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Glyoxalase System

The Glyoxalase System - An introduction


The glyoxalase system catalyses the conversion of methylglyoxal to D-lactate via the intermediate S-D-lactoylglutathione. It comprises two enzymes, glyoxalase I and glyoxalase II, and a catalytic amount of reduced glutathione.

The glyoxalase system is an enzymatic pathway found in the cytosol of all cells. Recent research has seen the development of novel anti-tumour and anti-malarial agents targeted to the glyoxalase system, and blood glyoxalase activity values emerge as risk factors for the development of diabetic complications. A resurgence of interest in this system in biomedical and pharmaceutical research is at hand. This review explains why.

The glyoxalase system is vital for life support from the earliest stages of embryogenesis, through maturation and development, until ageing and death. It has been implicated in control of cell growth, detoxification of α-oxoaldehydes and a bypass for the triosephosphate → pyruvate section of the Embden-Meyerhof pathway.

The glyoxalase system is a relatively simple pathway consisting of two consecutive enzymatic reactions with the terminal product D-lactate, utilising reduced glutathione as cofactor (only described with respect to the glyoxalase system here). The importance of this system is associated with the metabolism of the physiological substrate, methylglyoxal - a reactive a,β-dicarbonyl compound. The formation of methylglyoxal in glycolytic biological systems is unavoidable. With an impaired or inhibited glyoxalase system, methylglyoxal accumulates to toxic levels - a feature exploited in anti-cancer and anti-microbial therapy. Under dose-limiting conditions, methylglyoxal induces initially reversible, later irreversible modification of proteins. The former may be involved in metabolic regulation and the later in the chronic pathogenesis associated with diabetic complications.

This year is the 80th anniversary of the discovery of the glyoxalase system. In the spirit of the early pioneers, I describe the current state of knowledge, I briefly conjure with the prospects for the future, and from there on - I leave it with you.

Dr Paul J. Thornalley.

Preface from Thornalley, P.J. (1993) The glyoxalase system in health and disease. Mol. Aspects of Med. 14, 287-371

Chemotherapy of cancer by glyoxalase I inhibitors


To study the development of glyoxalase I inhibitor diester prodrugs as antitumour agents.


Methylglyoxal is an endogenous mutagen that is detoxified in all cells by the glyoxalase system. Pharmacological inhibition of methylglyoxal detoxification by inhibitors of glyoxalase I induced an acute increase in methylglyoxal, DNA modification and induction of apoptosis. We developed a glyoxalase I inhibitor diester prodrug with potent antitumour activity in vitro and in vivo. We demonstrated that methylglyoxal and glyoxalase I inhibitors were selectively toxic to tumour cells in vitro and induced apoptosis.


Crystal structure of human glyoxalase I (Cameron et al., EMBO J. 16, 3386-3395, 1997)



First demonstration of antitumour activity in vitro by a glyoxalase I inhibitor glutathione-S-conjugate diester prodrug:

  • Lo, T.W.C. and Thornalley, P.J. (1992) Inhibition of growth of human leukaemia 60 cells in culture by diethyl esters of glyoxalase inhibitors, Biochem. Pharmacol. 44, 2357-2363.

First demonstration of antitumour activity in vivo by a glyoxalase I inhibitor glutathione-S-conjugate diester prodrug:

  • Thornalley, P.J., Wyatt, C., Davies, N., Edwards, L.G., Kang, Y., Ladan, M.J. and Double, J. (1996) Antitumour activity of S-p-bromobenzylglutathione cyclopentyl diester in vitro and in vivo. Inhibition of glyoxalase I and induction of apoptosis. Biochem. Pharmacol. 51, 1365-1372.

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