Methylglyoxal and Its Adducts: Induction, Repair, and Association with Disease

Abstract

Metabolism is an essential part of life that provides energy for cell growth. During metabolic flux, reactive electrophiles are produced that covalently modify macromolecules, leading to detrimental cellular effects. Methylglyoxal (MG) is an abundant electrophile formed from lipid, protein, and glucose metabolism at intracellular levels of 1–4 μM. MG covalently modifies DNA, RNA, and protein, forming advanced glycation end products (MG-AGEs). MG and MG-AGEs are associated with the onset and progression of many pathologies including diabetes, cancer, and liver and kidney disease. Regulating MG and MG-AGEs is a potential strategy to prevent disease, and they may also have utility as biomarkers to predict disease risk, onset, and progression. Here, we review recent advances and knowledge surrounding MG, including its production and elimination, mechanisms of MG-AGEs formation, the physiological impact of MG and MG-AGEs in disease onset and progression, and the latter in the context of its receptor RAGE. We also discuss methods for measuring MG and MG-AGEs and their clinical application as prognostic biomarkers to allow for early detection and intervention prior to disease onset. Finally, we consider relevant clinical applications and current therapeutic strategies aimed at targeting MG, MG-AGEs, and RAGE to ultimately improve patient outcomes.

Fermented Supernatants of Lactobacillus plantarum GKM3 and Bifidobacterium lactis GKK2 Protect against Protein Glycation and Inhibit Glycated Protein Ligation

“…The results indicated that GKM3- and GKK2-fermented supernatants significantly inhibited MG-induced ketoamine production in the early stage of the in vitro MG-BSA glycation model ( p < 0.05) ( Figure 1 ). MG can modify amino residues, specifically lysine and arginine, generating adducted amino residues, which can further result in protein cross-linking and the formation of macromolecules in the late stage of protein glycation [ 2 ]. In the present study, MG-induced protein cross-links can be found in the late stage of the in vitro MG-BSA glycation model as evidenced by the graphs of SDS-PAGE ( Figure 2 ).…”

“…Argpyrimidine is an MG-derived advanced glycation end product (AGE), which is implicated in aging-related cognitive dysfunction [ 30 ] and other disorders [ 2 ]. Gomes et al found a high concentration of argpyrimidine in the patients with familial amyloidotic polyneuropathy, a neurologic disease [ 31 ].…”

“…Aging is often recognized as a progressive degeneration in physiological capacity, which may be a consequence of reactive oxygen species (ROS)-/reactive carbonyl species (RCS)-mediated biological events [ 1 , 2 ]. In this regard, RCS-induced protein glycation and the derived accumulation of advanced glycation end products (AGEs) during the aging process have received great attention, because these events may be the key bridge connecting aging with different human diseases such as atherosclerosis, diabetes, or neurodegenerative symptoms [ 3 ].…”

Structural Insights into Electrophiles and Electrophilic Metabolites Sensing and Signaling: The Missing Information

“…Beyond the reactive enals and ene-dicarbonyls such as respectively HNE and DMF, as discussed above, native reactive electrophilic molecules, such as methylglyoxal or 15-deoxy-Δ (12,14)-prostaglandin J₂ (15d-PGJ₂)-nature's small molecules playing functional roles in various disease-relevant biological processes-constitute additional classes of native reactive electrophiles, where gaining a comprehensive picture of how these electrophiles form functional covalent complexes with their target proteins, could prove helpful. [69][70][71] A couple of crystal structures of 15d-PGJ₂protein complexes have been reported, although we did not include them here as our discussion was restricted to native reactive electrophiles of 200 Da or less. [72][73][74] On the other hand, and to the best of our knowledge, no structural data exist for the non-Michael-acceptor-based electrophile methylglyoxal-bound proteins.…”

In Vitro Antiglycation and Methylglyoxal Trapping Effect of Peppermint Leaf (Mentha × piperita L.) and Its Polyphenols

“…MGO-derived AGEs have been shown to play a pivotal role in the onset and progression of vascular complications of diabetics. Methylglyoxal thus appears to be a significant contributor to endothelial dysfunction by increasing oxidation, as well as inducing inflammation and apoptosis [ 1 , 2 , 3 , 4 ]. Therefore, MGO scavenging and glycation inhibition are now recognized as promising therapeutic targets in diabetes, pre-diabetes, and early prevention of hyperglycemic complications.…”