Binding and modification of proteins by methylglyoxal under physiological conditions. A kinetic and mechanistic study with N alpha-acetylarginine, N alpha-acetylcysteine, and N alpha-acetyllysine, and bovine serum albumin.

Aldehydes are organic compounds that are widespread in nature. They can be formed endogenously by lipid peroxidation (LPO), carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation. This review compares the reactivity of many aldehydes towards biomolecules particularly macromolecules. Furthermore, it includes not only aldehydes of environmental or occupational concerns but also dietary aldehydes and aldehydes formed endogenously by intermediary metabolism. Drugs that are aldehydes or form reactive aldehyde metabolites that cause side-effect toxicity are also included. The effects of these aldehydes on biological function, their contribution to human diseases, and the role of nucleic acid and protein carbonylation/oxidation in mutagenicity and cytotoxicity mechanisms, respectively, as well as carbonyl signal transduction and gene expression, are reviewed. Aldehyde metabolic activation and detoxication by metabolizing enzymes are also reviewed, as well as the toxicological and anticancer therapeutic effects of metabolizing enzyme inhibitors. The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden; and the toxic effects of aldehydes in liver disease, embryo toxicity/teratogenicity, diabetes/hypertension, sclerosing peritonitis, cerebral ischemia/neurodegenerative diseases, and other aging-associated diseases.

Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health.

1. Methylglyoxal is a reactive alpha-oxoaldehyde and physiological metabolite formed by the fragmentation of triose-phosphates, and by the metabolism of acetone and aminoacetone. 2. Methylglyoxal modifies guanylate residues to form 6,7-dihydro-6,7-dihydroxy-6-methyl-imidazo[2,3-b]purine-9(8)one and N2-(1-carboxyethyl)guanylate residues and induces apoptosis. 3. Methylglyoxal modifies arginine residues in proteins to form N(delta)-(4,5-dihydroxy-4-methylimidazolidin-2-yl) ornithine, N(delta)-(5-hydro-5-methylimidazol-4-on-2-yl)ornithine and N(delta)-(5)methylimidazol-4-on-2-yl)ornithine residues. 4. Methylglyoxal-modified proteins undergo receptor-mediated endocytosis and lysosomal degradation in monocytes and macrophages, and induce cytokine synthesis and secretion. 5. Methylglyoxal is detoxified by the glyoxalase system. Decreased detoxification of methylglyoxal may be induced pharmacologically by glyoxalase I inhibitors which have anti-tumor and anti-malarial activities. 6. The modification of nucleic acids and protein by methylglyoxal is a signal for their degradation and may have a role in the development of diabetic complications, atherosclerosis, the immune response in starvation, aging and oxidative stress.

Pharmacology of methylglyoxal: formation, modification of proteins and nucleic acids, and enzymatic detoxification--a role in pathogenesis and antiproliferative chemotherapy.

Systems biology is a new field in biology that aims at system-level understanding ​ ofbiological systems. While molecular biology has led to remarkable ​ progress in our understanding ofbiological systems, the current ​ focus is mainly on identification of genes and functions of their products ​ which are components ofthe system. The next major challenge is to ​ understand at the system level biological systems that are composed of ​ components revealed by molecular biology. This is not the first attempt at ​ system-level understanding, since it is a recurrent theme in the scientific ​ community. Description: TOC,ILL,290P URI: http://hdl.handle.net/123456789/1685 Date: 2001-01-01

Foundations of systems biology

In Krebs-Ringer phosphate buffer, the rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate was first order with respect to the triose phosphate with rates constant values of 1.94 +/- 0.02 x 10(-5) s-1 (n = 18) and 1.54 +/- 0.02 x 10(-4) s-1 (n = 18) at 37 degrees C, respectively. The rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate in the presence of red blood cell lysate was not significantly different from the non-enzymatic value (P > 0.05). Methylglyoxal formation from glycerone phosphate was increased in the presence of triose phosphate isomerase but this may be due to the faster non-enzymatic formation from the glyceraldehyde 3-phosphate isomerisation product. For red blood cells in vitro, the predicted non-enzymatic rate of formation of methylglyoxal from glycerone phosphate and glyceraldehyde 3-phosphate may account for the metabolic flux through the glyoxalase system. The reactivity of glycerone phosphate and glyceraldehyde 3-phosphate towards the non-enzymatic formation of methylglyoxal under physiological conditions suggests that methylglyoxal formation is unavoidable from the Embden-Meyerhof pathway.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-1033.1993.tb17638.x

The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal.

