Glyoxalase Centennial conference: introduction, history of research on the glyoxalase system and future prospects

Abstract

On 27-29 November 2013, researchers gathered at the University of Warwick, Coventry, U.K., to celebrate the centennial of the discovery of the glyoxalase pathway. The glyoxalase system was discovered and reported in papers by Carl Neuberg and by Henry Drysdale Dakin and Harold Ward Dudley in 1913. All three were leading extraordinary investigators in the pioneering years of biochemistry. Neuberg proposed glyoxalase as the pathway of mainstream glycolysis and Gustav Embden correctly discounted this, later confirmed by Otto Meyerhof. Albert Szent-Györgyi proposed glyoxalase I as the regulator of cell growth and others discounted this. In the meantime, molecular, structural and mechanistic properties of the enzymatic components of the system, glyoxalase I and glyoxalase II, have been characterized. The physiological function of the glyoxalase pathway of enzymatic defence against dicarbonyl glycation, particularly by endogenous methylglyoxal, now seems secure. We are now in an era of investigation of the regulation of the glyoxalase system where a role in aging and disease, physiological stress and drug resistance and development of healthier foods and new pharmaceuticals is emerging. The history of glyoxalase research illustrates the scientific process of hypothesis proposal, testing and rejection or acceptance with further investigation, standing testament to the need for intuition guided by experience and expertise, as well as indefatigable experimentation.

Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease

“…[1] and related papers. Commercial sources of MG typically contain major contamination and there are many potential interferences in measurement of dicarbonyls.…”

“…Dicarbonyl stress is the abnormal accumulation of a-oxoaldehyde metabolites leading to increased modification of protein and DNA contributing to cell and tissue dysfunction in ageing and disease [1]. Examples are the increased methylglyoxal (MG) in ageing plants [2], increased MG-protein modification in ageing human lens [3], increased plasma and tissue concentration of MG in diabetes [4], and increased concentrations of MG, glyoxal, 3-deoxyglucosone (3-DG) and other dicarbonyls in renal failure [5].…”

Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression

“…6,7 It is catalyzed mainly by the glyoxalase system and is converted to D-lactate. 8 MG is extremely reactive and is toxic to cell. 9 MG exposure leads to decreased synthesis of protein, inhibition of enzymes activity, increased oxidative stress, activated signal transduction, and other cellular dysfunctions.…”

The Glyoxalase System and Methylglyoxal-Derived Carbonyl Stress in Sepsis: Glycotoxic Aspects of Sepsis Pathophysiology

“…These enzymes metabolize MG into lactate by using NADPH and glutathione [137,138]. Glyoxalase was first described in 1913 [139,140], but despite a hundred years of research [141], little is known about the actual mechanisms of its regulation. However, this way of MG detoxification seems to be severely disrupted in critical illness (Figure 2).…”