Methylglyoxal in cells elicits a negative feedback loop entailing transglutaminase 2 and glyoxalase 1

Glyoxalase 1 (Glxl) is the key enzyme that converts the highly reactive alpha-oxo-aldehydes into the corresponding alpha-hydroxy acids using t-glutathione as a cofactor. In our preliminary data. Glxl was identified as a substrate of transglutaminase 2 (TG2), a ubiquitous enzyme with multiple functions. According to the catalytic properties of TG2, protein cross-linking, polyamine conjugation, and/or deamidation are potential post-translational modifications. In this article, we have demonstrated that TG2 catalyzes either polyamine conjugation or cleamiclation to Glxl depending on the presence of polyamines or not. Deamidation leads to activation of Glxl while polyamine conjugation results in activation of Glxl as well as stabilization of Glxl against denaturation treatment. In cultured HeLa cells, methylglyoxal challenge causes increase in intracellular levels of reactive oxygen species (ROS) and calcium leading to TG2 activation and subsequent transamidation and activation of Glxl. The inhibition of TG2 significantly weakens the cell resistance to the methylglyoxal challenge. Thus, Glxl is a novel substrate of TG2 and is activated by TG2 in vitro and in cellulo. Exposure to methylglyoxal elicits a negative feedback loop entailing ROS, calcium, TG2 and Glxl, thus leading to attenuation of the increase in the methylglyoxal level. The results imply that cancer cells highly express TG2 or Glxl can endure the oxidative stress derived from higher glycolytic flux and may gain extra growth advantage from the aerobic glycolysis. (C) 2014 The Authors. Published by Elsevier B.V. All rights reserved,