1H NMR was used with methylglyoxal, purified by an HPLC technique, to study the kinetics of the human erythrocyte glyoxalase system. 1H NMR enabled the direct measurement of the time-dependent changes in concentrations of the two hydrates of methylglyoxal, which have not previously been directly measurable, as well as measurement of substrates and products of the glyoxalase enzyme system in the human red blood cell. A computer model of the reaction scheme was developed and NMR data numerically analyzed, thus allowing a complete kinetic description of the reactions. The rate constants describing the chemical equilibria between the hydrated species of methylglyoxal were determined by this numerical analysis or by a saturation-transfer technique, and found to be much slower (by several orders of magnitude) than previously determined by other methods. The kinetic parameters describing the enzyme-catalyzed reactions were also determined from experiments using a dilute haemolysate that was added to solutions of methylglyoxal and reduced glutathione (GSH). The maximal velocity of glyoxalase 1 is threefold greater (Vmax = 70.4 +/- 4.7 mmol.min-1.1 packed cells-1) than glyoxalase 2(Vmax = 24 +/- 5 mmol.min-1.1 packed cells-1) and it exhibits threefold-greater affinity for its substrate (Km = 0.46 +/- 0.04 mM) than the second enzyme (Km = 1.5 +/- 0.4 mM). Both enzymes are subject to competitive inhibition; glyoxalase 1 by reduced glutathione (KiGSH = 7.88 +/- 0.16 mM) and glyoxalase 2 by the hemithioacetal (HTA) of methylglyoxal and GSH (KiHTA = 0.29 +/- 0.04 mM).

Kinetic analysis of the human erythrocyte glyoxalase system using 1H NMR and a computer model

When erythrocytes are suspended in a solution of known composition the resultant values of such basic cell parameters as volume and pH are difficult to predict. To facilitate such predictions, we developed a mathematical model describing the passive transmembrane distribution of permeant species; three simultaneous equations were produced. Certain essential data required for the model were determined experimentally; these included the pH dependence of the charge on the hemoglobin molecule and the variation of the osmotic coefficient of hemoglobin with cell volume. Finally, cells were added to various solutions, and then titrated to produce a wide pH range (pH 6-8). We measured the resultant cell volume, cellular and extracellular pH using both conventional and 31P NMR methods. The expected equilibrium values of these electrochemical parameters were also calculated by solving (numerically) the three model equations. The accuracy of the model simulations was evaluated by direct comparison of calculated and experimentally determined values.

https://rupress.org/jgp/article-pdf/95/6/1183/1249589/1183.pdf

Evaluation of an electrochemical model of erythrocyte pH buffering using 31P nuclear magnetic resonance data.

Analytical expressions for the magnetic potential and the magnetic field strength vector in cells modelled as isolated confocal prolate and oblate spheroids have been derived. The important results which emerged from the analysis are that the magnetic field in the central spheroid, in a series of confocal spheroids, is always uniform; but its magnitude depends upon the orientation of the spheroids relative to the external field. Therefore, the NMR line-shape derived from an internal solute in a population of sparsely distributed spheroids, with random orientation of the members, is a superposition of Lorentzians; the resulting 'complicated' line shape may often appear to be Gaussian. This spectral phenomenon is at least part of the explanation for the non-Lorentzian character of NMR line-shapes in the spectra of many biological samples. Quantitative analysis of the NMR line-shape of an appropriate intracellular solute can in principal yield the orientational distribution of a dilute suspension of cells of uniform size and shape.

Brian T. Bulliman

Papers

Kinetic analysis of the human erythrocyte glyoxalase system using 1H NMR and a computer model

Evaluation of an electrochemical model of erythrocyte pH buffering using 31P nuclear magnetic resonance data.

Perturbation of homogeneous magnetic fields by isolated single and confocal spheroids. Implications for NMR spectroscopy of cells.

Overdetermined one-dimensional NMR exchange analysis. A 1D counterpart of the 2D EXSY experiment

Variances of rate constants estimated from 2D NMR exchange spectra