Mechanism for the formation of methylglyoxal from triosephosphates

Richard, John P.

doi:10.1042/bst0210549

Cited by 238 publications

(166 citation statements)

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“…unavoidable consequence of glycolytic metabolism (26). MG can also be formed from the leakage of the 1,2-enediolate intermediate in the active center of triosephosphate isomerase in a paracatalytic reaction (27). Consequently, ADTIQ is produced when DA reacts with MG (Fig.…”

Section: Discussionmentioning

confidence: 99%

Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes

Song

Xin

Xie

et al. 2013

International Journal of Molecular Medicine

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Abstract. There are statistical data indicating that diabetes is a risk factor for Parkinson's disease (PD). Methylglyoxal (MG), a biologically reactive byproduct of glucose metabolism, the levels of which have been shown to be increase in diabetes, reacts with dopamine to form 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ); this formation may provide further insight into the connection between PD and diabetes. In this study, we investigated the role of ADTIQ in these two diseases to determine in an aim to enhance our understanding of the link between PD and diabetes. To this end, a cell model of hyperglycemia and a rat model of diabetes were established. In the cell model of hyperglycemia, compared with the control group, the elevated glucose levels promoted free hydroxyl radical formation (p<0.01). An ADTIQ assay was successfully developed and ADTIQ levels were detected and quantified. The levels of its precursors, MG and dopamine (DA), were determined in both the cell model of hyperglycemia and the rat model of diabetes. The proteins related to glucose metabolism were also assayed. Compared with the control group, ADTIQ and MG levels were significantly elevated not only in the cell model of hyperglycemia, but also in the brains of rats with diabetes (p<0.01). Seven key enzymes from the glycolytic pathway were found to be significantly more abundant in the brains of rats with diabetes. Moreover, it was found that adenosine triphosphate (ATP) synthase and superoxide dismutase (SOD) expression levels were markedly decreased in the rats with diabetes compared with the control group. Therefore, ADTIQ expression levels were found to be elevated under hyperglycemic conditions. The results reported herein demonstrate that ADTIQ, which is derived from MG, the levels of which areincreased in diabetes, may serve as a neurotoxin to dopaminergic neurons, eventually leading to PD. IntroductionDiabetes mellitus (DM), as a state of chronic hyperglycemia, and Parkinson's disease (PD) are diseases which consist a global health threat. In recent years, there have been increasing data indicating that hyperglycemia is associated with an increased risk of developing PD (1,2). However, the mechanisms underlying the association between hyperglycemia and PD have not yet been elucidated.Deng and Rajput (6) were the first to report, in 2001, that 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (ADTIQ), a salsolinol-like compound, is found at highly concentrated levels in the brains of patients who suffer from PD (3). When the brains of deceased patients with PD were compared to those of normal subjects, it was found that patients with PD presented elevated levels of ADTIQ in all the examined brain areas. This finding indicated that elevated ADTIQ expression levels may be one of the mechanisms involved in the increased risk patients with diabetes have of developing PD (4).Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycem...

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Section: Discussionmentioning

confidence: 99%

Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes

Song

Xin

Xie

et al. 2013

International Journal of Molecular Medicine

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“…Z74948 and X87331). Previously, we had also mapped the GLO4 gene to chromosome 2 The gene names GLO2 and GLO4 were reserved in the SGD Gene Name Registry (internet: http://genome-www.stanford.edu.html); the gene name GLO3 was already registered for a gene encoding a zinc finger protein of yet unknown function with similarity to the Gcs1 protein (Gcs1p-like ORF).…”

Section: Molecular Cloning and Sequence Determination Of The Glyoxalamentioning

confidence: 99%

“…The most important substrate seems to be methylglyoxal. In most organisms, this toxic compound is formed as a by-product of glycolysis from triose phosphates through the action of triose-phosphate isomerase (2). But the main source for methylglyoxal in yeast and other microorganisms is dihydroxyacetone phosphate which is converted to methylglyoxal by the methylglyoxal synthase (3,4).…”

mentioning

confidence: 99%

Identification and Phenotypic Analysis of Two Glyoxalase II Encoding Genes from Saccharomyces cerevisiae,GLO2 and GLO4, and Intracellular Localization of the Corresponding Proteins

Bito

Haider

Hadler

et al. 1997

Journal of Biological Chemistry

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We have isolated and characterized two genes coding for the glyoxalase II enzyme from Saccharomyces cerevisiae. The coding region of the GLO2 gene corresponds to a protein with 274 amino acids and a molecular mass of 31,306 daltons. The open reading frame of the GLO4 gene could be translated into a protein with 285 amino acids and a molecular mass of 32,325 daltons. The amino acid sequences of the deduced proteins are 59.1% identical and show high similarities to the sequence of the human glyoxalase II. When grown on either glucose or glycerol as a carbon source, a glo2 glo4 double deletion strain contains no glyoxalase II activity at all and shows no obvious phenotype during vegetative growth. However, this strain showed a similar high sensitivity against exogenous methylglyoxal as compared with a glyoxalase I-deficient strain. Whereas the GLO2 gene is expressed on both glucose and glycerol, the GLO4 gene is only active on glycerol. The active Glo2p protein is localized in the cytoplasm and the active Glo4p in the mitochondrial matrix. Heterologous expression of the full-length GLO2 coding region in Escherichia coli resulted in an active protein. However, to get an active Glo4p protein in E. coli, the putative mitochondrial transit peptide at the N-terminal end had to be removed by shortening the 5 end of the GLO4 open reading frame.

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“…The elimination of phosphate from glyceraldehyde-3-phosphate and dihydroxyacetone phosphate is the major enzymatic source of MGO in vivo (Pompliano et al, 1990;Phillips and Thornalley, 1993;Richard, 1993). In Figure 2 the mechanism of the reaction is given.…”

Section: Enzymatic Reactionsmentioning

confidence: 99%

Interplay Between Oxidative and Carbonyl Stresses: Molecular Mechanisms, Biological Effects and Therapeutic Strategies of Protection

Semchyshyn¹,

Lushchak²

2012

Oxidative Stress - Molecular Mechanisms and Biological Effects

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Mechanism for the formation of methylglyoxal from triosephosphates

Cited by 238 publications

References 2 publications

Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes

Formation of a salsolinol-like compound, the neurotoxin, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, in a cellular model of hyperglycemia and a rat model of diabetes

Identification and Phenotypic Analysis of Two Glyoxalase II Encoding Genes from Saccharomyces cerevisiae,GLO2 and GLO4, and Intracellular Localization of the Corresponding Proteins

Interplay Between Oxidative and Carbonyl Stresses: Molecular Mechanisms, Biological Effects and Therapeutic Strategies of Protection

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