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    • Although only Leu CysAP IRAP Herbest

    2023-01-14

    Although only Leu/CysAP (IRAP) (Herbest et al., 1997, Keller, 2004) and DPPIV (Alponti and Silveira, 2010, Kirino et al., 2009) had been identified and studied in adipocytes, our kinetic analysis suggested the highest physiological significance for AspAP (highest affinity) and APM and PSA (highest efficiency). As its name suggests, IRAP in the adipocyte microsomal vesicles has the property to be translocated from low density microsomal fraction to plasma membrane under stimulation by insulin, afterwards also reported as stimulated by vasopressin, oxytocin and physical exercise (Herbest et al., 1997, Keller, 2004). IRAP remains in low density microsomal fraction under absent stimuli (Jordens et al., 2010). In this way, independently of food deprivation CysAP in plasma membrane was prevalent in both control and obese, suggesting the involvement of this enzyme in the regulation of peptides in the interstitial space of adipose tissue. It was noteworthy that CysAP in plasma membrane from all groups was prevalent over other AP activities, including LeuAP. In general, the catalytic action of IRAP has been evaluated only under a given baseline and using aminoacyl substrates with N-terminal Leu (Ross et al., 1996, Sano et al., 2005). IRAP and endoplasmic reticulum aminopeptidase (ERAP) types 1 and 2 are homologous proteins known to play critical roles in the generation of antigenic peptides (Hattori and Tsujimoto, 2013). However, available data on ERAPs also ignore the importance of the catalytic specificity of these enzymes. In this way, ERAPs have been known only based on their subcellular locations and this criterion seems not to be in accordance with a judicious enzyme classificatory system that serves to infer a physiological role. In fact, according to this criterion all AP activities identified in the present study can be classified as ERAPs, since they are found in high and low density microsomal fractions. Altered distribution and activity levels of AP Ghrelin (rat) during metabolic challenges, as detected in the present study, should alter concomitantly the levels of their susceptible peptide substrates. AspAP acts on ANG II to form ANG III (Johnson et al., 1984, Martínez-Martos et al., 2011) and a paracrine ANG system influences the insulin sensitivity and differentiation of adipose tissue (Weiland and Verspohl, 2009). Since obese and healthy animals, both under food deprivation, did not have AspAP activity, the metabolic challenge in these animals should be aggravated, because the absence of AspAP and consequent increased availability of ANG II should help the lipogenesis, but not the lipolysis. In food deprivation the lipolysis is required to provide energy substrate necessary for the maintenance of impaired physiological processes (Duarte et al., 2008, Stadler et al., 2005). Together with the proteasome (Duarte et al., 2008, Stadler et al., 2005), in which PSA is present, ERAPs are also involved in precursors hydrolysis of ligands. This hydrolytic activity of ERAPs is essential for generating peptides with appropriate size for binding to major histocompatibility complex type I, which enhances antigen presentation (Kloetzel and Ossendorp, 2004, Saveanu et al., 2009, Van Endert, 2011, Weimershaus et al., 2013). PSA activity of proteasome is the main responsible for the degradation of polyQ, which are highly toxic and associated with neurodegenerative diseases when accumulated (Bhutani et al., 2007, Menzies et al., 2010). Increased PSA activity found in low density microsomal fraction (proteasome-containing fraction) (Brooks et al., 2000) should affect the immune system in obese. Finally, MetAP is a metalloproteinase best known to be responsible for the removal of the amino acid Met from the N-terminus of newly synthesized proteins, facilitating their translocation from the ribosomes (Kishor et al., 2013, Mauriz et al., 2010). However, the relationship of energy metabolism dysfunction in obese with MetAP at plasma membrane location in adipocytes is probably due to the action of this enzyme in promoting a decreased adiponectin (Joharapurkar et al., 2014) and an increased formation of pro-angiogenic factors (Gonzalez-Perez et al., 2013).