Characterization of the Deoxyguanosine–Lysine Cross-Link of Methylglyoxal

Petrova, Katya V.; Millsap, Amy D.; Stec, Donald F.; Rizzo, Carmelo J.

doi:10.1021/tx500068v

Cited by 14 publications

(26 citation statements)

References 92 publications

(171 reference statements)

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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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“…The formation of DPC is not limited to oxidation by singlet oxygen. Numerous experimental studies have been carried out to explore the formation of DNA–protein cross‐links with isolated nucleobases and single‐ and double‐stranded DNA under different oxidative environments . Various oxidizing agents such as hydroxyl radicals, sulfate radicals, carbonate radicals, organic carcinogens such as aldehydes, transition‐metal ions such as Ni II , Cr VI , Fe II , Fe III , Ir IV , and ionizing radiation, UV‐, and visible light with photosensitizers are also found to induce DPC formation .…”

Section: Introductionmentioning

confidence: 99%

“…Numerouse xperimental studies have been carriedo ut to explore the formation of DNA-proteinc ross-links with isolatedn ucleobases and single-and double-stranded DNA under different oxidative environments. [12,17,30,[36][37][38][39][40][41][42][43][44][45][46][47][48] Various oxidizing agents such as hydroxyl radicals, sulfate radicals, carbonate radicals, organic carcinogens such as aldehydes,t ransition-metal ions such as Ni II ,C r VI ,F e II ,F e III ,I r IV ,a nd ionizing radiation, UV-, and visible light with photosensitizers are also found to induce DPC formation. [30, 36-38, 40, 49-53] The spectrum of the DPC products dependso nt he nature of the oxidizing agent.…”

Section: Introductionmentioning

confidence: 99%

Computational Study of Oxidation of Guanine by Singlet Oxygen (¹Δ_g) and Formation of Guanine:Lysine Cross‐Links

Thapa

Munk

Burrows

et al. 2017

Chemistry A European J

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Oxidation of guanine in the presence of lysine can lead to guanine-lysine cross-links. The ratio of the C4, C5 and C8 crosslinks depends on the manner of oxidation. Type II photosensitizers such as Rose Bengal and methylene blue can generate singlet oxygen, which leads to a different ratio of products than oxidation by type I photosensitizers or by one electron oxidants. Modeling reactions of singlet oxygen can be quite challenging. Reactions have been explored using CASSCF, NEVPT2, DFT, CCSD(T), and BD(T) calculations with SMD implicit solvation. The spin contamination in open-shell calculations were corrected by Yamaguchi's approximate spin projection method. The addition of singlet oxygen to guanine to form guanine endo- peroxide proceeds step-wise via a zwitterionic peroxyl intermediate. The subsequent barrier for ring closure is smaller than the initial barrier for singlet oxygen addition. Ring opening of the endoperoxide by protonation at C4-O is followed by loss of a proton from C8 and dehydration to produce 8-oxoG . The addition of lysine (modelled by methylamine) or water across the C5=N7 double bond of 8-oxoG is followed by acyl migration to form the final spiro products. The barrier for methylamine addition is significantly lower than for water addition and should be the dominant reaction channel. These results are in good agreement with the experimental results for the formation of guanine-lysine cross-links by oxidation by type II photosensitizers.

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“…4 MGO can also form lysine-lysine and lysine-arginine protein cross-links 10 and lysine-guanosine cross-link between proteins and DNA. 11 …”

Section: Introductionmentioning

confidence: 99%

5′-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls

Amarnath

Avance

et al. 2015

Chem. Res. Toxicol.

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Pyridoxamine (PM) is a prospective drug for treatment of diabetic complications. In order to make zwitterionic PM more lipophilic and improve its tissue distribution, PM derivatives containing medium length alkyl groups on the hydroxymethyl side-chain were prepared. The synthesis of these alkylpyridoxamines (alkyl-PMs) starting from pyridoxine offers high yields and is amenable to bulk preparations. Interestingly, alkyl-PMs were found to react with methylglyoxal (MGO), a major toxic product of glucose metabolism and autoxidation, several orders of magnitude faster than PM. This suggests the formation of non-ionic pyrido-1,3-oxazine as the key step in the reaction of PM with MGO. Since the primary target of MGO in proteins is the guanidine side-chain of arginine, alkyl-PMs were shown to be more effective than PM in reducing modification of N-α-benzoylarginine by MGO. Alkyl-PMs in the presence of MGO also protected the enzymatic activity of lysozyme that contains several arginine residues next to its active site. Alkyl-PMs can be expected to trap MGO and other toxic 1,2-carbonyl compounds more effectively than PM, especially in lipophilic tissue environments, thus protecting macromolecules from functional damage. This suggests potential therapeutic uses for alkyl-PMs in diabetes and other diseases characterized by the elevated levels of toxic dicarbonyl compounds.

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Characterization of the Deoxyguanosine–Lysine Cross-Link of Methylglyoxal

Cited by 14 publications

References 92 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

Computational Study of Oxidation of Guanine by Singlet Oxygen (¹Δ_g) and Formation of Guanine:Lysine Cross‐Links

5′-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls

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Characterization of the Deoxyguanosine–Lysine Cross-Link of Methylglyoxal

Cited by 14 publications

References 92 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

Computational Study of Oxidation of Guanine by Singlet Oxygen (1Δg) and Formation of Guanine:Lysine Cross‐Links

5′-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls

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Computational Study of Oxidation of Guanine by Singlet Oxygen (¹Δ_g) and Formation of Guanine:Lysine Cross‐Links