STUDIES ON METHYLGLYOXAL BIS(GUANYLHYDRAZONE) ANALOGS. IV. ACETYLATION STUDIES.
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Acetylation↗
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Aminoacetone induces oxidative modification to human plasma ceruloplasmin.
Aminoacetone (AA), a putative endogenous source of cytotoxic methylglyoxal, and ceruloplasmin (CP), the antioxidant plasma copper transporter, are known to increase in diabetes. AA was recently shown in vitro to act as a pro-oxidant toward ferritin and isolated mitochondria. We now report AA oxidative effects on CP mediated by AA-generated reactive oxygen species (ROS). Incubation of 1.5 microM human CP with 0.05-1 mM AA resulted in extensive protein aggregation. That ROS-driven thiol cross-linking underlies the CP aggregation was evidenced by the inhibitory effects of added superoxide dismutase, catalase, mannitol, and dithiothreitol. The addition of CP to AA (mM) solutions accelerated oxygen consumption by AA and caused CP copper ion release and loss of ferroxidase and aminoxidase activities. If operative in vivo, this reaction would impair the antioxidant role of CP and iron uptake by ferritin and hence contribute to intracellular iron-induced oxidative stress during AA accumulation in diabetes mellitus.
Acetone↗
Identification of DNA adducts of methylglyoxal.
Methylglyoxal (MG) is a sugar degradation product, which is endogenously formed by fragmentation of triose phosphates during glycolysis, ketone body metabolism of acetone, and catabolism of threonine. Food, beverages, and medical products are important exogenous sources with concentrations of up to 100 microM MG. MG is a reactive dicarbonyl compound, which easily modifies amino groups of proteins (glycation reaction) and thereby induces proinflammatory responses. Moreover, increased mutation frequencies in mammalian cells after treatment with MG have been reported, which are caused by stable modifications of DNA bases. Thus far, two types of adducts have been identified, which are formed during the reaction of free guanine or 2'-deoxyguanosine with high MG concentrations. In this study, we investigated the prolonged exposure of DNA to physiological MG concentrations. DNA was incubated with MG, enzymatically hydrolyzed to release the free nucleosides, and then analyzed by LC-MS/MS. We detected four products, which were derived from the reaction of 2'-deoxyguanosine and 2'-deoxyadenosine with 1 and 2 equiv of MG each. The adducts with 1 equiv of MG were identified as N2-(1-carboxyethyl)-2'-deoxyguanosine (CEdG) and N6-(1-carboxyethyl)-2'-deoxyadenosine. LC-MS/MS was optimized for these compounds, and incubation of DNA was repeated using physiological concentrations of 10 microM MG. Thereby, CEdG proved to be the most sensitive and suitable marker for the reaction of DNA with MG (negative MRM mode, three mass transitions [M - 1](-) 338-->178, 338-->106, and 338-->149).
Animals↗
Identification of 4-oxo-2-hexenal and other direct mutagens formed in model lipid peroxidation reactions as dGuo adducts.
We searched for mutagens that react with 2'-deoxyguanosine (dGuo) in model systems of lipid peroxidation. To autoxidation systems of methyl linoleate (model of omega-6 fat), methyl alpha-linolenate (MLN) (model of omega-3 fat), and commercial salad oil, dGuo was added. The reaction mixtures were analyzed by HPLC. Six adducts were detected, and their structures were determined by 1H and 13C NMR, UV, and mass spectra and by comparison with synthetic authentic samples. The mutagens that reacted with dGuo to form these adducts were proposed as glyoxal, glyoxylic acid, ethylglyoxal, and 4-oxo-2-hexenal (4-OHE). The formation of 8-hydroxy-dGuo, an oxidized product of dGuo, was also detected in the model reaction mixtures. Among them, glyoxal and glyoxylic acid are known mutagens, while ethylglyoxal and 4-OHE, produced from MLN, have not been reported as mutagens thus far. We confirmed the mutagenic activity of 4-OHE with Salmonella strains, TA100 and TA104, without S9 mix. These compounds may be involved in lipid peroxide-related cancers.
