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At least 217 records · Page 12Linked to original sources
PubMed1989

The oxidation of methylglyoxal by mammalian pyruvate dehydrogenase.

Mammalian pyruvate dehydrogenase actively catalyzed the oxidation of methylglyoxal to acetyl-CoA. The reaction was fully enzymatic with an estimated Km of 1.89 mM. On the other hand, methylglyoxal was a competitive inhibitor of the enzyme for pyruvate, the Ki being in the 1 mM range. The reaction was inhibited in the presence of HgCl2. The reaction products were quantitatively identified as acetyl-CoA and formic acid. A mechanism for the reaction is proposed.

Acetyl Coenzyme A↗
PubMed1991

Glyoxalase 2 deficiency in the erythrocytes of a horse: 1H NMR studies of enzyme kinetics and transport of S-lactoylglutathione.

In mammalian red blood cells the metabolism of methylglyoxal, and some alpha-ketoaldehydes, takes place via two, generally, highly active enzymes, glyoxalase 1 and 2. The 1H NMR spin-echo spectra of horse erythrocytes, and the various reactants in the glyoxalase system, were characterized as a prelude to obtaining series of spectra in time courses of methylglyoxal metabolism. We characterized the kinetics of the enzyme system in red cells from a normal horse and also from one which had very low activity of glyoxylase 2. The kinetics of the reaction scheme, with methylglyoxal as the starting substrate, were obtained from 1H NMR spectra and analyzed with a computer model of the scheme. The most salient feature of the normal system was the very high feed-forward inhibition (KiHTA = 0.1 microM) of glyoxalase 2 by the hemithioacetal which is the substrate of glyoxalase 1. The glyoxalase-2-deficient red cells were used to test whether S-lactoylglutathione is transported from red cells via the glutathione-S-conjugate transporter; this transport appeared not to occur. Because methylglyoxal is extremely rapidly removed (half-life, approximately 5 min) from normal red cells, it is difficult to assess the effect of this compound on glycolysis but the slow decline evident in the deficient cells allowed a study of the effects on L-lactate production; no effects were apparent.

Animals↗
PubMed1990

Arginine residues are involved in the transport function of bilitranslocase.

Specific guanido group reagents inhibit bilitranslocase transport activity in rat liver plasma membrane vesicles. Their reaction is shown to be affected by sulfobromophthalein, Thymol blue and bilirubin, which are translocated by bilitranslocase across the plasma membrane. It is concluded that the transport function of bilitranslocase depends on arginine residues, which are involved in the interaction with the molecules to be translocated.

Anions↗
PubMed1977

Purification and characterization of 2-oxoaldehyde dehydrogenase from rat liver.

The partial purification (123-fold) of 2-oxoaldehyde dehydrogenase (2-oxoaldehyde:NAD(P)+ oxidoreductase, 1.2.1.23) from rat liver was carried out using a purification procedure which involved (NH4)2SO4 fractionation, DEAE-Sephadex chromatography, Blue-Dextran affinity chromatography and CM-Sephadex chromatography. A single form of the enzyme was observed, mol. wt. approx. 50000 by gel chromatography. 2-Oxoaldehyde dehydrogenase appears to be highly specific for NADP+ and methylglyoxal. No activity is observed in the absence of certain amines which have vicinal amino and hydroxyl groups. The only known amine which activates the enzyme at physiological pH is L-serine methyl ester, suggesting that the regulation of this enzyme in vivo may require a derivative of serine.

Aldehyde Oxidoreductases↗
PubMed1981

Modification of essential arginine residues of pigeon liver malic enzyme.

