Proteasome Inhibition in Glyoxal-treated Fibroblasts and Resistance of Glycated Glucose-6-phosphate Dehydrogenase to 20 S Proteasome Degradation in Vitro (original) (raw)
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Glycation of proteins-their analysis and physiological aspects
2010
Posttranslational non-enzymatic modifications of proteins (as well as of lipoproteins and glycoproteins) are important protein reactions, which are believed to play an important role in several physiological and pathophysiological processes, such as aging, diabetes mellitus, etc. Non-enzymatic chemical reactions that occur between an oxo-group typically stemming from reducing sugars (or arising from lipid oxidation/peroxidation) and the free amino groups of proteins/peptides lead to the formation of a plethora of still poorly characterized reaction products (the so-called Maillard reaction). A typical example of these non-enzymatic changes is the formation of advanced glycation end products (AGEs). The accumulation of AGEs and the resulting structural alterations cause altered tissue properties (increased stiffness, reduced elasticity), which contribute to their reduced catabolism and to aging. The most susceptible proteins are those which are slowly metabolized, having a longer exp...
Glycated Lysine Residues: A Marker for Non-Enzymatic Protein Glycation in Age-Related Diseases
Disease Markers, 2011
Nonenzymatic glycosylation or glycation of macromolecules, especially proteins leading to their oxidation, play an important role in diseases. Glycation of proteins primarily results in the formation of an early stage and stable Amadori-lysine product which undergo further irreversible chemical reactions to form advanced glycation endproducts (AGEs). This review focuses these products in lysine rich proteins such as collagen and human serum albumin for their role in aging and age-related diseases. Antigenic characteristics of glycated lysine residues in proteins together with the presence of serum autoantibodies to the glycated lysine products and lysine-rich proteins in diabetes and arthritis patients indicates that these modified lysine residues may be a novel biomarker for protein glycation in aging and age-related diseases.
Mutual interaction between glycation and oxidation during non-enzymatic protein modification
Biochimica et Biophysica Acta (BBA) - General Subjects, 1997
Aging pathogenesis involves non-enzymatic modifications of proteins; protein oxidation, glycation and their interactions have aroused a particular interest. Possible interrelations between oxidation and glycation have been evaluated in vitro: bovine serum albumin was oxidized by gamma-irradiation and then exposed to in vitro glycation. Fluorescence modifications induced by radiolytic oxidation and glycation were similar and tended to be additive. Both non-enzymatic processes provoked a loss of free sulfhydryl groups and a strong increment of protein carbonyl content: this supports that glycation can act through oxidative mechanisms. The observed rearrangement of amino groups after irradiation could predispose proteins to glycation attacks. Protein peroxides generated during irradiation appear able to give birth to further protein modifications leading to the generation of carbonyl groups and to interact with monosaccharides, probably stimulating their autoxidation and in turn glycative protein damage. Glycation increases the oxidation-mediated structural damage revealed by SDS-PAGE. Therefore our data support the hypothesis of mutual enhancement between oxidation and glycation of proteins and suggest possible molecular mechanisms of interactions. q 1997 Elsevier Science B.V.
Molecular and Cellular Biochemistry, 2019
Hyperglycemia in diabetes causes protein glycation that leads to oxidative stress, release of cytokines, and establishment of secondary complications such as neuropathy, retinopathy, and nephropathy. Several other metabolic disorders, stress, and inflammation generate free radicals and oxidative stress. It is essential to study whether oxidative stress independently enhances protein glycation leading to rapid establishment of secondary complications. Oxidative stress was experimentally induced using rotenone and Fenton reagent for in vivo and in vitro studies, respectively. Results showed significant increase in the rate of modification of BSA in the form of fructosamine and protein-bound carbonyls in the presence of fenton reagent. Circular dichroism studies revealed gross structural changes in the reduction of alpha helix structure and decreased protein surface charge was confirmed by zeta potential studies. Use of rotenone demonstrated enhanced AGE formation, ROS generation, and liver and kidney tissue glycation through fluorescence measurement. Similar findings were also observed in cell culture studies. Use of aminoguanidine, a protein glycation inhibitor, demonstrated reduction in these changes; however, a combination of aminoguanidine along with vitamin E demonstrated better amelioration. Thus, oxidative stress accelerates the process of protein glycation causing gross structural changes and tissue glycation in insulin-independent tissues. Use of antioxidants and protein glycation inhibitors in combination are more effective in preventing such changes and could be an effective therapeutic option for preventing establishment of secondary complications of diabetes.
Glycation Damage: A Possible Hub for Major Pathophysiological Disorders and Aging
Aging and Disease, 2018
Glycation is both a physiological and pathological process which mainly affects proteins, nucleic acids and lipids. Exogenous and endogenous glycation produces deleterious reactions that take place principally in the extracellular matrix environment or within the cell cytosol and organelles. Advanced glycation end product (AGE) formation begins by the non-enzymatic glycation of free amino groups by sugars and aldehydes which leads to a succession of rearrangements of intermediate compounds and ultimately to irreversibly bound products known as AGEs. Epigenetic factors, oxidative stress, UV and nutrition are important causes of the accumulation of chemically and structurally different AGEs with various biological reactivities. Cross-linked proteins, deriving from the glycation process, present both an altered structure and function. Nucleotides and lipids are particularly vulnerable targets which can in turn favor DNA mutation or a decrease in cell membrane integrity and associated biological pathways respectively. In mitochondria, the consequences of glycation can alter bioenergy production. Under physiological conditions, anti-glycation defenses are sufficient, with proteasomes preventing accumulation of glycated proteins, while lipid turnover clears glycated products and nucleotide excision repair removes glycated nucleotides. If this does not occur, glycation damage accumulates, and pathologies may develop. Glycation-induced biological products are known to be mainly associated with aging, neurodegenerative disorders, diabetes and its complications, atherosclerosis, renal failure, immunological changes, retinopathy, skin photoaging, osteoporosis, and progression of some tumors.
