تسجيل الدخول

تسجيل

Lipoxygenase

المؤلف:  Norman, A. W., & Henry, H. L.

المصدر:  Hormones

الجزء والصفحة:  3rd edition , p178-179

2026-07-25

87

The open-chain eicosanoids are synthesized from arachidonic acid released from membrane glycerophospholipids by PLA2. In this case the first committed step of the pathway is not catalyzed by cyclooxygenase but by a lipoxygenase. There are at least three of these enzymes which are named for the carbon on which they bring about oxygenation. Detail regarding all of them is beyond the scope of this book, but a look at the 5-lipoxygenase pathway will serve as a good example of such a pathway that leads important arachidonic acid derivatives.

Arachidonic acid 5-lipoxygenase (5-LO) is a 78 kDa nonheme iron protein that requires another protein, 5-lipoxygenase activating protein (FLAP), for its activity. 5-LO catalyzes the addition of molecular oxy gen to the substrate, followed by the removal of water to produce LTA4. This unstable leukotriene can be enzymatically converted to the biologically active LTB4 by LTB4 hydrolase, as depicted in Figure1. LTA4 can also be converted to LTC4 by conjugation with glutathione, catalyzed by the glutathione-S-transferase, LTC4 synthase. The enzymatic shortening of the glutathione moiety results in the biologically active sulfated leu kotrienes, LTD4 and LTE4 (along with LCT4, the cysteinal leukotrienes or cyc-LTs). The activity of 5-LO is regulated by Ca2+ and phosphorylation of specific serine residues. In addition, the high concentrations of the product, LTA4, irreversibly inhibits the enzyme so that its continued production requires synthesis of new 5-LO.

Fig1. Leukotriene biosynthesis. The pathway from arachidonic acid through 5-lipoxygenase (5-LO) is shown. 5-LO requires a membrane protein, FLAP (5-lipoxygenase activating protein) for the two reactions it catalyzes to form leukotriene A4 (LTA4), which is converted to leukotriene B4 (LTB4) through the removal of a water molecule by LTA4 hydrolase. LTC4 arises from the addition of glutathione to carbon-6 by LTC4 synthase. The sequential removal of glutamate and glycine leads to the active leukotrienes D4 and E4. These three LTs are referred to as the cysteinal leukotrienes or cys-LTs.