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Review
. 2022 Oct 17;35(10):1720-1746.
doi: 10.1021/acs.chemrestox.2c00160. Epub 2022 Oct 5.

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

Seigmund Wai Tsuen Lai  1 , Edwin De Jesus Lopez Gonzalez  1 , Tala Zoukari  1 , Priscilla Ki  1 , Sarah C Shuck  1
Affiliations
Review

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

Seigmund Wai Tsuen Lai et al. Chem Res Toxicol. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
MG production from metabolic pathways. (A) During glycolysis, glucose is converted into DHAP or G3P which is metabolized by MS or TPI into MG. (B) In lipid metabolism, triacylglycerol undergoes hydrolysis to form fatty acids which are converted into acetol and acetone and then into MG by AMOO. (C) Ketones such as acetone, β-hydroxybutyric acid, and acetoacetic acid are converted to MG by cytochrome P450, AMOO, or MP. (D) During protein metabolism, amino acids such as glycine or threonine are metabolized by TDH into aminoacetone which is converted into MG by SSAO.
Figure 2
Figure 2
Various pathways for MG detoxification. (A) Glyoxalase system. MG reacts nonenzymatically with GSH to form a hemithioacetal which is recognized by GLO1. GLO1 converts the hemithioacetal to S-d-lactoylglutathione which is recognized by GLO2 to form d-lactate. (B) In addition to GLO1, AR also recognizes the hemithioacetal formed from the reaction of MG with GSH to lactaldehyde through an NADPH-dependent reaction. Lactaldehyde can undergo reduction, forming propanediol. (C) AR also recognizes MG directly through a GSH-independent mechanism, forming acetol which is reduced to form propanediol. GSH-independent reduction of MG by AR. (D) MG is oxidized by ALDH in an NAD-dependent mechanism to form pyruvate. (E) MG is oxidized by 2-ODH in an NADP-dependent reaction to form pyruvate.
Figure 3
Figure 3
Chemical structures of MG-modified nucleic and amino acids. (A) MG modifies dG, forming three main adducts, CEdG, cMG-dG, and MG-CEdG. Stereocenters are indicated by asterisks, and MG addition is shown in red. dR represents the deoxyribose sugar. (B) Proposed structure of MG-modified RNA adduct CEG. R represents the ribose sugar. (C) Arginine, lysine, and cysteine are primary targets for MG modification. Lysine modification forms CEL, and arginine modification forms MG-H1, MG-H2, and MG-H3. MG-H1 and MG-H3 can be hydrolyzed to form CEA. (D) MG can form lysine dimers MOLD and MODIC.
Figure 4
Figure 4
MG forms DNA MG-AGEs. (A) Adducts formed on deoxyguanosine bases can lead to improper base transversions in which guanine incorrectly base pairs with either adenine or guanine. (B) AGEs activate RAGE, and downstream signaling cascades to trigger NF-kB activation, leading to ROS production, inflammation, oxidative stress, etc. Created with BioRender.com.
Figure 5
Figure 5
MG and MG-AGEs have systemic physiological impacts on the body. MG and MG-AGEs have been implicated in the pathogenesis of numerous diseases throughout the body. This includes the brain, heart, skeletomuscular system, liver, pancreas, kidney, and immune system. Created with BioRender.com.
Figure 6
Figure 6
Approaches for measuring and targeting MG, MG-AGEs, and RAGE. (A) MG-AGEs can be quantified in vitro and in biological samples using LC-MS/MS. Example chromatogram is shown of the elution of MG-modified protein and DNA. (B) Molecules such as aminoguanidine and curcumin can be used to scavenge MG. MG and the formation of MG-AGEs can be targeted via scavenger compounds and using thiamine or benfoatiamine. AGEs can be targeted using sRAGE or alagebrium. RAGE activation can be inhibited using DNA aptamers, anti-RAGE antibodies, fusion proteins, peptides, or pharmacological inhibitors. Created with BioRender.com.
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