Aldehydes↗
N2,7-bis(1-hydroxy-2-oxopropyl)-2'-deoxyguanosine: identical noncyclic adducts with 1,3-dichloropropene epoxides and methylglyoxal.
cis- and trans-1,3-dichloropropene epoxides (1,3-D-epoxides) are proposed to be the penultimate or ultimate genotoxic metabolites of the major soil fumigant nematicide 1,3-dichloropropene. The 1, 3-D-epoxide isomers and the potential aldehydes from their degradation readily form adducts with 2'-deoxyguanosine (dGuo) but not with 2'-deoxyadenosine or 2'-deoxycytidine. The reaction of dGuo with the 1,3-D-epoxides (1:20 molar equiv) in phosphate buffer at pH 7.4 for 24 h at 37 degreesC results in complete conversion to four adducts that can be separated by HPLC with the same UV spectra and electrospray (ES)/MS molecular ion and fragmentation patterns. These adducts contain no chlorine and are identical to those obtained more rapidly with methylglyoxal in place of the 1,3-D-epoxides. The four isomeric methylglyoxal adducts with dGuo were proposed originally by others to be the cyclic adducts 1,N2-(1, 2-dihydroxy-2-methyl)ethano-dGuo, but they are reassigned here as the four diastereomers of the noncyclic bis adducts N2, 7-bis(1-hydroxy-2-oxopropyl)-dGuo. The assignments are based on HPLC/UV and HPLC/ES/MS experiments and 1H NMR spectral analysis of the first of the four adducts eluted with HPLC. Acid-catalyzed depurination converts the four dGuo derivatives to the two corresponding isomers of N2,7-bis(1-hydroxy-2-oxopropyl)guanine, assigned by ES/MS and 1H and 13C NMR. Although identical adducts are formed from dGuo with the 1,3-D-epoxides or methylglyoxal, the latter alpha,beta-dicarbonyl compound is not an intermediate in the reaction; instead, the 1,3-D-epoxides hydrolyze to 3-chloro-2-hydroxypropanal which adds to dGuo at N2 and N7. The adducts dehydrochlorinate, in a rate-limiting reaction, thereby giving the same end products obtained on direct reaction with methylglyoxal. Thus, 3-chloro-2-hydroxypropanal (not the 1, 3-D-epoxides or methylglyoxal) is the derivatizing agent for dGuo and therefore probably the mutagenic agent on 1,3-D bioactivation. On the basis of the dGuo model studied here, the DNA adducts of 1, 3-D and its epoxides may be the same as those with methylglyoxal [Vaca, C. E., Fang, J.-L., Conradi, M., and Hou, S.-M. (1994) Carcinogenesis 15, 1887-1894].
Allyl Compounds↗
Detoxification of methylglyoxal by the nucleophilic bidentate, phenylacylthiazolium bromide.
Dicarbonyl-containing compounds such as methylglyoxal (MG) are toxic to cells since they can interact with the nucleophilic centers of macromolecules. MG has been found to accumulate during hyperglycemia, and it has been suggested that this reactive dicarbonyl may contribute to the tissue damage and long-term complications of diabetes. A sensitive bacterial assay for investigating the ability of nucleophilic agents to interact with and detoxify MG has been developed. This assay utilizes the sensitivity of exponential phase cells of an Escherichia coli double mutant lacking the KefB and KefC potassium channels toward MG. The bidentate nucleophile, phenylacylthiazolium bromide (PTB), was found to protect and allow the growth of E. coli cells in the presence of either externally added or endogenously produced MG. In the absence of PTB, growth was completely inhibited and rapid cell death occurred under these conditions. PTB protected E. coli against MG almost as well as aminoguanidine, a compound shown previously to be involved in detoxification. The level of protection by PTB against MG was much greater than for the endogenous nucleophile, glutathione. These data suggested that PTB could interact with and detoxify MG. The mechanism of this interaction was characterized by NMR and mass spectroscopy.
Antiporters↗
Inactivation of glyceraldehyde-3-phosphate dehydrogenase of human malignant cells by methylglyoxal.
