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Enzymatic defence against glycation

Executive summary

Glycation of proteins, nucleotides and basic phospholipids by glucose, glyoxal, methylglyoxal, 3-deoxyglucosone and other saccharide derivatives is potentially damaging to the proteome and mutagenic. It is now recognized that there is an enzymatic defence against glycation – a group of enzymes that suppress the physiological levels of potent glycating agents and repair glycated proteins: glyoxalase I, aldehyde reductases and dehydrogenases, amadoriase and fructosamine 3-phosphokinase. The enzymatic defence against glycation influences the morbidity and efficiency of drug therapy in certain diseases. Improved understanding of the balance between glycation and the enzymatic anti-glycation defence will advance disease diagnosis and therapy.

Overview

The enzymatic defence against glycation is a new and emerging concept in biochemical metabolism that compares well with the enzymatic defence against oxidative stress [1]. Glycation is the non-enzymatic reaction of glucose, a-oxoaldehydes and other saccharide derivatives with proteins, nucleotides and basic phospholipids. It involves a complex series of parallel and sequential reactions, often termed collectively “the Maillard reaction”, that form many different adducts, some of which are fluorescent and coloured “browning pigments”. Fructosamines and advanced glycation endproducts (AGEs) are formed. Accumulation of protein glycation adducts is associated with enzyme inactivation, protein denaturation and a cellular-mediated immune response. Excessive nucleotide glycation is associated with mutagenesis and apoptosis, and excessive lipid glycation with membrane lipid bilayer disruption [2]. It is has been recognized recently that there is an enzymatic defence against glycation protecting against glycation-mediated cell damage. It involves the enzymatic activities that suppress the formation of glycation adducts and repair sites of early glycation: glyoxalase I and certain aldehyde reductase and dehydrogenase isozymes detoxify reactive carbonyl and a-oxoaldehyde glycating agents (glyoxal, methylglyoxal, 3-deoxyglucosone and others) [3;4], and amadoriase and fructosamine 3-phosphokinase catalyse the removal of fructosamine glycation adducts formed by glycation of proteins by glucose [5-7]. Oxidative stress is inextricably linked to glycation because the depletion of GSH and NADPH in oxidative stress also decreases the in situ activities of glyoxalase I and NADPH-dependent aldehyde reductases [8]. The enzymatic defence against glycation suppresses damage to biological macromolecules but it is an imperfect defence; glycation adducts of proteins, nucleotides and basic phospholipids are formed in normal physiological states. Steady state levels of glycation adducts are 0.1-1% lysine and arginine residues in proteins, 1 in 107 nucleotides in DNA, and 0.1% basic phospholipids. Protein glycation adducts are removed by proteasomal and lysosomal proteolysis [9;10]. Nucleotide glycation adducts are cleared by nucleotide excision repair [11], and phospholipid AGEs are removed by lipid turnover [12]. The glycation adducts thereby liberated are eliminated as free glycation adducts in the urine, along with glycation adducts absorbed from food. The enzymatic defence against glycation is overwhelmed in some disease states and glycation adduct concentrations increase. Glycation contributes to morbidity and mortality of diseases of major social impact (diabetes, heart disease and endstage renal disease) and is suspected to contribute to others (Alzheimer’s disease, arthritis and ageing) [2]. Novel therapeutic approaches to prevent the chronic complications of diabetes and improve dialysis therapy in endstage renal disease strive to minimize vascular dysfunction linked to excessive glycation and increase clearance of glycation adducts from the body, respectively [13-15]. Nucleotide glycation is implicated in saccharide-linked mutagenesis and the pharmacological mechanism of cytotoxic antitumour drugs modifying DNA and DNA metabolism. Overexpression of glyoxalase I was associated with clinical multidrug resistance in tumours of high incidence and mortality – carcinomas of the lung, breast and prostate. For these tumours, glyoxalase I inhibitors provided effective therapy [16]. There is now a renaissance in the development of glyoxalase I inhibitor antitumour agents. Glycation is an omnipresent process in biological systems as a consequence of the reactivity of monosaccharide intermediates of glycolysis and a-oxoaldehydes formed by their spontaneous degradation. Improved understanding of the balance between glycation and the enzymatic anti-glycation defence will advance understanding of chronic and degenerative diseases with concomitant improvements in diagnosis and therapy.

