Platelet 12-lipoxygenase (12-LOX)

Platelet 12-lipoxygenase (12-LOX) is a dioxygenase enzyme that catalyzes the conversion of arachidonic acid to 12S-hydroxyeicosatetraenoic acid (12S-HETE), a bioactive lipid mediator critical for platelet activation, promoting integrin αIIbβ3 engagement, glycoprotein VI signaling, and protease-activated receptor-4 responses. Expressed predominantly in platelets, it exists as a dimer in its functional form, with higher oligomers like tetramers and hexamers potentially regulating activity through conformational changes and membrane interactions; the active site contains a nonheme iron cofactor bound to conserved histidine residues. In disease, 12-LOX contributes to thrombosis, cardiovascular risks such as hypertension and stroke, cancer progression (e.g., tumor promotion in skin carcinogenesis), and inflammation by enhancing platelet reactivity and clot formation. Its inhibition represents a promising antiplatelet strategy to prevent occlusive thrombosis while preserving hemostasis better than existing therapies like COX-1 or P2Y12 inhibitors. Selective inhibitors like ML355 block 12S-HETE production, reducing thrombosis in models without excessive bleeding, though challenges include off-target effects and the need for optimized compounds based on recent cryo-EM structures revealing oligomeric states and substrate binding.

Other names

platelet-type 12-(S)-lipoxygenasehp-12LOXhuman platelet 12-lipoxygenase12S-lipoxygenasep12-LOX

Selective inhibition of enzymatic activity to reduce 12S-HETE production, thereby attenuating platelet activation and aggregation without prolonging bleeding time