The effect of methylglyoxal on the activity of glyceraldehyde-3-phosphate dehydrogenase (GA3PD) of several normal human tissues and benign and malignant tumors has been tested. Methylglyoxal inactivated GA3PD of all the malignant cells (47 samples) and the degree of inactivation was in the range of 25-90%, but it had no inhibitory effect on this enzyme from several normal cells (24 samples) and benign tumors (13 samples). When the effect of methylglyoxal on other two dehydrogenases namely glucose 6-phosphate dehydrogenase (G6PD) and L-lactic dehydrogenase (LDH) of similar cells was tested as controls it has been observed that methylglyoxal has some inactivating effect on G6PD of all the normal, benign and malignant samples tested, whereas, LDH remained completely unaffected. These studies indicate that the inactivating effect of methylglyoxal on GA3PD specifically of the malignant cells may be a common feature of all the malignant cells, and this phenomenon can be used as a simple and rapid device for the detection of malignancy.
Carcinoma, Squamous Cell↗
Similar nature of inhibition of mitochondrial respiration of heart tissue and malignant cells by methylglyoxal. A vital clue to understand the biochemical basis of malignancy.
The effect of methylglyoxal on the oxygen consumption of mitochondria of heart and of several other organs of normal animals of different species has been tested. The results indicate that methylglyoxal (3.5 mM) strongly inhibits ADP-stimulated alpha-oxoglutarate and malate plus pyruvate-dependent respiration of exclusively heart mitochondria of normal animals of different species. Whereas, with the same substrates, but at a higher concentration of methylglyoxal (7.5 mM), the respiration of mitochondria of other organs of normal animals is not inhibited. Methylglyoxal also inhibits the respiration of slices of rat and toad hearts. But this inhibition is less pronounced. However, methylglyoxal (15 mM) fails to have any effect on perfused toad heart. Using rat heart mitochondria as a model, the effect of methylglyoxal on the oxygen consumption was also tested with different respiratory substrates, electron donors at different segments of the mitochondrial respiratory chain and site-specific inhibitors to identify the specific respiratory complex which might be involved in the inhibitory effect of methylglyoxal. The results strongly suggest that methylglyoxal inhibits the electron flow through complex I of rat heart mitochondrial respiratory chain. Moreover, lactaldehyde (0.6 mM), a catabolite of methylglyoxal, can exert a protective effect on the inhibition of rat heart mitochondrial respiration by methylglyoxal (2.5 mM). The effect of methylglyoxal on heart mitochondria as described in the present paper is strikingly similar to the results of our previous work with mitochondria of Ehrlich ascites carcinoma cells and leukemic leukocytes. We have recently proposed a new hypothesis on cancer which suggests that excessive ATP formation in cells may lead to malignancy. The above mentioned similarity apparently provides a solid experimental foundation for the proposed hypothesis which has been discussed.
Animals↗
Passive cigarette smoke and the renal glyoxalase system.
Cigarette smoking is associated with a number of fatal diseases, including cancer of different organs. A number of oxoaldehydes are found in cigarette smoke, among which methylglyoxal (MG) is known to cause toxicity to cells upon accumulation. In biological systems, MG is converted to s-d-lactoylglutathione by glyoxalase I with reduced glutathine (GSH) as a cofactor, and s-d-lactoylglutathione is converted to D-lactic acid with simultaneous regeneration of GSH, by glyoxalase II. In the present study, we have investigated the status of the glyoxalase enzymes in kidney tissues from rats exposed to passive cigarette smoke. No significant change has been noted in glyoxalase I activity. Glyoxalase II was decreased during 1 and 2 weeks of exposure, and after that the activity was increased. The initial decrease in the activity of gly II may be due to the excess amount of methylglyoxal generated due to smoke exposure or the adduct formed by MG and GSH which known to inhibit gly II activity. Both enzymes help in the detoxification of cigarette smoke induced chemicals and biochemicals.
Animals↗
Molecular mechanisms of the cross-impact of pathological processes in combined diabetes and cancer. Research and clinical aspects.
