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  • br Regulation and pharmacology of mPGES

    2024-05-14


    Regulation and pharmacology of mPGES-1 mPGES-1 (16 kDa, 152 amino acids) is a trimeric integral membrane protein of the endoplasmic reticulum with each monomer containing four transmembrane domains (Samuelsson et al., 2007; Sjogren et al., 2013). The three active site cavities are located at the interface of the monomers and have their entrance in proximity to the cytoplasmic side of the transmembrane region. The peroxofuran group of PGH2 enters mPGES-1 at the interface of the membrane and cytosolic region and is bound in the substrate channel mdm2 inhibitor near the essential cofactor glutathione. Based on site-directed mutagenesis studies and the recently resolved crystal structure, a crystallographic water together with Arg126 and Asp49 has been proposed to activate glutathione as thiolate, which then attacks the peroxide of PGH2 (Brock et al., 2016; Raouf et al., 2016b; Sjogren et al., 2013). Access to the substrate channel is limited by so-called gate keeper mdm2 inhibitor which differ between species and explain the different susceptibility of human, mouse and rat mPGES-1 to high-affinity inhibitors (Pawelzik et al., 2010; Sjogren et al., 2013). The inducible isoenzyme mPGES-1, which is strongly upregulated at inflammatory sites (Samuelsson et al., 2007), plays a major role in inflammation, fever and pain, and essentially contributes to diseases with a chronic inflammatory component, such as arthritis, atherosclerosis and neurodegeneration (Bahia et al., 2014; Brenneis et al., 2011; Hara et al., 2010; Samuelsson et al., 2007; Wang and FitzGerald, 2010). Moreover, mPGES-1 is overexpressed in many types of cancer and promotes tumor initiation, progression as well as escape from the immune system (Koeberle and Werz, 2009; Larsson and Jakobsson, 2015; Radmark and Samuelsson, 2010; Samuelsson et al., 2007; Sasaki et al., 2015), the latter by regulating PD-L1 expression in tumor-associated macrophages (Prima et al., 2017). Constitutive expression of mPGES-1 is found in distinct organs including lung, kidney, the reproductive system, and gastric mucosa, though deletion of mPGES-1 seems not detrimental unless pathological or stress conditions are imposed (Bahia et al., 2014; Koeberle and Werz, 2015; Samuelsson et al., 2007). Homeostatic functions of mPGES-1 have been proposed in stressed kidneys, e.g., upon injury, high-salt diet, water loading or water deprivation (Jia et al., 2015; Yang and Chen, 2016), and contradictory results were obtained for the regulation of blood pressure and cardiac function (Chen et al., 2013; Ozen et al., 2017; Wang and FitzGerald, 2010). Other cardiovascular events, such as thrombosis, vascular inflammation and cardiac pathologies were either not affected or even reduced by deletion of mPGES-1 (Chen et al., 2013; Raouf et al., 2016a; Wang and FitzGerald, 2010). The COX-2/mPGES-1 axis mediates the excessive formation of PGE2 during inflammation (Samuelsson et al., 2007). Both enzymes are localized at the endoplasmic reticulum with mPGES-1 preferentially accepting the substrate PGH2 from COX-2. PGH2 is produced on the luminal side of the endoplasmic reticulum and has to transfuse through the membrane to reach the entrance of the mPGES-1 substrate channel (Jegerschold et al., 2008). The functional coupling of mPGES-1 to COX-2 is not irrevocable. Under specific conditions, for example in distinct regions of the kidney, COX-1 predominantly provides PGH2 to mPGES-1 (Schneider et al., 2004). PGE2 is also transcellularly synthesized which requires a rapid exchange of PGH2 between cells due to its short half-life (Folco and Murphy, 2006). The expression of both COX-2 and mPGES-1 is induced by diverse pro-inflammatory stimuli through the transcription factors NF-κB and early growth response protein (EGR)-1 (Koeberle and Werz, 2015; Samuelsson et al., 2007). In consequence, COX-2 and mPGES-1 are often co-expressed under inflammatory conditions, though with different protein expression kinetics. For example, the protein but not mRNA expression of mPGES-1 is delayed compared to COX-2 in LPS-challenged murine macrophages (Xiao et al., 2012), which suggests that either mRNA processing or translation are differentially regulated for the two inducible enzymes.