The reaction of pigeon liver malic enzyme (L-malate:NADP+ oxidoreductase (oxaloacetate-decarboxylating), EC 1.1.1.40) with dicarbonyl compounds (2,3-butanedione, methylglyoxal, 2,4-pentanedione, and phenylglyoxal) resulted in a rapid loss of its enzymatic activity. The inactivation showed pseudo-first-order kinetics for all the dicarbonyls studied. All the log (pseudo-first-order rate constants) vs. log (dicarbonyl concentration) plots had slopes of near one, indicating approx. 1 : 1 reagent-active site complexes. Butanedione inactivation was reversible and was buffer-dependent. Pentanedione-modified enzyme showed a new absorption peak at 310 nM. NADP could completely protect the enzyme from inactivation. Oxaloacetate, ADP, AMP, NMN and adenosine were also effective in protection. Complete inactivation of the enzyme was accompanied by a loss of about six arginine residues per enzyme monomer. Butanedione-modified enzyme still bound NADPH as shown by fluorescence titration, nor was it binding with NADP impaired as determined by equilibrium gel filtration. The arginine residues, therefore, do not function in the coenzyme binding. However, the binding between the modified enzyme and [14C]malate was significantly decreased. These results led us to conclude that the arginine residues of malic enzyme are involved in the binding of the carboxyl group of substrate malate.

Animals↗
PubMed1985

Labeling of a specific arginine residue at the active site of glutamine synthetase (E.coli).

Chemical modification of a specific arginine residue of Escherichia coli glutamine synthetase has been accomplished by the use of the arginine-specific reagents p-hydroxyphenylglyoxal, phenylglyoxal, and methylglyoxal. Modification of one arginine residue results in complete inactivation of the enzyme and the modified enzyme seems to be extremely stable since no reactivation is observed upon addition of free arginine or dialysis. Saturating levels of ATP but not L-glutamate, L-methionine sulfoximine, or inorganic phosphate provide substantial protection against inactivation of the enzyme suggesting the modified amino acid is at or near the ATP substrate binding site. However, an ATP affinity analog is not prevented from binding upon modification of the arginine residue indicating that the reduction in catalytic activity is not solely due to alteration in substrate binding but may also reflect a catalytic role for the arginine residue.

Arginine↗
PubMed1987

Molecular cloning of the Pseudomonas putida glyoxalase I gene in Escherichia coli.

The glyoxalase I gene of Pseudomonas putida was cloned onto a vector plasmid pBR 322 as a 7.5 kilobase Sau 3AI fragment of chromosomal DNA and the hybrid plasmid was designated pGI 318. The gene responsible for the glyoxalase I activity in pGI 318 was recloned in pBR 322 as a 2.2 kilobase Hin dIII fragment and was designated pGI 423. The P. putida glyoxalase I gene on pGI 318 and pGI 423 was highly expressed in E. coli cells and the glyoxalase I activity level was increased more than 150 fold in the pGI 423 bearing strain compared with that of E. coli cells without pGI 423. The E. coli transformants harboring pGI 318 or pGI 423 could grow normally in the presence of methylglyoxal, although the E. coli cells without plasmid were inhibited to grow and showed the extremely elongated cell shape.

Cell Division↗
PubMed1985

Red blood cell oxidative metabolism induced by hydroxypyruvaldehyde.

Hydroxypyruvaldehyde is a substrate for the red cell glyoxalase system. It was metabolized by glyoxalase I with reduced glutathione to S-glyceroyl glutathione which was subsequently enzymatically hydrolyzed to reduced glutathione and glycerate by glyoxalase II. There was a competing spontaneous reaction of hydroxypyruvaldehyde with oxygen, which produced hydrogen peroxide, inducing oxidative metabolism in hydroxypyruvaldehyde-treated red cells. The incubation of red cells with hydroxypyruvaldehyde produced a stimulation in the flux of glucose oxidized through the hexose monophosphate shunt pathway, a stimulation in lactate production with a decrease in pyruvate production in the Embden-Meyerhoff pathway, an oxidation of reduced pyridine nucleotides and reduced glutathione to their oxidized cogeners, and changes in the oxidative status of hemoglobin. Overall, the majority of hydroxypyruvaldehyde consumption in red cell suspensions appeared to occur via non-oxidative routes, e.g. glyoxalase and/or 2-ketoaldehyde dehydrogenase, and non-enzymic protein binding. Although the observed oxidative metabolism induced by hydroxypyruvaldehyde in red cells was not severe (reduced glutathione levels in hydroxypyruvaldehyde-treated red cells were ca. 80% of the control values in untreated cells), the oxidative effects may be important in red cell ageing processes.

