In humans the major LOs are subdivided by their

In humans, the major LOs are subdivided by their positional specificity into 5-(ALOX5), 12-(ALOX12) and 15-LO (ALOX15) (Kuhn et al., 2015). 5-LO is the key enzyme for LT biosynthesis and mainly found in mature cells from myeloid origin, including neutrophil, eosinophil and basophil granulocytes, monocytes, macrophages and mast cells (Radmark et al., 2015a). 12-LO is abundant in platelets, erythroleukemia cells and endothelial cells and catalyzes the peroxidation of AA at C12 under formation of 12-hydroperoxyeicosatetraenoic b 35 (HPETE) (Kuhn et al., 2015). 15-LOs, which are highly expressed in reticulocytes, eosinophils and bronchial epithelium (ALOX15) as well as in epithelial cells and macrophages (ALOX15B), accordingly synthesize 15-HPETE from AA. LOs accept a wide range of PUFAs and generate by successive (partially transcellular) oxygenation pleiotropic mono-, di- and trihydroxylated metabolites, including hydroxyoctadecadienoic acids (HODEs), (di)hydroxyeicosatrienoic acids (HETrEs), (di)HETEs, (di)hydroxypentaenoic acids (HEPEs), (di)hydroxydocosahexaenoic acids (HDHAs), lipoxins, resolvins, protectins and maresins (Serhan, 2014; Stables and Gilroy, 2011). The variety of LO products is further increased by cytochrome P450 monooxygenase-derived precursors that can undergo further enzymatic lipoxygenation. LTs have established roles in asthma, allergic rhinitis and autoimmune diseases, but also in neurodegeneration, atherosclerosis and cancer (Peters-Golden and Henderson Jr, 2007; Radmark and Samuelsson, 2010; Radmark et al., 2015a). After translocation to the nuclear membrane, 5-LO receives its substrate AA from 5-LO-activating protein (FLAP) and subsequently catalyzes the synthesis of LTA4 via oxygenation of AA to the intermediate 5-HPETE. LTA4 is converted by LTA4 hydrolase to LTB4, which is a potent chemoattractant and activates leukocytes, among others by inducing neutrophil degranulation, the formation of reactive oxygen species, neutrophil-endothelial cell adhesion, nuclear factor (NF)-κB signaling and cytokine production (Peters-Golden and Henderson Jr, 2007). Conjugation of glutathione to LTA4 by LTC4 synthase yields LTC4, which is further cleaved by extracellular peptidases to LTD4 and LTE4. These so-called cysteinyl-LTs induce vascular leakage and the contraction of smooth muscles, thereby inducing bronchoconstriction in asthma (Haeggstrom et al., 2010; Peters-Golden and Henderson Jr, 2007; Radmark et al., 2015a). LOs (particularly 15-LOs) also essentially contribute to membrane lipid peroxidation (by oxygenation of esterified PUFAs) and mediate ferroptosis leading to pathological cell death in degenerative diseases (Kagan et al., 2017; Yang et al., 2016; Yang and Stockwell, 2016). Among the eicosanoids produced via the COX/LO pathways, LTs and PGE2 are the most important pro-inflammatory lipid mediators that are the major target molecules of pharmacological approaches for intervention with inflammatory disorders. Single targeting of either 5-LO, FLAP, LTA4 hydrolase or LTC4 synthase abrogates LT formation, while inhibitors of COX-1/2 or PGES cause blockade of PGE2 biosynthesis (Table 1). Notably, most of the compounds that cause simultaneous suppression of LT and PGE2 biosynthesis are dual 5-LO/mPGES-1 inhibitors followed by dual 5-LO/COX-2 inhibitors.
Regulation and pharmacology of 5-lipoxygenase Among the six LOs in humans, 5-LO is likely the most prominent enzyme related to inflammation due to its crucial function in the biosynthesis of pro-inflammatory LTs (Radmark et al., 2015b). The structural properties and the cellular regulation of 5-LO are rather unique as compared to other LOs. For example, conversion of endogenously released AA to LTA4 by 5-LO in the cell strikingly depends on the presence of the nuclear membrane-bound FLAP (Dixon et al., 1990), while other LOs convert AA without the need for FLAP. The current view of the role of FLAP for 5-LO is to facilitate AA transfer and correct positioning of the substrate to the 5-LO active site (Ferguson et al., 2007) within a 5-LO/FLAP complex that is formed after 5-LO has been translocated from a soluble pool to the nuclear envelope (Gerstmeier et al., 2016). Knowledge of the complex regulation of 5-LO may offer valuable opportunities for pharmacological strategies that can be exploited to intervene with the enzyme's activity and thus with the biosynthesis of pro-inflammatory LTs.