References

1. Finkel T and Holbrook NJ, Oxidants, oxidative stress and the biology of ageing. Nature 408: 239-247, 2003. 2. Thornalley PJ, Clinical significance of glycation. Clin.Lab. 45: 263-273, 1999. 3. Shinohara M, Thornalley PJ, Giardino I, Beisswenger PJ, Thorpe SR, Onorato J, and Brownlee M, Overexpression of glyoxalase I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycaemia-induced increases in macromolecular endocytosis. J.Clin.Invest. 101: 1142-1147, 1998. 4. Suzuki K, Koh YH, Mizuno H, Hamaoko R, and Taniguchi N, Overexpression of aldehyde reductase protects PC12 cells from the cytotoxicity of methylglyoxal or 3-deoxyglucosone. J.Biochem. 123: 353-357, 1998.5. Takahashi M, Pischetsrieder M, and Monnier VM, Isolation, purification, and characterization of Amadoriase isoenzymes (fructosyl amine-oxygen oxidoreductase EC 1.5.3) from Aspergillus sp. J.Biol.Chem. 272: 3437-3443, 1997. 6. Delpierre G, Rider MH, Collard F, Stroobant V, Vanstapel F, Santos H, and Van Schaftingen E, Identification, cloning, and heterologous expression of a mammalian fructosamine-3-kinase. Diabetes 49: 1627-1634, 2000. 7. Szwergold BS, Howell S, and Beisswenger PJ, Human fructosamine-3-kinase. Purification, sequencing, substrate specificity , and evidence of activity in vivo. Diabetes 50: 2139-2147, 2001.8. Abordo EA, Minhas HS, and Thornalley PJ, Accumulation of a-oxoaldehydes during oxidative stress. A role in cytotoxicity. Biochem.Pharmacol. 58: 641-648, 1999. 9. Michalek MT, Grant EP, and Rock KL, Chemical denaturation and modification of ovalbumin alters its dependence on ubiquitin conjugation for class I antigen presentation. J.Immunol. 157: 617-624, 1996. 10. Westwood ME, Argirov OK, Abordo EA, and Thornalley PJ, Methylglyoxal-modified arginine residues - a signal for receptor-mediated endocytosis and degradation of proteins by monocytic THP-1 cells. Biochim.Biophys.Acta 1356: 84-94, 1997. 11. Murata-Kamiya N, Kamiya H, Kaji H, and Kasai H, Methylglyoxal induces G:C to C:G and G:C to T:A transversions in the supF gene on a shuttle vector plasmid replicated in mammalian cells. Mutat.Res. 468: 173-182, 2000. 12. Requena JR, Ahmed MU, Fountain CW, Degenhardt TP, Reddy S, Perez C, Lyons TJ, Jenkins AJ, Baynes JW, and Thorpe SR, Carboxymethylethanolamine, a biomarker of phospholipid modification during the Maillard reaction in vivo. J.Biol.Chem. 272: 17473-17479, 1997. 13. Hammes H-P, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, and Brownlee M, Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nature Medicine 9: 294-299, 2003. 14. Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, and Thornalley PJ, Prevention of incipient diabetic nephropathy by high dose thiamine and Benfotiamine. Diabetes 52: 2110-2120, 2003. 15. Dawnay A and Millar DJ, The pathogenesis and consequences of AGE formation in uraemia and its treatment. Cell.Molec.Biol. 44: 1081-1094, 1998. 16. Sakamoto H, Mashima T, Sato S, Hashimoto Y, Yamori T, and Tsuruo T, Selective activation of apoptosis program by S-p-bromobenzylglutathione cyclopentyl diester in glyoxalase I-overexpressing human lung cancer cells. Clin.Cancer Res. 7: 2513-2518, 2001. 