Glo1

Fig1. Glo1 can be regulated at transcriptional and post-translational levels. (Cinzia Antognelli, 2018)

What is GLO1 protein?

GLO1 (glyoxalase I) gene is a protein coding gene which situated on the short arm of chromosome 6 at locus 6p21. GLO1 is a cytoplasmic enzyme that belongs to the metallic beta-lactamases superfamily. This enzyme has important biological functions in living organisms and is mainly involved in the detoxification process of methylglyoxal (MG). MG is a highly active alpha-ketoaldehydes, and its excessive accumulation in cells leads to non-enzymatic glycosylation of proteins, nucleic acids, and phospholipids, resulting in cytotoxicity. The GLO1 protein is consisted of 184 amino acids and its molecular mass is approximately 20.8 kDa.

What is the function of GLO1 protein?

The functions of GLO1 include: reducing the cytotoxic effect of MG by promoting its binding to GSH; Prevent protein glycosylation and dysfunction caused by MG; Protects cells from oxidative stress and inflammatory damage by reducing the formation of AGEs; Since the binding of MG to GSH reduces the level of GSH, Glyoxalase I is indirectly involved in the regulation of cellular REDOX balance.

GLO1 Related Signaling Pathway

At the signaling pathway level, GLO1 is associated with several important pathways: MG has pro-inflammatory and pro-apoptotic properties, and GLO1 indirectly regulates signaling pathways involved in inflammation and cell survival, such as the NF-κB (nuclear factor κB) and MAPK (mitogen-activated protein kinase) pathways, by reducing MG levels. As a form of programmed cell death associated with iron-dependent lipid peroxidation, changes in GLO1 expression during iron death may affect cell fate, suggesting that GLO1 may interact with signaling pathways associated with lipid metabolism and antioxidant defense. In addition, there are oxidative stress response and cell proliferation regulation.

GLO1 Related Diseases

Genetic neuropathy: Defects in the GLO1 protein can lead to genetic neuropathy such as therapeutic neuropathy with linolenic acid (linolenic acid is a substrate for GLO1) and Fabry disease (substrate accumulation due to alpha-galactosidase deficiency).

Cancer: Abnormal function of GLO1 protein may be associated with the occurrence and development of certain cancers, especially breast and colorectal cancers. The important role of GLO1 protein in glucose metabolism makes it related to the pathogenesis of diabetes mellitus and cardiovascular diseases.

Bioapplications of GLO1

GLO1's role in fighting oxidative stress and maintaining cell function has made it a focus of antioxidant and anti-aging research, which has helped to develop new health products and interventions. In plant science, GLO1 research has helped to develop crop varieties that are more resistant to environmental stresses (such as drought, salinity, etc.) and improve agricultural productivity.

Case Study 1: Fabiola Garcia Cortizo, 2022

Methylglyoxal (MG) is a highly reactive α-oxoaldehyde that glycates proteins. MG has been linked to the development of diabetic complications: MG is the major precursor of advanced glycation end products (AGEs), a risk marker for diabetic complications in humans. MG is detoxified in large part through the glyoxalase system, whose rate-limiting enzyme is glyoxalase I (Glo1). Hence, the researchers aimed to study how Glo1 activity is regulated. They studied the regulation and effect of post-translational modifications of Glo1 in tissue culture and in mouse models of diabetes.

The results show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. They find that Glo1 Y136 phosphorylation responds in a bimodal fashion to glucose levels, increasing in cell culture from 0 mM to 5 mM (physiological) glucose, and then decreasing at higher glucose concentrations, both in cell culture and in mouse models of hyperglycemia. These data elevated MG leads to hyperglycemia, suggest the existence of a deleterious positive feedback loop whereby hyperglycemia leads to reduced Glo1 activity, contributing to elevated MG levels, which in turn promote hyperglycemia.

Fig1. Mutation of Glo1 Y136 to alanine reduces Glo1 activity.

Fig2. Multiple different kinases can phosphorylate Glo1 Y136 in an in vitro kinase assay, including members of the Src family.

Case Study 2: Tomonori Hara, 2021

Carbonyl stress, a specific form of oxidative stress, is reported to be involved in the pathophysiology of schizophrenia; however, little is known regarding the underlying mechanism. Here, the researchers found that disruption of GLO1, the gene encoding a major catabolic enzyme scavenging the carbonyl group, increases vulnerability to external carbonyl stress, leading to abnormal phenotypes in human induced pluripotent stem cells (hiPSCs). The viability of GLO1 knockout (KO)-hiPSCs decreased and activity of caspase-3 was increased upon addition of methylglyoxal (MGO), a reactive carbonyl compound. In the GLO1 KO-hiPSC-derived neurons, MGO administration impaired neurite extension and cell migration. Further, accumulation of methylglyoxal-derived hydroimidazolone (MG-H1; a derivative of MGO)-modified proteins was detected in isolated mitochondria. Mitochondrial dysfunction, including diminished membrane potential and dampened respiratory function, was observed in the GLO1 KO-hiPSCs and derived neurons after addition of MGO and hence might be the mechanism underlying the effects of carbonyl stress. The susceptibility to MGO was partially rescued by the administration of pyridoxamine, a carbonyl scavenger.

Fig3. Western blot of WT- and GLO1 KO-hiPSCs using an antibody against GLO1.

Fig4. Plot of OCR in WT- and GLO1 KO-hiPSCs versus measurement time.

Glo1 has several biochemical functions, for example, lactoylglutathione lyase activity,zinc ion binding. Some of the functions are cooperated with other proteins, some of the functions could acted by Glo1 itself. We selected most functions Glo1 had, and list some proteins which have the same functions with Glo1. You can find most of the proteins on our site.

Glo1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with Glo1 here. Most of them are supplied by our site. Hope this information will be useful for your research of Glo1.

IKBKE;MAP3K13;IKBKG;MAP1LC3B