The mechanisms of interaction and cross-impact of metabolic processes in a combined diabetes and cancer condition are discussed. A hypothesis is proposed whereby the processes responsible for destruction of the organism in the case of diabetes--long-term hyperglycemia and generation of methylglyoxal--may substantially impact tumor development. The hypothesis is based on the fact that both diabetes and carcinogenesis cause dysfunction of the vital cellular signal system regulated by the protein kinase C (PKC) family. Normalization of the PKC functional activity in the case of diabetes restrains development of diabetic complications and inhibits the processes of tumor growth and metastasizing in carcinogenesis. On this basis, an attempt is made to interpret both the detrimental and beneficial effects of diabetes on cancer. The resultant effect is determined by the type of tumor and the duration and level of hyperglycemia. The mechanisms of the impact of diabetes mellitus on cancer are analyzed to develop recommendations for combined cancer therapy options.
Animals↗
Accumulation of methylglyoxal in the gingival crevicular fluid of chronic periodontitis patients.
BACKGROUND, AIMS: Methylglyoxal (MG), a toxic product of cellular metabolism, is elevated in tissues and fluids in a number of human diseases. A cross-sectional study was undertaken to determine whether MG accumulates in the gingival crevicular fluid (GCF) of chronic periodontitis patients. METHODS: GCF samples were collected for 30 s each from three teeth with pocket depths greater than 3 mm (DD sites), from 14 chronic periodontitis patients. Control samples were taken from three healthy sites (DH sites) in the same patients, as well as from seven subjects who were periodontally healthy (HH sites). Fluid volumes were determined and the strips were placed in 0.5 N perchloric acid. Subsequently, samples were derivatized with o-phenylenediamine and the resulting methylquinoxaline was assayed by high-performance liquid chromatography on Lichrospher(R)-100 RP-18, with UV detection. RESULTS: Mean pocket depths were 5.7+/-0.7, 2.7+/-0.6 and 2.7+/-0.5 mm (mean+/-SD) for the DD, DH and HH sites, respectively. Mean MG levels were found to be 208.7+/-241.7 and 142.9+/-235.7 pmol/site in the GCF from DD and DH sites, respectively (p=0.0023), but only 11.5+/-4.4 pmol/site for the HH sites. Bacteroides forsythus has been found to accumulate high levels of MG in culture (unpublished data) and, consistent with this, the sampled diseased sites contained higher levels of B. forsythus than the corresponding healthy sites (2.7+/-4.2 x 10(5) versus 0.7+/-1.1 x 10(5), respectively; p=0.022). Total "red complex" microorganisms were significantly elevated in the DD sites. CONCLUSIONS: In view of the known protein- and DNA-modifying effects of MG, the finding of elevated levels of MG in the GCF from chronic periodontitis patients supports the hypothesis that MG may contribute to destructive tissue damage in this disease.
Bacteroides↗
Crosstalk between S-nitrosylation and glycation defines a metabolic vulnerability in liver and renal cancers.
Metabolic reprogramming is a defining feature of cancer; however, how it contributes to therapeutic resistance remains incompletely understood. Here we show that loss of aldo-ketoreductase 1A1 (AKR1A1) in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) disrupts terminal glycolytic flux and lactate production through S-nitrosylation-mediated inhibition of pyruvate kinase, resulting in the accumulation of methylglyoxal (MGO). In multiple AKR1A1-deficient models, but not in those endogenously expressing the C423/424 A mutant of pyruvate kinase M2, elevated MGO triggers autophagic degradation of Kelch-like ECH-associated protein 1, leading to Nuclear factor erythroid 2-Related Factor 2 (NRF2) activation and transcriptional reprogramming. This NRF2-driven response enhances chemoresistance and promotes tumor cell migration, two hallmarks of aggressive cancer. Therapeutically, we demonstrate that pharmacological inhibition of the glyoxalase system-the major pathway for MGO detoxification-restores drug sensitivity in patient-derived cells and xenograft models, revealing a context-dependent metabolic vulnerability in AKR1A1 loss conditions. These findings identify AKR1A1 as a metabolic tumor suppressor and uncover crosstalk between S-nitrosylation and glycation as a key regulatory axis linking metabolic reprogramming to NRF2-driven therapy resistance, offering glyoxalase inhibition as a potential precision treatment strategy for RCC and HCC.
