Methylglyoxal, an endogenous aldehyde, crosslinks DNA polymerase and the substrate DNA

Murata‐Kamiya, Naoko

doi:10.1093/nar/29.16.3433

Cited by 97 publications

(95 citation statements)

References 36 publications

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“…2). These findings emphasize the complexity of the AGE/RAGE interaction in mediating DAA, with evidence of a role for AGEs and precursors such as MGO, which can be generated by glucose and lipid peroxidation products (34), which are also elevated in subjects with diabetes. Furthermore, it appears that AGEs and dicarbonyl intermediates, such as MGO, can induce vascular inflammation independent of RAGE, although the identity of these other receptors are as yet unproven; however, Toll receptors and various scavenger receptors are likely candidates.…”

Section: Advanced Glycation Pathwaymentioning

confidence: 58%

Metabolic Karma—The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture

et al. 2018

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Cardiovascular disease, despite all the recent advances in treatment of the various risk factors, remains the major cause of mortality in both type 1 and type 2 diabetes. Experimental models of diabetes-associated atherosclerosis, despite their limitations in recapitulating the human context, have assisted in the elucidation of molecular and cellular pathways implicated in the development and progression of macrovascular injury in diabetes. Our own studies have emphasized the role of oxidative stress and advanced glycation and identified potential targets for vasoprotective therapies in the setting of diabetes. Furthermore, it has been clearly shown that previous episodes of hyperglycemia play a key role in promoting end-organ injury in diabetes, as shown in clinical trials such as the UK Prospective Diabetes Study (UKPDS), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation Observational Study (ADVANCE-ON), and the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC). The cause of this phenomenon, known as metabolic memory, remains to be elucidated, but it appears that epigenetic pathways, including glucose-induced histone methylation, play a central role. Further delineation of these pathways and their link to not only glucose but also other factors implicated in vascular injury should lead to more rational, potentially more effective therapies to retard diabetes-associated cardiovascular disease.

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Section: Advanced Glycation Pathwaymentioning

confidence: 58%

Metabolic Karma—The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture

et al. 2018

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“…Methylglyoxal is known to interact with several cellular proteins and nucleic acids, thereby leading to cytotoxic effects (25,45). The cytotoxic action occurs mainly through the induction of ROS, and methylglyoxal can increase oxidative stress by inactivating glutathion reductase (46).…”

Section: Discussionmentioning

confidence: 99%

Methylglyoxal Impairs the Insulin Signaling Pathways Independently of the Formation of Intracellular Reactive Oxygen Species

et al. 2006

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Nonenzymatic glycation is increased in diabetes and leads to elevated levels of advanced glycation end products (AGEs), which link hyperglycemia to the induction of insulin resistance. In hyperglycemic conditions, intracellularly formed ␣-ketoaldehydes, such as methylglyoxal, are an essential source of intracellular AGEs, and the abnormal accumulation of methylglyoxal is related to the development of diabetes complications in various tissues and organs. We have previously shown in skeletal muscle that AGEs induce insulin resistance at the level of metabolic responses. Therefore, it was important to extend our work to intermediates of the biosynthetic pathway leading to AGEs. Hence, we asked the question whether the reactive ␣-ketoaldehyde methylglyoxal has deleterious effects on insulin action similar to AGEs. We analyzed the impact of methylglyoxal on insulin-induced signaling in L6 muscle cells. We demonstrate that a short exposure to methylglyoxal induces an inhibition of insulin-stimulated phosphorylation of protein kinase B and extracellular-regulated kinase 1/2, without affecting insulin receptor tyrosine phosphorylation. Importantly, these deleterious effects of methylglyoxal are independent of reactive oxygen species produced by methylglyoxal but appear to be the direct consequence of an impairment of insulin-induced insulin receptor substrate-1 tyrosine phosphorylation subsequent to the binding of methylglyoxal to these proteins. Our data suggest that an increase in intracellular methylglyoxal content hampers a key molecule, thereby leading to inhibition of insulin-induced signaling. By such a mechanism, methylglyoxal may not only induce the debilitating complications of diabetes but may also contribute to the pathophysiology of diabetes in general.

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“…The latter effect is based on some experimental data [29,30] and should be equally conceptualized by theoretical analysis, such as an analysis based on the principle of Moller-Plesset perturbation [17]. This means that any opinion about cellular metabolism and telomere shortening needs to be debated, and we do not know whether the afore mentioned problem is solved completely or only partially.…”

Section: Discussionmentioning

confidence: 99%

DNA Replication and Telomere Shortening: Key Factors Related to the Production of C3-Aldehydes and the Interaction of One of them with DNA Guanine Residues

VN¹

2014

J Gerontol Geriatr Res

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The ketoaldehyde methylglyoxal (MG) is an aldehyde produced during aging. During cellular senescence, the ultimate and irreversible loss of replicative capacity of somatic cells takes place. The aging process needs to be explored carefully, as the well-known aging theory requires two additional ideas. One of these ideas is related to the MG-dependent loss of the hole-trapping property of the minor groove of DNA structure. The second idea pertains to local restriction and telomere shortening, which show some resemblance to the Olovnikov-Blackburn model. The ordering of such preliminary shortening is to eliminate the flawed part of the telomere and to expose the telomere to the activity of helicase.

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Methylglyoxal, an endogenous aldehyde, crosslinks DNA polymerase and the substrate DNA

Cited by 97 publications

References 36 publications

Metabolic Karma—The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture

Metabolic Karma—The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture

Methylglyoxal Impairs the Insulin Signaling Pathways Independently of the Formation of Intracellular Reactive Oxygen Species

DNA Replication and Telomere Shortening: Key Factors Related to the Production of C3-Aldehydes and the Interaction of One of them with DNA Guanine Residues

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