a stereochemistry that is inadequate for MaR1 biosynthesis.

Construction of a Novel Mitochondria-Associated Gene Model for Assessing ESCC Immune Microenvironment and Predicting Survival

“…ALOX12 is a lipoxygenase in the 12-LOX family, which is primarily responsible for controlling intracellular peroxyl lipid signaling and metabolism [ 32 ]. ALOX12 has been identified a biomarker and therapeutic target in many human malignancies [ 33 ]; it is closely linked to the prognosis, tumor proliferation, invasion, and metastasis of colorectal cancer, and its high expression predicts a better immunotherapy response [ 34 ].…”