Getting the lowdown on GLO2

Researchers publish new data on the enzyme glyoxalase II and its role in cellular metabolism

November 25, 2020
Kelsey Kaustinen

TUCSON, Ariz.—The enzyme glyoxalase II (GLO2) plays a role in a variety of biological functions, including the rate of cell growth. The glyoxalase system is comprised of biological compounds that accelerate chemical reactions in the body and aid in defending against cellular damage, and it includes glyoxalase I and II. What is drawing new interest from researchers is the enzyme’s potential as a therapeutic target for certain diseases.

A preliminary study, “Non-enzymatic Lysine Lactoylation of Glycolytic Enzymes,” was published Cell Chemical Biology examining the enzyme. The work was led by Dr. James Galligan, assistant professor at the University of Arizona College of Pharmacy. In it, Galligan and researchers at the University of Colorado Anschutz Medical Campus detail their findings that when GLO2 function is inhibited, glycolysis is slowed down as well, which consequently leads to a slower rate of cell growth.

“Post-translational modifications (PTMs) regulate enzyme structure and function to expand the functional proteome. Many of these PTMs are derived from cellular metabolites and serve as feedback and feedforward mechanisms of regulation,” the authors explained in their paper. “We have identified a PTM that is derived from the glycolytic by-product, methylglyoxal. This reactive metabolite is rapidly conjugated to glutathione via glyoxalase 1, generating lactoylglutathione (LGSH). LGSH is hydrolyzed by glyoxalase 2 (GLO2), cycling glutathione and generating D-lactate.

“We have identified the non-enzymatic acyl transfer of the lactate moiety from LGSH to protein Lys residues, generating a “LactoylLys” modification on proteins. GLO2 knockout cells have elevated LGSH and a consequent marked increase in LactoylLys. Using an alkyne-tagged methylglyoxal analog, we show that these modifications are enriched on glycolytic enzymes and regulate glycolysis. Collectively, these data suggest a previously unexplored feedback mechanism that may serve to regulate glycolytic flux under hyperglycemic or Warburg-like conditions.”

That impact on cell growth makes it a target of interest in certain types of cancer, including breast and prostate cancer. Glyoxalase is thought to be implicated in insulin-dependent diabetes mellitus as well, as GLO1 and GLO2 expression is elevated in diabetes patients of that subtype. The team pinpointed a protein modification that uses the GLO2 enzyme to regulate cell growth and the breakdown of glucose.

As for how GLO2’s functions are altered in the case of disease, Galligan says that’s one of the many things the team is looking to follow up on. They’re also interested in further exploring what happens when GLO2 activity is compromised, how or if it changes metabolism, and if there are any other metabolic pathways that are affected as well. Previously, most work on the glyoxalase system has focused on GLO1, he explains, so this is some of the first research solely on GLO2.

“I’m not a firm believer in genomics being an end-all, be-all,” Galligan tells DDN. “For the longest time, the central focus in most biome research has been on genomics, and then it branched out into proteomics, and now it’s really understanding that the metabolism, the metabolome is really the most critical thing. So there’s really been a huge push in really establishing what overall metabolism, cell health looks like, a huge push on the role of cell metabolism and how that’s being disregulated in both health and disease.”

A study is planned—supported by a five-year, $1.8-million grant funded by the National Institute of General Medical Studies, part of the National Institutes of Health—to further explore GLO2’s role in protein modification, health and disease onset.

“We aim to understand how glyoxalase II regulates cell growth and energy production in cells in the short-term, although the ultimate goal is to generate small-molecule therapeutics targeting glyoxalase II for the treatment of diseases such as cancer and diabetes,” Galligan remarked.

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