Endogenous alpha-oxoaldehydes and formation of protein and nucleotide advanced glycation endproducts in tissue damage.
Human and other biological tissues face a continual threat of damage by alpha-oxoaldehydes formed endogenously. Glyoxal, methylglyoxal and 3-deoxyglucosone are formed by the degradation of glycolytic intermediates, glycated proteins and lipid peroxidation. They are potent glycating agents of protein and nucleotides leading to the formation of advanced glycation endproducts (AGEs). With proteins, they are arginine residue-directed glycating agents forming mainly hydroimidazolones, found at 0.1-1% of total arginine residues in tissues (2-20% of proteins modified). With nucleotides, imidazopurinone- and N2-carboxyalkyl- derivatives of deoxyguanosine are formed, found at 0.1-0.8 per 10(6) nucleotides in DNA. Glycation occurs in all tissues and body fluids. Cellular proteolysis of AGE-modified proteins and DNA releases glycated amino acids and nucleosides. Glycated amino acids and nucleosides are released into plasma, undergo glomerular filtration and are excreted in urine. The damage to tissue protein and nucleotides by alpha-oxoaldehydes is suppressed by the metabolism of alpha-oxoaldehyde glycating agents by the glutathione-dependent enzyme, glyoxalase I, and aldo-keto reductases. These enzymatic activities are part of the enzymatic defence against glycation. Tissue damage by alpha-oxoaldehyde glycation is implicated in diabetic and non-diabetic vascular disease, renal failure, cirrhosis, Alzheimer's disease, arthritis and ageing.
Thornalley
Paul J
PJ
Protein Damage and Systems Biology Research Group, Warwick Medical School and Systems Biology Centre, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry CV2 2DX, UK.
D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D024141:Collagen Type IV / Q000378:metabolism; D004260:DNA Repair; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D015416:Maillard Reaction; D008954:Models, Biological; D015394:Molecular Structure; D016296:Mutagenesis; D009711:Nucleotides / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D056264:Sin3 Histone Deacetylase and Corepressor Complex
D000447:Aldehydes; D042702:Angiopoietin-2; D024141:Collagen Type IV; D017127:Glycation End Products, Advanced; D009711:Nucleotides; D011506:Proteins; D012097:Repressor Proteins; C099683:SIN3A transcription factor; D012709:Serum Albumin; D056264:Sin3 Histone Deacetylase and Corepressor Complex