Abstract
The reactive dicarbonyl metabolite methylglyoxal (MG) is the precursor of the major quantitative advanced glycation endproducts (AGEs) in physiological systems - arginine-derived hydroimidazolones and deoxyguanosine-derived imidazopurinones. The glyoxalase system in the cytoplasm of cells provides the primary defence against dicarbonyl glycation by catalysing the metabolism of MG and related reactive dicarbonyls. Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in ageing and disease. It is produced endogenously by increased formation and/or decreased metabolism of dicarbonyl metabolites. Dicarbonyl stress contributes to ageing, disease and activity of cytotoxic chemotherapeutic agents. It contributes to ageing through age-related decline in glyoxalase 1 (Glo-1) activity. Glo-1 has a dual role in cancer as a tumour suppressor protein prior to tumour development and mediator of multi-drug resistance in cancer treatment, implicating dicarbonyl glycation of DNA in carcinogenesis and dicarbonyl-driven cytotoxicity in mechanism of action of anticancer drugs. Glo-1 is a driver of cardiovascular disease, likely through dicarbonyl stress-driven dyslipidemia and vascular cell dysfunction. Dicarbonyl stress is also a contributing mediator of obesity and vascular complications of diabetes. There are also emerging roles in neurological disorders. Glo-1 responds to dicarbonyl stress to enhance cytoprotection at the transcriptional level through stress-responsive increase of Glo-1 expression. Small molecule Glo-1 inducers are in clinical development for improved metabolic, vascular and renal health and Glo-1 inhibitors in preclinical development for multidrug resistant cancer chemotherapy.
Highlights
The reactive dicarbonyl metabolite methylglyoxal (MG) is the precursor of the major quantitative advanced glycation endproducts (AGEs) in physiological systems - arginine-derived hydroimidazolones and deoxyguanosine-derived imidazopurinones
Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased modification of protein and DNA contributing to cell and tissue dysfunction in ageing and disease [1]
Examples of physiological dysfunction mediated by dicarbonyl glycation of arginine residues of proteins are: mitochondrial protein dysfunction and increased formation of reactive oxygen species (ROS) [52], inflammatory protein expression (RAGE, S100 proteins and high mobility group box-1) [53], mitochondrial pathway activated apoptosis [54] and cell detachment from the extracellular matrix and anoikis [55]
Summary
Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased modification of protein and DNA contributing to cell and tissue dysfunction in ageing and disease [1]. The glyoxalase system is a cytoplasm enzymatic pathway, which metabolises the most highly reactive acyclic dicarbonyls – mainly MG and glyoxal It thereby plays a major role in suppressing dicarbonyl stress in physiological systems, keeping dicarbonyl metabolites at low, tolerable levels. Examples of dicarbonyl stress are the increased MG in ageing plants [2], increased MG-protein modification in ageing human lens [5], increased plasma and tissue concentration of MG in diabetes [6], and increased concentrations of MG and glyoxal in renal failure [4]. Other recent reviews focussing mostly on dicarbonyl stress in obesity and diabetes have been given elsewhere [7, 8]
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