2. Thornalley PJ, Clinical significance of glycation. Clin.Lab. 45: 263-273, 1999. 3. Shinohara M, Thornalley PJ, Giardino I, Beisswenger PJ, Thorpe SR, Onorato J, and Brownlee M, Overexpression of glyoxalase I in bovine endothelial cells inhibits intracellular advanced glycation endproduct formation and prevents hyperglycaemia-induced increases in macromolecular endocytosis. J.Clin.Invest. 101: 1142-1147, 1998. 4. Suzuki K, Koh YH, Mizuno H, Hamaoko R, and Taniguchi N, Overexpression of aldehyde reductase protects PC12 cells from the cytotoxicity of methylglyoxal or 3-deoxyglucosone. J.Biochem. 123: 353-357, 1998.5. Takahashi M, Pischetsrieder M, and Monnier VM, Isolation, purification, and characterization of Amadoriase isoenzymes (fructosyl amine-oxygen oxidoreductase EC 1.5.3) from Aspergillus sp. J.Biol.Chem. 272: 3437-3443, 1997. 6. Delpierre G, Rider MH, Collard F, Stroobant V, Vanstapel F, Santos H, and Van Schaftingen E, Identification, cloning, and heterologous expression of a mammalian fructosamine-3-kinase. Diabetes 49: 1627-1634, 2000. 7. Szwergold BS, Howell S, and Beisswenger PJ, Human fructosamine-3-kinase. Purification, sequencing, substrate specificity , and evidence of activity in vivo. Diabetes 50: 2139-2147, 2001.8. Abordo EA, Minhas HS, and Thornalley PJ, Accumulation of a-oxoaldehydes during oxidative stress. A role in cytotoxicity. Biochem.Pharmacol. 58: 641-648, 1999. 9. Michalek MT, Grant EP, and Rock KL, Chemical denaturation and modification of ovalbumin alters its dependence on ubiquitin conjugation for class I antigen presentation. J.Immunol. 157: 617-624, 1996. 10. Westwood ME, Argirov OK, Abordo EA, and Thornalley PJ, Methylglyoxal-modified arginine residues - a signal for receptor-mediated endocytosis and degradation of proteins by monocytic THP-1 cells. Biochim.Biophys.Acta 1356: 84-94, 1997. 11. Murata-Kamiya N, Kamiya H, Kaji H, and Kasai H, Methylglyoxal induces G:C to C:G and G:C to T:A transversions in the supF gene on a shuttle vector plasmid replicated in mammalian cells. Mutat.Res. 468: 173-182, 2000. 12. Requena JR, Ahmed MU, Fountain CW, Degenhardt TP, Reddy S, Perez C, Lyons TJ, Jenkins AJ, Baynes JW, and Thorpe SR, Carboxymethylethanolamine, a biomarker of phospholipid modification during the Maillard reaction in vivo. J.Biol.Chem. 272: 17473-17479, 1997. 13. Hammes H-P, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, and Brownlee M, Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nature Medicine 9: 294-299, 2003. 14. Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, and Thornalley PJ, Prevention of incipient diabetic nephropathy by high dose thiamine and Benfotiamine. Diabetes 52: 2110-2120, 2003. 15. Dawnay A and Millar DJ, The pathogenesis and consequences of AGE formation in uraemia and its treatment. Cell.Molec.Biol. 44: 1081-1094, 1998. 16. Sakamoto H, Mashima T, Sato S, Hashimoto Y, Yamori T, and Tsuruo T, Selective activation of apoptosis program by S-p-bromobenzylglutathione cyclopentyl diester in glyoxalase I-overexpressing human lung cancer cells. Clin.Cancer Res. 7: 2513-2518, 2001.