Glyoxylase I (GloΙ) Inhibitor COTC

Glyoxalase system is known as an enzymatic network having an important role of detoxication in a lot of organisms. This enzymatic network is composed of Glyoxalase 1 (GLO1), Glyoxalase 2 (GLO2), and reduced form of Glutathione (GSH), and detoxifies harmful metabolites such as methylglyoxal (MG) in cells. ⁷⁾

MG has two sets of carbonyl groups (C=O), and is also called a dicarbonyl compound. It is known that the dicarbonyl compounds as metabolites from the system are composed from alpha-Oxoaldehydes Glyoxal, 3-Deoxyglucosone (3-DG), and Glucosone etc.

These dicarbonyl compounds has high reactivity to DNA and protein to generate dicarbonyl stress which cause functional disorders of cells and tissues in disease and senescence. Then, the undesired metabolites cause adversely affect to physiological system. CLO1 in cytosol suppresses generation of the harmful metabolites by degradation of dicarbonyl compounds such as MG. First, GLO1 metabolizes MG to S-D-lactoylgluthathione. Then, GLO2 catalyzes hydrolysis of S-D-lactoylgluthathione into D-lactate, and regenerate GSH which was consumed by the metabolic reaction of GLO1. ⁸⁾

Dicarbonyl compounds to cause dicarbonyl stress, especially MG and Advanced Glycation End Products (AGE) produced from MG which is a precursor of it, relate variety of diseases including diabetes, cardiovascular diseases, neurodegenerative diseases, cancer disease etc. It can be said that GLO1 is an important rate-determining enzyme (key enzyme) that protects glycation in vivo. Therefore, GLO1 is expected to an important drug target, and to determine its regulatory mechanism is of interest to researchers. ⁷⁾