Inactivation of cellular enzymes by carbonyls and protein-bound glycation/glycoxidation products
Archives of Biochemistry and Biophysics, 2002
Diabetic plasma contains elevated levels of glucose and various low-molecular-weight carbonyl compounds derived from the metabolism of glucose and related materials. These compounds react with protein side chains (Arg, Lys, Cys, and His) to give glycated materials and advanced glycation end products. In this study, we have examined the effect of glucose and carbonyl compounds (methylglyoxal, glyoxal, glycolaldehyde, and hydroxyacetone), and glycation products arising from reaction of these materials with model proteins, on the activity of three key cellular enzymes: glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glutathione reductase, and lactate dehydrogenase, both in isolation and in cell lysates. In contrast to glucose (1 M, both fresh and aged for 8 weeks), which had no effect, marked inhibition of all three enzymes was observed with methylglyoxal and glyoxal. GAPDH was also inhibited by glycolaldehyde and hydroxyacetone. Incubation of these enzymes with proteins that had been preglycated with methylglyoxal, but not glucose, also resulted in significant time-and concentration-dependent inhibition with both isolated enzymes and cell lysates. This inhibition was not metal ion, oxygen, superoxide dismutase, or catalase dependent, suggesting that inhibition is not radical mediated. These effects are suggested to be due to direct adduction of the free-or proteinbound carbonyls with the target enzyme. Such an interpretation is supported by the detection of the loss of thiol groups on GAPDH and the detection of cross-linked materials on protein gels. Though direct comparison of the extent of inhibition induced by free versus protein-bound carbonyls was not possible, the significantly higher concentrations of the latter materials over the former in diabetic plasma and cells lead us to suggest that alterations in the activity of key cellular enzymes induced by glycated proteins may play a significant role in the development of diabetic complications. Ó Diabetic plasma contains elevated levels of glucose and various low-molecular-weight aldehydes and carbonyl compounds derived either from the metabolism of glucose or from related physiological substrates . Thus glyoxal and 3-deoxyglucosone can be generated from glucose , methylglyoxal (MGX) 2 from glucose, glycerone phosphate, glyceraldehyde-3-phosphate, acetone, and aminoacetone , and glycolaldehyde from glucose and amino acid oxidation . These compounds react with the side chains of proteins, chiefly arginine and lysine residues, to give glycated materials via the Maillard reaction, leading to the formation of
Biochemistry, 1995
Advanced glycation end products (AGEs) and glycoxidation products are formed during Maillard or browning reactions between sugars and proteins and are implicated in the pathophysiology of aging and the complications of diabetes. To determine the structure of AGEs, antibodies were prepared to protein browned by incubation with glucose and used in ELISA assays to measure AGEs formed in model reactions between bovine serum albumin (BSA) or Nu-acetyllysine and glucose, fructose, or glyoxal. AGEs were formed from glucose and fructose only under oxidative conditions, but from glyoxal under both oxidative and antioxidative conditions. Gel permeation chromatographic analysis indicated that a similar AGE was formed in reactions of Na-acetyllysine with glucose, fructose, and glyoxal and that this AGE co-eluted with authentic Na-acetyl-Nc-(carboxymethyl)lysine. Amino acid analysis of AGE proteins revealed a significant content of Ne-(carboxymethy1)lysine (CML). In ELISA assays using polyclonal antibodies against AGE proteins, CML-BSA (-25 mol of CMWmol of BSA), prepared by chemical modification of BSA, was a potent inhibitor of the recognition of AGE proteins and of AGES in human lens proteins. We conclude that AGEs are largely glycoxidation products and that CML is a major AGE recognized in tissue proteins by polyclonal antibodies to AGE proteins.
European Journal of Biochemistry, 1992
The degradation of fructosamines, formed from the non-enzymic glycation of proteins under physiological conditions, to advanced glycation end products was investigated by studying the model peptide fructosamine NE-(1-deoxy-D-fructos-1-y1)hippuryl-lysine (DHL). At pH 7.4 and 37°C in aerobic phosphate buffer, DHL degraded to form N,-carboxymethyl-hippuryl-lysine, and hippuryllysine over a 29-day incubation period. The expected NE-(3-1actato)hippuryl-lysine and 'hippuryllysylpyrraline' derivatives were not found. Superoxide radicals and hydrogen peroxide were formed during the degradation of DHL but were also both consumed during the degradation reaction. Reversal of the Amadori rearrangement was not a major fate of the fructosamine.
Non-enzymatic glycation of proteins: a cause for complications in diabetes
Indian journal of biochemistry & biophysics, 2006
Diabetes mellitus is one of the most common non-communicable diseases, and is the fifth leading cause of death in most of the developed countries. It can affect nearly every organ and system in the body and may result in blindness, end stage renal disease, lower extremity amputation and increase risk of stroke, ischaemic heart diseases and peripheral vascular disease. Hyperglycemia in diabetes causes non-enzymatic glycation of free amino groups of proteins (of lysine residues) and leads to their structural and functional changes, resulting in complications of the diabetes. Glycation of proteins starts with formation of Shiff's base, followed by intermolecular rearrangement and conversion into Amadori products. When large amounts of Amadori products are formed, they undergo cross linkage to form a heterogeneous group of protein-bound moieties, termed as advanced glycated end products (AGEs). Rate of these reactions are quite slow and only proteins with large amounts of lysine res...