Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance

Thornalley, Paul J.; Waris, Sahar; Fleming, Thomas; Santarius, Thomas; Larkin, Sarah J.; Winklhofer‐Roob, Brigitte M.; Stratton, Michael R.; Rabbani, Naila

doi:10.1093/nar/gkq306

Cited by 101 publications

(119 citation statements)

References 35 publications

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“…The major function of the glyoxalase pathway is detoxification of the reactive dicarbonyl metabolite, methylglyoxal, converting it to D-lactate. Methylglyoxal is a highly potent glycating agent of protein that forms the quantitatively major advanced glycation end product, hydroimidazolone MG-H1, linked to protein inactivation and cell dysfunction (4,5) (Fig. 1B).…”

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confidence: 99%

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

et al. 2016

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Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)-an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal-may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m 2 ), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P < 0.05) and decreased plasma methylglyoxal (237%, P < 0.05) and total body methylglyoxal-protein glycation (214%, P < 0.01). It decreased fasting and postprandial plasma glucose (25%, P < 0.01, and 28%, P < 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL $ min 21 $ m 22, P < 0.02), and improved arterial dilatation Dbrachial artery flowmediated dilatation/Ddilation response to glyceryl nitrate (95% CI 0.13-2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-1 (210%, P < 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations.

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Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

et al. 2016

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“…Dicarbonyl stress increases modification of both protein and DNA by MG [4,5]. MG modification is a major cause of endogenous DNA damage: MGdG is the major quantitative adduct of endogenous DNA damage in vivo and is associated with mutagenesis [5].…”

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confidence: 99%

“…MG modification is a major cause of endogenous DNA damage: MGdG is the major quantitative adduct of endogenous DNA damage in vivo and is associated with mutagenesis [5]. Increased functional Glo1 copy number provides for cytoprotective response and survival against dicarbonyl stress.…”

Section: Discussionmentioning

confidence: 99%

“…We previously found increased GLO1 copy number in some drug naïve human tumours associated with increased Glo1 expression. Increased GLO1 copy number was often functional giving rise to high Glo1 expression and activity permissive for tumour growth in a background of high flux of MG formation [5,68]. Increased Glo1 expression also confers MDR in cancer chemotherapy [69].…”

Section: Discussionmentioning

confidence: 99%

“…0.1% glucose flux from anaerobic glycolysis [2,3]. MG is a highly potent glycating agent and, although formed at relatively low flux, its high reactivity leads to formation of some of the most quantitatively important endogenous damaging modifications of protein and DNA: arginine-derived hydroimidazolone MG-H1 and deoxyguanosine-derived imidazopurinone MGdG [4,5] (Figure 1b and 1c). Glo1 suppresses the steady-state level of MG and thereby also suppresses the level of MG-H1 and MGdG to low tolerable levels; 1 -2% of protein and 1 in 10 5 nucleotides, respectively [4,5].…”

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Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

Shafie

Xue

Barker

et al. 2016

Biochemical Journal

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Glyoxalase 1 (Glo1) is a cytoplasmic enzyme with a cytoprotective function linked to metabolism of the cytotoxic side product of glycolysis, methylglyoxal (MG). It prevents dicarbonyl stress — the abnormal accumulation of reactive dicarbonyl metabolites, increasing protein and DNA damage. Increased Glo1 expression delays ageing and suppresses carcinogenesis, insulin resistance, cardiovascular disease and vascular complications of diabetes and renal failure. Surprisingly, gene trapping by the International Mouse Knockout Consortium (IMKC) to generate putative Glo1 knockout mice produced a mouse line with the phenotype characterised as normal and healthy. Here, we show that gene trapping mutation was successful, but the presence of Glo1 gene duplication, probably in the embryonic stem cells (ESCs) before gene trapping, maintained wild-type levels of Glo1 expression and activity and sustained the healthy phenotype. In further investigation of the consequences of dicarbonyl stress in ESCs, we found that prolonged exposure of mouse ESCs in culture to high concentrations of MG and/or hypoxia led to low-level increase in Glo1 copy number. In clinical translation, we found a high prevalence of low-level GLO1 copy number increase in renal failure where there is severe dicarbonyl stress. In conclusion, the IMKC Glo1 mutant mouse is not deficient in Glo1 expression through duplication of the Glo1 wild-type allele. Dicarbonyl stress and/or hypoxia induces low-level copy number alternation in ESCs. Similar processes may drive rare GLO1 duplication in health and disease.

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Crystal structures of human glyoxalase I and its complex with TLSC702 reveal inhibitor binding mode and substrate preference

et al. 2022

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Human glyoxalase I (hGLO I) is an enzyme for detoxification of methylglyoxal (MG) and has been considered an attractive target for the development of new anticancer drugs. In our previous report, the GLO I inhibitor TLSC702 induced apoptosis in tumor cells. Here, we determined the crystal structures of hGLO I and its complex with TLSC702. In the complex, the carboxyl O atom of TLSC702 is coordinated to Zn2+, and TLSC702 mainly shows van der Waals interaction with hydrophobic residues. In the inhibitor‐unbound structure, glycerol, which has similar functional groups to MG, was bound to Zn2+, indicating that GLO I can easily bind to MG. This study provides a structural basis to develop better anticancer drugs.

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Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance

Cited by 101 publications

References 35 publications

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

Improved Glycemic Control and Vascular Function in Overweight and Obese Subjects by Glyoxalase 1 Inducer Formulation

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

Crystal structures of human glyoxalase I and its complex with TLSC702 reveal inhibitor binding mode and substrate preference

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