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Advanced Glycation Endproducts in Aging Skin
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Paraskevi Gkogkolou, Markus Böhm
It was initially believed that AGEs, once formed, can be only removed when the modified proteins degrade, with cathepsins D and L representing major enzymes for the intracellular degradation of endocytosed AGE-modified proteins (Grimm et al. 2012). However, it is now known, that many cells have intrinsic AGE-detoxifying pathways. The glutathione-dependent glyoxalase system consists of Glo I and II (Glyoxalase I and II), and uses reduced GSH to catalyze the conversion of glyoxal, methylglyoxal and other α-oxoaldehydes to the less toxic D-lactate (Xue et al. 2011). Fructosamine kinases are intracellular enzymes which phosphorylate and destabilize Amadori products leading to their spontaneous breakdown (Van Schaftingen et al. 2012). FN3K (Fructosamine-3-kinase), one of the most studied enzymes in this system, is almost ubiquitously expressed in human tissues, including the skin (Conner et al. 2005). Interestingly, decreased activity of such defense systems against AGEs has been reported during aging (Ramasamy et al. 2005). These age-related changes may increase the extent of deposited AGEs over time.
The role of soluble receptor for advanced glycation end-products (sRAGE) in the general population and patients with diabetes mellitus with a focus on renal function and overall outcome
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Mieke Steenbeke, Sander De Bruyne, Marc De Buyzere, Bruno Lapauw, Reinhart Speeckaert, Mirko Petrovic, Joris R. Delanghe, Marijn M. Speeckaert
A significant relationship between fructosamine 3-kinase (FN3K, an intracellular enzyme responsible for deglycation of proteins) polymorphisms and serum sRAGE concentrations has been demonstrated in patients with type 1 and type 2 diabetes. Higher circulating sRAGE values were associated with a mutation in rs3848403 (major/minor allele: C/T), whereas lower concentrations were found in patients with a mutation in rs1056534 (major/minor allele: C/G) [110]. On investigation of the diurnal variations of plasma sRAGE, overnight fasting in type 1 diabetes patients showed that short-term energy restriction resulted in an upregulation of sRAGE isoforms and a decrease in circulating AGE-free adducts (more specifically, methylglyoxal-derived hydroimidazolone Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1, a methylglyoxal-derived AGE; in this case, its circulating form)), which may be protective against AGE accumulation. However, a similar evolution of other AGE-free adducts (e.g. CML) was not observed. The exact direct or indirect mechanism by which sRAGE attenuates circulating MG-H1 concentrations is not yet resolved [111].
Enzymatic kinetics regarding reversible metabolism of CS-0777, a sphingosine 1-phosphate receptor modulator, via phosphorylation and dephosphorylation in humans
Published in Xenobiotica, 2018
Shin-Ichi Inaba, Maki Yamaguchi-Goto, Kaoru Tanaka-Takanaka, Kiyoaki Yonesu, Hidetaka Sakurai, Kazuishi Kubota, Takashi Izumi
In regard to CS-0777, it was recently revealed that fructosamine 3-kinase (FN3K) and FN3K related protein (FN3K-RP) are enzymes responsible for M1 formation (Yonesu et al., 2011), and alkaline phosphatase, a tissue nonspecific isozyme, which is also called ALPL, is one of the enzymes responsible for CS-0777 formation from M1 (Sakurai et al., 2013). These enzymes are considered to have no relationship with sphingosine metabolism. It is very interesting that the mechanism of action and the activation processes of Gilenya and CS-0777 are similar; however, the enzymes responsible for their activation processes are quite different.