Adult↗
PubMed1992

The metabolism of aminoacetone to methylglyoxal by semicarbazide-sensitive amine oxidase in human umbilical artery.

The aliphatic amine aminoacetone has been described previously as a product of mitochondrial metabolism of threonine and glycine. Here, aminoacetone is shown to be deaminated to methylglyoxal by supernatants obtained by low speed centrifugation (600 g/10 min) of human umbilical artery homogenates, and also by membrane fractions isolated by high speed centrifugation (105,000 g/60 min) of these supernatants. Metabolism of 100 microM aminoacetone was completely inhibited by 1 mM propargylamine and MDL 72145, drugs which are capable of inhibiting the membrane-bound semicarbazide-sensitive amine oxidase (SSAO) activity found in vascular smooth muscle cells, whereas 1 mM pargyline and deprenyl which are inhibitors of monoamine oxidase, were without inhibitory effect. Estimated kinetic constants (at pH 7.8) for aminoacetone metabolism were Km = 92 microM; Vmax = 270 nmol/hr/mg protein. In addition, aminoacetone was a competitive inhibitor (Ki = 83 microM and 128 microM in low speed supernatants and high speed membrane fractions, respectively) of [14C]benzylamine metabolism by SSAO in this tissue. Aminoacetone would appear to be an endogenously occurring amine with a Km for metabolism by SSAO far lower than other aliphatic and aromatic biogenic amines examined previously as potential physiological substrates for the human vascular enzyme and possible implications of this are discussed.

Acetone↗
PubMed1993

Modification of the glyoxalase system in streptozotocin-induced diabetic rats. Effect of the aldose reductase inhibitor Statil.

The glyoxalase system was characterized in tissue (liver, skeletal muscle, kidney cortex and medulla, lens and sciatic nerve) and blood from streptozotocin-induced diabetic rats and normal controls. The effect of the aldose reductase inhibitor, Statil [3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazine-1-yl-acetic acid; ICI 128 436], was also investigated. Glyoxalase I and glyoxalase II activities were decreased in the liver and increased in skeletal muscle of diabetic rats and of Statil-treated diabetic rats, relative to normal controls. The concentration of non-protein sulphydryl (NPSH) was decreased in the liver and lens of diabetic rats, relative to normal controls; Statil prevented these effects. The concentrations of methylglyoxal in the kidney cortex and medulla, lens and blood were increased in diabetic rats, relative to normal controls. Statil prevented these increases except in the kidney cortex. The concentration of D-lactate was increased in the lens and blood of diabetic rats, relative to normal controls, which was partially prevented in blood but not in the lens by Statil. These data suggest that the glyoxalase system is modified in tissues and blood of streptozotocin-induced diabetic rats and some of the modifications may be prevented by Statil. The increased concentrations of methylglyoxal in the kidney, lens and blood, and the decreased concentration of NPSH in the lens may be related to the development of diabetic complications.

Aldehyde Reductase↗
PubMed1995

Aminoacetone metabolism by semicarbazide-sensitive amine oxidase in rat aorta.

High speed (105,000 g/60 min) membrane fractions from rat aorta homogenates metabolized the aliphatic amine aminoacetone (AA) to methylglyoxal (MG) with a Km of 19 +/- 3 microM, and Vmax of 510 +/- 169 nmol MG/hr/mg protein. This deaminating activity appears to be due to a semicarbazide-sensitive amine oxidase (SSAO), which is associated with smooth muscle cells in blood vessels of the rat and other species. AA was a competitive inhibitor (Ki of 28 +/- 6 microM) of the metabolism of benzylamine, a synthetic amine often used as an assay substrate for SSAO. AA is produced endogenously from mitochondrial metabolism of threonine and glycine, and thus could be a physiological substrate for SSAO, whereas the production of MG by SSAO could have cytotoxic implications for cellular function.

Acetone↗
PubMed1994

Antimalarial activity in vitro of the glyoxalase I inhibitor diester, S-p-bromobenzylglutathione diethyl ester.

