Catalyzes the oxygenation of arachidonate to 5-hydroperoxyeicosatetraenoate (5-HPETE) followed by the dehydration to 5,6- epoxyeicosatetraenoate (Leukotriene A4/LTA4), the first two steps in the biosynthesis of leukotrienes, which are potent mediators of inflammation. Also catalyzes the oxygenation of arachidonate into 8-hydroperoxyicosatetraenoate (8-HPETE) and 12-hydroperoxyicosatetraenoate (12-HPETE). Displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene. Although arachidonate is the preferred substrate, this enzyme can also metabolize oxidized fatty acids derived from arachidonate such as (15S)-HETE, eicosapentaenoate (EPA) such as (18R)- and (18S)-HEPE or docosahexaenoate (DHA) which lead to the formation of specialized pro-resolving mediators (SPM) lipoxin and resolvins E and D respectively, therefore it participates in anti-inflammatory responses (By similarity). Oxidation of DHA directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma). It does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxin isomers. In addition to inflammatory processes, it participates in dendritic cell migration, wound healing through an antioxidant mechanism based on heme oxygenase-1 (HO-1) regulation expression, monocyte adhesion to the endothelium via ITGAM expression on monocytes. Moreover, it helps establish an adaptive humoral immunity by regulating primary resting B cells and follicular helper T cells and participates in the CD40-induced production of reactive oxygen species (ROS) after CD40 ligation in B cells through interaction with PIK3R1 that bridges ALOX5 with CD40. May also play a role in glucose homeostasis, regulation of insulin secretion and palmitic acid-induced insulin resistance via AMPK. Can regulate bone mineralization and fat cell differentiation increases in induced pluripotent stem cells (By similarity). (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = H2O + leukotriene A4 18-HEPE + O2 = (5S)-hydroperoxy-18-hydroxy-(7E,9E,11Z,14Z,16E)-eicosapentaenoate (18R)-hydroxy-(5Z,8Z,11Z,14Z,16E)-eicosapentaenoate + O2 = (5S)-hydroperoxy-(18R)-hydroxy-(6E,8Z,11Z,14Z,16E)-eicosapentaenoate (18S)-hydroxy-(5Z,8Z,11Z,14Z,16E)-eicosapentaenoate + O2 = (5S)-hydroperoxy-(18S)-hydroxy-(6E,8Z,11Z,14Z,16E)-eicosapentaenoate (5S)-hydroperoxy-(18S)-hydroxy-(6E,8Z,11Z,14Z,16E)-eicosapentaenoate = (5S,6S)-epoxy-(18S)-hydroxy-(7E,9E,11Z,14Z,16E)-eicosapentaenoate + H2O (5S)-hydroperoxy-(18R)-hydroxy-(6E,8Z,11Z,14Z,16E)-eicosapentaenoate = (5S,6S)-epoxy-(18R)-hydroxy-(7E,9E,11Z,14Z,16E)-eicosapentaenoate + H2O (5S)-hydroperoxy-18-hydroxy-(7E,9E,11Z,14Z,16E)-eicosapentaenoate = (5S,6S)-epoxy-18-hydroxy-(7E,9E,11Z,14Z,16E)-eicosapentaenoate + H2O (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = (5S)-hydroperoxy-(6E,8Z,11Z,14Z)-eicosatetraenoate (5Z,8Z,11Z,13E,15S)-hydroxyeicosatetraenoate + O2 = (5S)-hydroperoxy-(15S)-hydroxy-(6E,8Z,11Z,13E)-eicosatetraenoate (5S)-hydroperoxy-(6E,8Z,11Z,14Z)-eicosatetraenoate = H2O + leukotriene A4 (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = (8S)-hydroperoxy-(5Z,9E,11Z,14Z)-eicosatetraenoate (5Z,8Z,11Z,14Z)-eicosatetraenoate + O2 = (12S)-hydroperoxy-(5Z,8Z,10E,14Z)-eicosatetraenoate (5Z,8Z)-eicosadienoate + O2 = (5S)-hydroperoxy-(6E,8Z)-eicosadienoate (12S)-hydroxy-(5Z,8Z,10E,14Z)-eicosatetraenoate + O2 = (5S)-hydroperoxy-(12S)-hydroxy-(6E,8Z,10E,14Z)-eicosatetraenoate (5Z,8Z,11Z,14Z,17Z)-eicosapentaenoate + O2 = 5-hydroperoxy-(6E,8Z,11Z,14Z,17Z)-eicosapentaenoate (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + O2 = (14S)-hydroperoxy-(4Z,7Z,10Z,12E,16Z,19Z)-docosahexaenoate (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + O2 = (7S)-hydroperoxy-(4Z,8E,10Z,13Z,16Z,19Z)-docosahexaenoate (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + O2 = (17S)-hydroperoxy-(4Z,7Z,10Z,13Z,15E,19Z)-docosahexaenoate Binds 1 Fe cation per subunit. Lipid metabolism; leukotriene A4 biosynthesis. Homodimer. Interacts with ALOX5AP and LTC4S. Interacts with COTL1, the interaction is required for stability and efficient catalytic activity. Interacts with PIK3R1; this interaction bridges ALOX5 with CD40 after CD40 ligation in B cells and leads to the production of reactive oxygen species (ROS). Interacts (via PLAT domain) with DICER1 (via Dicer dsRNA-binding fold domain); this interaction enhances arachidonate 5-lipoxygenase activity and modifies the miRNA precursor processing activity of DICER1. Shuttles between cytoplasm and nucleus. Found exclusively in the nucleus, when phosphorylated on Ser-272. Calcium binding promotes translocation from the cytosol and the nuclear matrix to the nuclear envelope and membrane association. Serine phosphorylation by MAPKAPK2 is stimulated by arachidonic acid. Phosphorylation on Ser-523 by PKA has an inhibitory effect. Phosphorylation on Ser-271 prevents export from the nucleus. Phosphorylation at Ser-523 is stimulated by 8-bromo-3',5'-cyclic AMP or prostaglandin E2. Belongs to the lipoxygenase family.