Membrane topology of proteins involved in eicosanoid synthesis. The active sites of LTC₄ synthase, COX1, COX2, and the lipid-binding domain of FLAP are all oriented to the lumen of the ER and the nuclear envelope.

LT biosynthesis and assembly. Upon cellular activation of a mast cell or macrophage by IgE-antigen complexes or other stimuli, a cascade of cell activation events results in LT biosynthesis. A concomitant rise in free calcium induces translocation of cPLA₂ to intracellular membranes, where it releases arachidonic acid. In parallel, 5-LO is phosphorylated by MAP kinase kinase and traffics through the nuclear pore to the nucleus (possibly in association with NF-κB) or directly to the outer nuclear envelope. 5-LO then associates with the nuclear membrane, and possibly with FLAP. FLAP facilitates arachidonic acid presentation to 5-LO and subsequent conversion of arachidonic acid to LTA₄. LTA₄ interacts with LTA₄ hydrolase to form LTB₄, or with LTC₄ synthase to form LTC₄. The synthesis of LTs A₄, B₄, and C₄probably takes place within the lumen of, or in close proximity to, the nuclear membranes. However, for clarity they are shown here throughout the cytosol. FLAP is present on both the inner and the outer nuclear envelope, but LTC₄ synthase is exclusively expressed on the outer nuclear membrane and ER.