Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N alpha-acetylarginine, N alpha-acetylcysteine, and N alpha-acetyllysine, and bovine serum albumin.

Lo, Theodore W. C.; Westwood, Marie; McLellan, Antony C.; Selwood, Trevor; Thornalley, Paul J.

doi:10.1016/s0021-9258(18)31635-1

Cited by 627 publications

(179 citation statements)

References 27 publications

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“…Although the concentration of MGO in plasma is~25,000fold lower than that of glucose, MGO is up to 50,000-fold more reactive than glucose with regard to glycation (562). Thus MGO causes very fast generation of glycation adducts on cellular and extracellular proteins (135,340,626), lipids (526), and DNA (326), potentially modifying their function.…”

Section: Metabolism Of Methylglyoxalmentioning

confidence: 99%

“…MGO is present in different forms. Only 1% of MGO exists in a free unhydrated, monohydrated, or dihydrated form (340), and the major part is reversibly bound to proteins, peptides, and amino acids. The free and reversibly bound comparison to extracellular levels are difficult to explain.…”

Section: A Formation Of Methylglyoxalmentioning

confidence: 99%

“…Glo1 expression is also under stress-responsive control by transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) (636). Transcription factor Nrf2 binds to this ARE in the 5=-untranslated region of exon 1 of GLO1 gene, increasing basal (340). In an irreversible reaction with arginine, MGO leads mainly to the formation of methylglyoxal-derived cyclic hydroimidazolones (MG-Hs).…”

Section: Glyoxalasementioning

confidence: 99%

“…MGO is one of the most important precursors of AGEs in vivo (FIGURE 1). MGO-derived AGEs result from modifica-tion of the amino acids arginine and, to a much lesser extent, lysine (340). In an irreversible reaction with the guanidine group of arginine, MGO leads mainly to the formation of three cyclic MGO-derived hydroimidazolones (MG-H): MG-H1, MG-H2 and MG-H3.…”

Section: Modification Of Proteins By Methylglyoxalmentioning

confidence: 99%

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Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Schalkwijk

Stehouwer

2020

Physiological Reviews

367

330

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The formation and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl compound, has been implicated in the pathogenesis of type 2 diabetes, vascular complications of diabetes, and several other age-related chronic inflammatory diseases such as cardiovascular disease, cancer and disorders of the central nervous system. MGO is mainly formed as a byproduct of glycolysis and, under physiological circumstances, detoxified by the glyoxalase system. MGO is the major precursor of non-enzymatic glycation of proteins and DNA, subsequently leading to the formation of advanced glycation endproducts (AGEs). MGO and MGO-derived AGEs can impact on organs and tissues affecting their functions and structure. This 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 diabetes, vascular complications of diabetes and other age-related diseases. Although therapies to treat MGO-associated complications are not yet available for application in clinical practice, several strategies to lower MGO have been developed over the years. We will summarize several new directions to target MGO stress including glyoxalase inducers and MGO scavengers. Diminishing MGO burden 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: Metabolism Of Methylglyoxalmentioning

confidence: 99%

Section: A Formation Of Methylglyoxalmentioning

confidence: 99%

Section: Glyoxalasementioning

confidence: 99%

Section: Modification Of Proteins By Methylglyoxalmentioning

confidence: 99%

See 2 more Smart Citations

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Schalkwijk

Stehouwer

2020

Physiological Reviews

367

330

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“…In healthy tissue, levels of free MG are around 1 -10 μM [6,26,27] and approximately double in disease [28]. However, the majority of MG is found on glycated proteins [29], meaning these measurements of free MG significantly underestimate the amount of MG glycation that occurs. To ensure this MG treatment increased glycation of the myofilament, we treated mouse left ventricular skinned myocytes with 100 μ M MG for 20 mins.…”

Section: Computational Predications Of Molecular Processes Dysregulated By Mgmentioning

confidence: 99%

Myofilament Glycation in Diabetes Reduces Contractility by Inhibiting Tropomyosin Movement, is Rescued by cMyBPC Domains

Papadaki

Kampaengsri

Barrick

et al. 2021

Preprint

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Diabetes doubles the risk of developing heart failure (HF). As the prevalence of diabetes grows, so will HF unless the mechanisms connecting these diseases can be identified. Methylglyoxal (MG) is a glycolysis by-product that forms irreversible modifications on lysine and arginine, called glycation. We previously found that myofilament MG glycation causes sarcomere contractile dysfunction and is increased in patients with diabetes and HF. The aim of this study was to discover the molecular mechanisms by which MG glycation of myofilament proteins cause sarcomere dysfunction and to identify therapeutic avenues to compensate. In humans with type 2 diabetes without HF, we found increased glycation of sarcomeric actin compared to non-diabetics and it correlated with decreased calcium sensitivity. Depressed calcium sensitivity is pathogenic for HF, therefore myofilament glycation represents a promising therapeutic target to inhibit the development of HF in diabetics. To identify possible therapeutic targets, we further defined the molecular actions of myofilament glycation. Skinned myocytes exposed to 100 μM MG exhibited decreased calcium sensitivity, maximal calcium-activated force, and crossbridge kinetics. Replicating MG’s functional affects using a computer simulation of sarcomere function predicted simultaneous decreases in tropomyosin’s blocked-to-closed rate transition and crossbridge duty cycle were consistent with all experimental findings. Stopped-flow experiments and ATPase activity confirmed MG decreased the blocked-to-closed transition rate. Currently, no therapeutics target tropomyosin, so as proof-of-principal, we used a n-terminal peptide of myosin-binding protein C, previously shown to alter tropomyosin’s position on actin. C0C2 completely rescued MG-induced calcium desensitization, suggesting a possible treatment for diabetic HF.

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Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons: Synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases

et al. 1999

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In this study, we investigate the neurotoxicity of glycation, particularly early-stage glycation, and its mechanisms, which are possibly synergized with oxidative stress. Methylglyoxal (MG) and 3-deoxyglucosone (3DG), intermediate products of glycation, are known to further accelerate glycation and advanced glycation endproducts (AGEs) formation. Both compounds showed neurotoxicity on cultured cortical neurons and these effects were associated with reactive oxygen species production followed by neuronal apoptosis. Pretreatment with N-acetylcysteine induced neuroprotection against MG and 3DG. Cotreatment, but not pretreatment, with aminoguanidine protected neurons against the neurotoxicities of both compounds. The present study provides the first evidence that MG and 3DG are neurotoxic to cortical neurons in culture. Interference with the process by which glycation and AGEs formation occur may provide new therapeutic opportunities to reduce the pathophysiological changes associated with neurodegeneration, if, as indicated here, the participation of glycoxidation in the pathogenesis of neurodegenerative diseases is essential.

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Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N alpha-acetylarginine, N alpha-acetylcysteine, and N alpha-acetyllysine, and bovine serum albumin.

Cited by 627 publications

References 27 publications

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Methylglyoxal, a Highly Reactive Dicarbonyl Compound, in Diabetes, Its Vascular Complications, and Other Age-Related Diseases

Myofilament Glycation in Diabetes Reduces Contractility by Inhibiting Tropomyosin Movement, is Rescued by cMyBPC Domains

Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons: Synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases

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