Role of glyoxalase 1 in methylglyoxal detoxification–the broad player of psychiatric disorders

Abstract

Methylglyoxal (MG) is a highly reactive α-ketoaldehyde formed endogenously as a byproduct of the glycolytic pathway. To remove MG, various detoxification systems work together in vivo , including the glyoxalase system, which enzymatically degrades MG using glyoxalase 1 (GLO1) and GLO2. Recently, numerous reports have shown that GLO1 expression and MG accumulation in the brain are involved in the pathogenesis of psychiatric disorders, such as anxiety disorder, depression, autism, and schizophrenia. Furthermore, it has been reported that GLO1 inhibitors may be promising drugs for the treatment of psychiatric disorders. In this review, we discuss the recent findings of the effects of altered GLO1 function on mental behavior, especially focusing on results obtained from animal models.

Brain Proteome-Wide Association Study Identifies Candidate Genes that Regulate Protein Abundance Associated with Post-Traumatic Stress Disorder

“…As an enzyme protein-coding gene, GLO1 encodes glyoxalase I and is involved in detoxification of methylglyoxal (MG) in the cellular glycolysis pathway [ 35 ]. Previous studies have found that GLO1 expression and MG accumulation in the brain are associated with the pathogenesis of psychiatric disorders, such as anxiety disorder, depression, autism, and schizophrenia [ 36 ]. A recent hospital-based case-control study found significant differences in the distribution of GLO1 variation, RNA expression, and enzyme activity between schizophrenia patients and controls, suggesting GLO1 is associated with dysfunction in the left middle frontal gyrus in schizophrenia [ 37 ].…”

RAGE Against the Glycation Machine in Synucleinopathies: Time to Explore New Questions

“…Methylglyoxal (MGO), a byproduct from the glycolytic pathway (and also from other metabolic pathways), is an intermediate of these non-enzymatic reaction sequences and is considered a main causative agent of glycation reactions in biological systems [36]. In fact, mammalian cells express a suitable enzymatic system for MGO detoxification, the glyoxalase system [37,38].…”

Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer’s Disease

“…N-Boc-L-Dap(N-Fmoc)-OH (18). Using a literature-reported procedure, 49 a slurry of Boc-L-asparagine (17, 5.0 g, 21.5 mmol) in ethyl acetate (24 mL), acetonitrile (24 mL), water (12 mL), and iodosobenzene diacetate (8.32 g, 25.8 mmol) was cooled and stirred at 16 °C for 30 min.…”

“…It forms irreversible adducts with amino acids arginine and lysine, resulting in the formation of hydroimidazolone (MG-H1) and Nε-carboxyethyl-lysine (CEL), respectively . Under physiological conditions, MEG is detoxified by a conserved enzyme system, the ubiquitous glutathione (GSH)-dependent glyoxalase system (GLO), consisting of enzymes GLO1 and GLO2 . Reduced brain GLO1 function has been associated with the buildup of AGEs and cause of neurodegeneration in AD .…”

“… 17 Under physiological conditions, MEG is detoxified by a conserved enzyme system, the ubiquitous glutathione (GSH)-dependent glyoxalase system (GLO), consisting of enzymes GLO1 and GLO2. 18 Reduced brain GLO1 function has been associated with the buildup of AGEs and cause of neurodegeneration in AD. 19 Expression of GLO1 is upregulated in the early and middle stages of AD, 20 , 21 hence the dysfunction of this enzyme system is likely due to the unavailability of the cofactor GSH.…”