Figure 3 Metabolism of arachidonic acid (AA) to prostaglandin (PG) PGF2q, PGI2 (prostacyclin), PGE2, TXA2, and PGD2 by the COX pathway. PGI2 and TXA2 have very short half-lives (30s) and are converted to the stable but inactive 6-keto PGF1a and TXB2, respectively.
An alternative pathway available for the metabolism of AA is the 5-lipoxygenase (5-LO) pathway, which gives rise to the LTs which contain a conjugated triene structure. The 5-LO enzyme catalyzes the addition of oxygen at the 5th carbon of AA to produce 5-hydroperoxyeicosatetraenoic acid (5-HPETE) as well as the subsequent conversion of 5-HPETE to LTA4. 5-LO is dependent on ATP and Ca2+ for activation, following which it translocates from the cytosol to the cell membrane in association with a transmembrane protein termed FLAP (5-LO activating protein). This translocation step facilitates substrate presentation, since the majority of AA is found in the cell membrane. LTA4 may undergo one of two enzymatic reactions depending on the cell type. In the first, glutathione S-transferase (LTC synthase) catalyzes the addition of glutathione to the 6 position of LTA4 to produce the first of three cysteinyl LTs (CysLTs), LTC4. LTC4 is then exported to the extracellular space through a specific transmembrane transporter. In the extracellular space subsequent peptide cleavage yields LTD4 and then LTE4. This represents metabolism from one active mediator to another and not a catabolic inac-tivation process. Collectively, these three CysLTs (historically known as the slow-reacting substance of anaphylaxis) contribute to the bronchoconstrict-ing activity generated during anaphylaxis and they
Arachidonic acid 5-LO 5-HPETE
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