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Advanced Glycation End Products—A Special Hazard in Diabetes
Published in Robert Fried, Richard M. Carlton, Type 2 Diabetes, 2018
Robert Fried, Richard M. Carlton
Concerning the metabolic fate of glyoxal, the large majority is enzymatically converted into glycolate by a glutathione (GSH)-dependent glyoxalase system, which comprises two isozymes differing for tissue and subcellular localization (Mannervik. 2008). When GSH is depleted, as happens in many oxidative-based disorders, other enzymes including aldehyde reductase, aldose reductase, carbonyl reductase, aldehyde dehydrogenase, and 2-oxoaldehyde dehydrogenase can contribute to the glyoxal metabolism (Shangari, Bruce, Poon et al. 2003).
Carbonyl Toxification Hypothesis of Biological Aging
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
α,β-Unsaturated carbonyls have also been found in many other biological interactions, such as the base-propenals, which are oxidation products of sugars attached to DNA bases; acrolein and crotonaldehyde, which are air pollutants; and trans, trans-muconaldehyde, which is a microsomal metabolite of benzene.68 Pyruvaldehyde, also named methylglyoxal (MG), is another example of a cytotoxic and genotoxic DMcarbonyl. MG exists widely in food and beverages69 and may be produced during Maillard reactions.38 In biological systems, however, MG may also be synthesized by several metabolic pathways. For example, MG is synthesized from dihydroxylacetone phosphate when catalyzed by MG synthetase; MG may also be made from aminoacetone during the catabolism of L-threonine.70,71 On the other hand, MG may be eliminated by several biological pathways, including (1) conversion into D-lactate by the glutathione-requiring glyoxalase system, and (2) oxidation to pyruvate catalyzed by MG dehydrogenases.70 Although the functions of MG and its conversion to lactic acid by glyoxalase in biological system are still unclear, the glyoxalase system was found to be clearly related to DNA synthesis and cell proliferation, which may provide insights into cellular senescence.70
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.
Methylglyoxal enhances the proliferation of vascular smooth muscle cells via Akt phosphorylation
Published in Journal of Receptors and Signal Transduction, 2022
MGO is a glycolysis by-product that carries aldehyde and ketone reactive groups, making it very reactive. Its concentration is elevated in people with diabetes and has an active role in diabetic complications. Moreover, MGO is associated with hypertension and cardiovascular diseases [1]. Although glucose is a well-known agent to trigger advanced glycation end product (AGEs) formation, MGO is 20,000 times more potent than it. The glyoxalase system detoxifies more than 99% of MGO and keeps its concentration 50,000 times lower than glucose. Thus, MGO does not cause a problem in a healthy organism [2]. However, the system is impaired in people with diabetes; hence MGO concentration rises, resulting in dicarbonyl stress. This stress is described as high concentrations of dicarbonyl metabolites such as MGO, leading to increased protein and DNA damage that contributes to cell and tissue dysfunction [3].
Methylglyoxal disturbs DNA repair and glyoxalase I system in Saccharomyces cerevisiae
Published in Toxicology Mechanisms and Methods, 2021
Sandra Sartoretto Pavin, Alessandro de Souza Prestes, Matheus Mulling dos Santos, Gabriel Teixeira de Macedo, Sabrina Antunes Ferreira, Mariana Torri Claro, Cristiane Dalla Corte, Nilda Vargas Barbosa
The pathways for MG detoxification have been studied in many organisms (Inoue and Kimura 1995; Kalapos 1999). In yeast, the catabolism of MG encompasses the glyoxalase system, and the enzymes MG reductase, aldolase reductase, and D-lactate dehydrogenases (Marmstål et al. 1979; Inoue and Kimura 1996; Aguilera and Prieto 2004; Gomes et al. 2005; Scheckhuber 2019). Among them, the glyoxalase system has been thought to be the major detoxifying route for MG. The system comprises the enzyme glyoxalase I (encoded by the Glo1 gene) that converts MG to S-D-lactoylglutathione using GSH as specific cofactor; and the enzyme glyoxalase II (encoded by the Glo2 and Glo4 genes) that hydrolyzes the glutathione thioester to D-lactic acid (Bito et al. 1997; Aguilera and Prieto 2004; Inoue et al. 2011). Herein, we analyzed the effects of MG in strains lacking Glo1, Glo2, and Gsh genes. We found that MG inhibited the growth and decreased the cell viability of S. cerevisiae Glo1 and Gsh1 mutant strains without causing disruptions in Glo2 mutants (Figures 2 and 4(D,E)). Taken together, these findings indicate an especial participation of glyoxalase I system on the MG detoxification in S. cerevisiae. In agreement, there is evidence that carbonyl compounds as glycerol and MG provoke growth arrest and cell killing in S. cerevisiae glyoxalase I deficient mutant strains (Penninckx et al. 1983; Inoue et al.1999; Takatsume et al. 2004, 2006; Gomes et al. 2005). It has been shown that MG is able to activate the expression of Glo1 and Gre3, two genes involved in MG metabolism, and also the GPD1, a gene engaged in glycerol synthesis (Aguilera and Prieto 2004).
Methylglyoxal stimulates endoplasmic reticulum stress in vascular smooth muscle cells
Published in Journal of Receptors and Signal Transduction, 2022
It seems MGO could stimulate ER stress transiently. In addition to our p-PERK, IRE1α, and ATF6 data, we did not observe a change in MGO-induced BiP (Grp78) and CHOP expressions. While Liu et al. [26] reported that they did not find any effect of MGO on BiP and CHOP levels parallel to our findings, Palsamy et al. [25] highlighted that MGO application reduced BiP and CHOP expressions. Other studies displayed that MGO induction resulted in enhanced BiP and CHOP expressions [21,23,24]. Moreover, Lenin et al.’s [27] mRNA data supported their findings. As Thornalley [28] indicates, utilizing a high concentration of MGO (mM levels) is of unlikely physiological relevance because of the intracellular concentration of MGO at 1–5 µM levels. Besides, our findings did not show enhanced apoptosis of VSMCs (data are not shown), which correlates with unchanged CHOP expression. The reason behind this phenomenon could arise from applied MGO detoxified by the glyoxalase system before it triggered an apoptotic response. It means healthy VSMCs might handle MGO-induced ER stress without enhancing CHOP expression and sparking apoptosis. When the glyoxalase system fails, as in diabetics, MGO might activate CHOP expression and apoptosis. This situation may be dangerous when VSMCs stabilize plaque structure to prevent the rupture. Applying a high concentration of MGO to overcome MGO disposal does not seem plausible because Liu et al. [26] highlighted that administering high MGO concentration increased Glo1 expression in vitro. Glo1 silencing to elevate intracellular MGO may be preferred. Finally, AGH, 4-PBA, and TUDCA were effective against MGO-induced ER stress, which was compatible with the literature.