Humans↗
Spectrophotometric determination of zinc in potable water and insulin with methylglyoxal bis(4-phenyl-3-thiosemicarbazone).
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Indicators and Reagents↗
New stereoselective reaction of methylglyoxal with 2-aminopyridine and adenine derivatives: formation of imino acid-nucleic base derivatives in water under mild conditions.
A remarkable stereoselective reaction of methylglyoxal with 2-aminopyridine, the nucleic base adenine and adenine nucleosides leads in good yield to heterocycles of a new family in water under mild conditions and should be of interest in the understanding of the biological effects of methylglyoxal which is toxic, mutagenic and involved in diabetic complications.
Adenine↗
Glyoxalase and methylglyoxal in thiamine-deficient rats.
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Aldehydes↗
Purification of 2-oxoaldehyde dehydrogenase and its dependence on unusual amines.
1. 2-Oxoaldehyde dehydrogenase was purified from sheep liver and gave one band on polyacrylamide-gel electrophoresis. 2. The enzyme was completely dependent for its activity on the presence of Tris or one of a number of related amines, all of general structure: (See article). When more than one R group was hydrogen no enzyme activity was observed. 3. Only one of these amines is known to exist in living tissues and large concentrations of all amines were required for maximum activity. L-2-Aminopropan-1-ol was the most effective amine on the basis of substrate Km and Vmax. values and the amine Km values. 4. The enzyme was activated by phosphate which lowered the Km values for methylglyoxal, amine and NAD+. 5. The pH optimum of the enzyme was 9.3 and there was no activity at pH values below 7.8. A search for activators that might produce activity at pH 7.4 proved unsuccessful. 6. The enzyme was inhibited by rather large concentrations of barbiturates (6-46 mM) and nitro-alcohol analogues of the activating amines (66-139 mM).
Aldehyde Oxidoreductases↗
Utilization of gluconate by Escherichia coli. A role of adenosine 3':5'-cyclic monophosphate in the induction of gluconate catabolism.
1. Cultures of Escherichia coli growing on gluconate use both gluconate and glucose when glucose is added. 2. Glycerol-grown cells adapt to gluconate utilization even in media containing glucose as well as gluconate. 3. The rates of gluconate utilization by cells growing on a mixture of glucose and gluconate, and the specific activities of the gluconate uptake system and of gluconate kinase, are greater if adenosine 3':5'-cyclic monophosphate (cyclic AMP) is present in the medium than in its absence. 4. Growth on media containing gluconate and cyclic AMP is accompanied by the formation of methyl glyoxal and pyruvate, and progressive inhibition of growth. 5. A mutant devoid of adenylate cyclase activity (cya) grew well on glucose in the absence of exogenous cyclic AMP but grew only poorly on gluconate; neither the gluconate uptake system nor gluconate kinase was adequately induced. The addition of cyclic AMP promoted growth on gluconate and facilitated the induction of proteins required for gluconate catabolism. 6. Phage Pl-mediated transduction of cya+ into the cya-mutant also restored the wild-type phenotype in its ability to adapt to gluconate utilization.
Adenylyl Cyclases↗
Some observations on the NADP+-linked oxidation of methylglyoxal catalysed by 2-Oxoaldehyde dehydrogenase.
In the oxidation of methylglyoxal by 2-oxoaldehyde dehydrogenase, the apparent Km value for NADP+ was about 2.5 times lower than the corresponding Km for NAD+; the apparent Km values for methylglyoxal and for the amine activator L-2-aminopropan-1-ol, with NADP+ as cofactor, were also different from those obtained with NAD+. In the presence of NADP+, the enzyme was not activated by P1, in contrast with the activation of the enzyme when NAD+ was used. The significance of the results is discussed.
Aldehyde Oxidoreductases↗