Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments

Abstract

Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in aging and disease. It is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites. MG (methylglyoxal) is a dicarbonyl metabolite of relatively high flux of formation and precursor of the most quantitatively and functionally important spontaneous modifications of protein and DNA clinically. Major MG-derived adducts are arginine-derived hydroimidazolones of protein and deoxyguanosine-derived imidazopurinones of DNA. These are formed non-oxidatively. The glyoxalase system provides an efficient and essential basal and stress-response-inducible enzymatic defence against dicarbonyl stress by the reduced glutathione-dependent metabolism of methylglyoxal by glyoxalase 1. The GLO1 gene encoding glyoxalase 1 has low prevalence duplication and high prevalence amplification in some tumours. Dicarbonyl stress contributes to aging, disease and activity of cytotoxic chemotherapeutic agents. It is found at a low, moderate and severe level in obesity, diabetes and renal failure respectively, where it contributes to the development of metabolic and vascular complications. Increased glyoxalase 1 expression confers multidrug resistance to cancer chemotherapy and has relatively high prevalence in liver, lung and breast cancers. Studies of dicarbonyl stress are providing improved understanding of aging and disease and the basis for rational design of novel pharmaceuticals: glyoxalase 1 inducers for obesity, diabetes and cardiovascular disease and glyoxalase 1 inhibitors for multidrug-resistant tumours. The first clinical trial of a glyoxalase 1 inducer in overweight and obese subjects showed improved glycaemic control, insulin resistance and vascular function.

Diabetic retinopathy: hyperglycaemia, oxidative stress and beyond

“…Nawroth and colleagues and Thornalley and colleagues [52,53] proposed that the role of the AGE precursor methylglyoxal is of profound interest since its formation depends not on hyperglycaemia but on the balance between formation and enzymatic detoxification through the glyoxalase 1 and 2 system. In addition, increased dicarbonyl stress not only arises from hyperglycaemia but also occurs in conditions that promote accelerated ageing and metabolic and vascular complications.…”

Methylglyoxal induces retinopathy‐type lesions in the absence of hyperglycemia: studies in a rat model

“…A number of important clinical factors determine the onset and progression of diabetic retinopathy (DRP), with glycemia and disease duration among the strongest determinants (2,3). Among the critical glucosetriggered downstream pathways is the mitochondrial overproduction of reactive oxygen species, which, either upstream or downstream, involve the generation of reactive dicarbonyls such as methylglyoxal (MG) (4). Their levels are elevated in plasma and target tissues of preclinical diabetes models with complications, and in patients.…”

Glyoxalase 1 expression is downregulated in preimplantation blastocysts of diabetic rabbits

“…(c) Relative GLO1 protein activities were calculated as the quotient of GLO1 activity and relative GLO1 protein amount increase the MGO level (Beisswenger, Delucia, Lapoint, Sanford, & Beisswenger, 2005). Furthermore, it has been shown that catabolism of glycogenic amino acids, mainly L-threonine, also increases MGO levels in the cell (Rabbani, Xue, & Thornalley, 2016).…”