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    • LO is a soluble kDa enzyme composed of an helix

    2024-04-29

    5-LO is a soluble 78 kDa enzyme, composed of an α-helix-rich catalytic domain and a regulatory β-sheet-rich C2-like domain. Depending on the cell type, 5-LO may be located in the cytosol, in the nucleoplasm, or in both compartments (Werz, 2002). Upon cell stimulation by agents that elevate intracellular Ca2+ levels and/or activate mitogen-activated protein kinase (MAPK) family members, 5-LO rapidly translocates to the nuclear membrane where it binds to phosphatidylcholine via the C2-like domain in a Ca2+-dependent fashion (Radmark et al., 2015b). ATP binds and stimulates 5-LO, which is subject of 1568 at serine residues that either promote 5-LO activation (Ser271 and Ser663) or suppress the enzymatic activity (Ser523). Moreover, PC and diacylglycerols as well as lipid hydroperoxides govern 5-LO activation as well (Radmark et al., 2015b). For pharmacological suppression of LT biosynthesis, inhibition of 5-LO is the most common strategy, although among the plethora of candidate compounds developed during the past 35 years, only zileuton reached the marked (Steinhilber and Hofmann, 2014). These direct 5-LO inhibitors are divided into redox-active (antioxidants or redox uncoupling agents like nordihydroguaiaretic acid) and iron-chelating compounds (e.g., zileuton) that act at the active site iron of 5-LO, nonredox-type inhibitors that either compete with AA at the active site, and compounds that interfere with 5-LO via putative allosteric sites (e.g., AA861, ZM230487, hyperforin, or sulindac sulfide) (Pergola and Werz, 2010). Blockade of FLAP (e.g., by MK886, GSK2190915, or BRP-187) is an attractive alternative to 5-LO inhibition with comparable effect on LT formation, and promising results have recently encouraged for intensive preclinical evaluations of novel FLAP-targeting compounds (Werz et al., 2017). It is emphasized that the development of 5-LO and FLAP inhibitors was strongly hampered because of two major issues in preclinical and clinical studies: (i) toxicity (mainly 5-LO inhibitors) and (ii) lack of efficiency and thus efficacy (Steinhilber and Hofmann, 2014). In fact, 5-LO is highly susceptible for inhibition by various types of small molecules, and a plethora of synthetic and natural compounds that inhibit 5-LO activity in vitro were reported that failed to inhibit 5-LO under biological relevant conditions and/or were inactive in vivo. The lack of therapeutic efficacy of 5-LO and FLAP inhibitors might be due to multiple reasons. First, the pathophysiological role of 5-LO products could be limited and thus 5-LO and FLAP are poor drug targets. However, trials with LT receptor antagonists and genetic deletion of 5-LO and FLAP clearly proved for the pathological relevance of LTs (Peters-Golden and Henderson Jr, 2007; Steinhilber and Hofmann, 2014). Second, inappropriate pharmacokinetics (e.g., poor bioavailability, plasma protein binding, short half-lives) hampered the efficiency of 5-LO and FLAP inhibitors. Especially, the rather lipophilic FLAP inhibitors and fatty acid-mimicking 5-LO inhibitors were found to be prone to plasma albumin binding. Third, an androgen-mediated sex bias in the regulation of 5-LO and FLAP that significantly reduced the efficiency of clinical relevant LT biosynthesis inhibitors in males (Pace et al., 2017) may have blunted the action of anti-LT agents in male study subjects that were primarily used in the past for (pre-)clinical evaluation of such drugs. Pharmacological interference with 5-LO or FLAP is anticipated to block the formation of all LTs and 5-LO pathway-derived products. In contrast, inhibitors of LTA4 hydrolase (e.g., bestatin, DG-051 or JNJ-40929837) block solely the formation of LTB4 while maintaining LTC4 and 5-HETE synthesis (Werz et al., 2017). These agents are highly interesting as they may redirect the produced LTA4 towards lipoxins that are anti-inflammatory lipid mediators (Caliskan and Banoglu, 2013). Finally, inhibition of LTC4 synthase (e.g., by MK886, thymoquinone or TK04a) to selectively suppress formation of cysteinyl-LTs without blocking LTB4 and 5-HETE, is considered as pharmacological strategy particularly for treatment of asthma (Werz et al., 2017). It should be noted that FLAP, LTC4 synthase and mPGES-1 belong to the same family of proteins, the so-called membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEGs) that are similar in structure with high homology, and they share many features. In fact, several compounds were reported to interfere with all three proteins, such as MK886 or BRP-187 that in analogy to dual 5-LO/mPGES-1 inhibitors dually block LT/PGE2 formation (Werz et al., 2017).