S-p-Bromobenzylglutathione diethyl ester induced toxicity in the malarial parasite Plasmodium falciparum in infected human red blood cells in culture. The median inhibitory concentration, IC50, was 4.77 +/- 0.12 microM (N = 10) for incorporation of [3H]hypoxanthine in nucleotide synthesis and 5.20 +/- 0.1 microM (N = 10) for incorporation of [14C]isoleucine into protein. The prospective mechanism of action is inhibition of glyoxalase I by the de-esterified metabolite, S-p-bromobenzylglutathione, and accumulation of the cytotoxic substrate methylglyoxal.

Animals↗
PubMed1994

The reaction of methylglyoxal with aminoguanidine under physiological conditions and prevention of methylglyoxal binding to plasma proteins.

Increased formation of methylglyoxal in clinical diabetes mellitus and metabolism by the glyoxalase system has been linked to the development of clinical complications of diabetes: retinopathy, neuropathy and nephropathy. Aminoguanidine has been proposed as a prophylactic agent for preventive therapy of diabetic complications. Methylglyoxal reacted with aminoguanidine under physiological conditions to form two isomeric triazines, 3-amino-5-methyl-1,2,4-triazine and 3-amino-6-methyl-1,2,4-triazine. The mean second order rate constant for the reaction of methylglyoxal with aminoguanidine, kMG.AG = 0.39 +/- 0.06 M-1 sec-1 at pH 7.4 and 37 degrees. Under these conditions, no methylglyoxal bisguanylhydrazone was detected. Aminoguanidine prevented the irreversible modification of human plasma protein by a physiological concentration of methylglyoxal (1 microM); the median inhibitory concentration IC50 value of aminoguanidine was 203 +/- 16 microM (N = 28). The scavenging of methylglyoxal by aminoguanidine may contribute to the beneficial effects of aminoguanidine in the prevention of vascular pathogenesis in diabetes.

Blood Proteins↗
PubMed1995

Kinetic characteristics of ZENECA ZD5522, a potent inhibitor of human and bovine lens aldose reductase.

Aldose reductase (aldehyde reductase 2) catalyses the conversion of glucose to sorbitol, and methylglyoxal to acetol. Treatment with aldose reductase inhibitors (ARIs) is a potential approach to decrease the development of diabetic complications. The sulphonylnitromethanes are a recently discovered class of aldose reductase inhibitors, first exemplified by ICI215918. We now describe enzyme kinetic characterization of a second sulphonylnitromethane, 3',5'-dimethyl-4'-nitromethylsulphonyl-2-(2-tolyl)acetanilide (ZD5522), which is at least 10-fold more potent against bovine lens aldose reductase in vitro and which also has a greater efficacy for reduction of rat nerve sorbitol levels in vivo (ED95 = 2.8 mg kg-1 for ZD5522 and 20 mg kg-1 for ICI 215918). ZD5522 follows pure noncompetitive kinetics against bovine lens aldose reductase when either glucose or methylglyoxal is varied (K(is) = K(ii) = 7.2 and 4.3 nM, respectively). This contrasts with ICI 215918 which is an uncompetitive inhibitor (K(ii) = 100 nM) of bovine lens aldose reductase when glucose is varied. Against human recombinant aldose reductase, ZD5522 displays mixed noncompetitive kinetics with respect to both substrates (K(is) = 41 nM, K(ii) = 8 nM with glucose and K(is) = 52 nM, K(ii) = 3.8 nM with methylglyoxal). This is the first report of the effects of a sulphonylnitromethane on either human aldose reductase or utilization of methylglyoxal. These results are discussed with reference to a Di Iso Ordered Bi Bi mechanism for aldose reductase, where the inhibitors compete with binding of both the aldehyde substrate and alcohol product. This model may explain why aldose reductase inhibitors follow noncompetitive or uncompetitive kinetics with respect to aldehyde substrates, and X-ray crystallography paradoxically locates an ARI within the substrate binding site. Aldehyde reductase (aldehyde reductase 1) is closely related to aldose reductase. Inhibition of bovine kidney aldehyde reductase by ZD5522 follows uncompetitive kinetics with respect to glucuronate (K(ii) = 39 nM), indicating a selectivity greater than 5-fold for bovine aldose reductase relative to aldehyde reductase.

Acetanilides↗