vascular endothelial model system. Leukotriene synthase activity The PUFA epoxide of arachidonic acid made by ALOX15 - eoxin A4 may also be conjugated with glutathione to form eoxin B4 which product can be further metabolized to eoxin C4, and eoxin D4. Substrates, substrate metabolites, and metabolite activities Among their physiological substrates, human and rodent AlOX15 enzymes act on linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid when presented not only as free acids but also when incorporated as esters in phospholipids, glycerides, or Cholesteryl esters. The human enzyme is particularly active on linoleic acid, preferring it over arachidonic acid. It is less active on PUFA that are esters within the cited lipids. Arachidonic acid Arachidonic acid (AA) has double bonds between carbons 5-6, 8-9, 11-12, and 14-15; these double bonds are in the cis (see Cis–trans isomerism or Z as opposed to the trans or E configuration). ALOX15 adds a hydroperoxy residue to AA at carbons 15 and to a lesser extent 12 to form 15(S)-hydroperoxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15(S)-HpETE) and 12(S)-hydroperoxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12(S)-HpETE); the purified enzyme makes 15(S)-HpETE and 12(S)-HpETE in a product ratio of ~4-9 to 1. Both products may be rapidly reduced by ubiquitous cellular Glutathione peroxidase enzymes to their corresponding hydroxy analogs, 15(S)-HETE (see 15-Hydroxyeicosatetraenoic acid) and 12(S)-HETE (see 12-Hydroxyeicosatetraenoic acid). 15(S)-HpETE and 15(S)-HETE bind to and activate the Leukotriene B4 receptor 2, activate the Peroxisome proliferator-activated receptor gamma, and at high concentrations cause cells to generate toxic reactive oxygen species; one or more of these effects may be at least in part responsible for their ability to promote inflammatory responses, alter the growth of various times of human cancer cell lines, contract various types of blood vessels, and stimulate pathological fibrosis in pulmonary arteries and liver (see 15-Hydroxyicosatetraenoic acid#15(S)-HpETE and 15(S)-HETE). 15(S)-HpETE and 15(S)-HETE are esterified into membrane phospholipids where they may be stored and subsequently released during cell stimulation. As one aspect of this processing, the two products are progressively esterified in mitochondria membrane phospholipids during the maturation of red blood cells (see erythropoiesis) and thereby may serve to signal for the degradation of the mitochondria and the maturation of these precursors to red blood cells in mice. This pathway operates along with two other mitochondria-removing pathways and therefore does not appear essential for mouse red blood cell maturation. 15-(S)-HpETE and 15(S)-HETE may be further metabolized to various bioactive products including: