Methylglyoxal induces DNA crosslinks in ECV304 cells via a reactive oxygen species-independent protein carbonylation pathway

Tu, Chih-Yu; Chen, Yun-Fang; Lii, Chong‐Kuei; Wang, Tsu-Shing

doi:10.1016/j.tiv.2013.02.011

Cited by 20 publications

(13 citation statements)

References 52 publications

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“…Up to 1 in 100 000 nucleotides in DNA is an MGdG adduct [61]. Modification of DNA by MGO results in higher numbers of DNA strand breaks [61], nucleotide transversions [62], DNA-DNA cross-links [63], DNA-protein cross-links [64] and glycation of the nucleosomal protein histone H2A [65]. Although the biological consequences of MGOderived DNA adducts have not yet been fully established, the non-enzymatic glycation of DNA by MGO may have severe implications for various pathological conditions, such as age-related complications.…”

Section: Modification Of Dna By Mgo and Its Functional Consequencesmentioning

confidence: 99%

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

2015

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The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.

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Section: Modification Of Dna By Mgo and Its Functional Consequencesmentioning

confidence: 99%

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

2015

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“…25−28 DNA–protein cross-links have been observed when Chinese hamster ovary, human skin, or human endothelial (ECV304) cells were exposed to methylglyoxal. 29−31 Additionally, cross-links between the dGuo adduct of glyoxal and other DNA bases have been characterized and observed from the DNA of exposed cells. 32−34 …”

Section: Introductionmentioning

confidence: 99%

Characterization of the Deoxyguanosine–Lysine Cross-Link of Methylglyoxal

Petrova

Millsap

Stec

et al. 2014

Chem. Res. Toxicol.

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Methylglyoxal is a mutagenic bis-electrophile that is produced endogenously from carbohydrate precursors. Methylglyoxal has been reported to induce DNA–protein cross-links (DPCs) in vitro and in cultured cells. Previous work suggests that these cross-links are formed between guanine and either lysine or cysteine side chains. However, the chemical nature of the methylglyoxal induced DPC have not been determined. We have examined the reaction of methylglyoxal, deoxyguanosine (dGuo), and Nα-acetyllysine (AcLys) and determined the structure of the cross-link to be the N2-ethyl-1-carboxamide with the lysine side chain amino group (1). The cross-link was identified by mass spectrometry and the structure confirmed by comparison to a synthetic sample. Further, the cross-link between methylglyoxal, dGuo, and a peptide (AcAVAGKAGAR) was also characterized. The mechanism of cross-link formation is likely to involve an Amadori rearrangement.

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“…Methylglyoxal‐induced modifications on DNA are 3‐(2′‐deoxyribosyl)‐6,7‐dihydro‐6,7‐dihydroxy‐6‐methylimidazo‐[2,3‐ b ]purine‐9(8)one (dG‐MG) and N 2‐(1‐carboxyethyl)‐deoxyguanosine (CEdG). Apart from initiating nucleotide AGE formation, methylglyoxal also mediates interpolymer (DNA–DNA, DNA–protein, and protein–protein) crosslinking . Few examples of such interpolymer interactions are as follows: DNA polymerase Klenow fragment crosslinked with DNA strand on exposure to 1 mM methylglyoxal for 60 min , crosslinkage of calf thymus DNA , and DNA–protein crosslink in Chinese hamster ovary (CHO)cells on exposure to 1.5 mM methylglyoxal for 90 min .…”

Section: Cytotoxicity: Ages and Crosslinked Adductsmentioning

confidence: 99%

“…A recent report by Tu et al . suggested that the process of crosslinking is independent of ROS; however, accumulation of methylglyoxal has typically been observed under oxidative stress.…”

Section: Cytotoxicity: Ages and Crosslinked Adductsmentioning

confidence: 99%

Cells producing their own nemesis: Understanding methylglyoxal metabolism

2014

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Methylglyoxal, which is technically known as 2-oxopropanal or pyruvaldehyde, shows typical reactions of carbonyl compounds as it has both an aldehyde and a ketone functional group. It is an extremely cytotoxic physiological metabolite, which is generated by both enzymatic and nonenzymatic reactions. The deleterious nature of the compound is due to its ability to glycate and crosslink macromolecules like protein and DNA, respectively. However, despite having toxic effects on cellular processes, methylglyoxal retains its efficacy as an anticancer drug.Indeed, methylglyoxal is one of the well-known anticancer therapeutic agents used in the treatment. Several studies on methylglyoxal biology revolve around the manifestations of its inhibitory effects and toxicity in microbial growth and diabetic complications, respectively. Here, we have revisited the chronology of methylglyoxal research with emphasis on metabolism of methylglyoxal and implications of methylglyoxal production or detoxification on bacterial pathogenesis and disease progression. V C 2014 IUBMB Life, 66(10): [667][668][669][670][671][672][673][674][675][676][677][678] 2014

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Methylglyoxal induces DNA crosslinks in ECV304 cells via a reactive oxygen species-independent protein carbonylation pathway

Cited by 20 publications

References 52 publications

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

Characterization of the Deoxyguanosine–Lysine Cross-Link of Methylglyoxal

Cells producing their own nemesis: Understanding methylglyoxal metabolism

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