The 12-lipoxygenase (12-LOX) is one of the primary enzymes involved in platelet activation. The enzyme 12-LOX oxidizes arachidonic acid to produce 12-hydroperoxyeicosatetraeonic acid (12-HpETE), a small molecule with a pro-thrombotic role in thrombogenesis. Because of this, 12-LOX dysregulation leads to occlusive thrombotic events, myocardial infarction, and stroke. Biochemical evidence of 12-LOX suggests that it exists in multiple oligomeric states that may affect its enzymatic activity and, therefore is likely to influence its regulation.
To that end, we have determined the first structures of human 12-LOX and include structures in different oligomeric states using cryo-EM. High-resolution structures of 12-LOX dimer and a tetramer provide unique insights into the assembly of 12-LOX oligomers and provide some understanding of its catalytic mechanism.