Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome

Abstract

Methylglyoxal (MG) is a potent protein glycating agent. Glycation is directed to guanidino groups of arginine residues forming mainly hydroimidazolone N (δ)-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) residues. MG-H1 formation is damaging to the proteome as modification is often directed to functionally important arginine residues. MG-H1 content of proteins is quantified by stable isotopic dilution analysis tandem mass spectrometry and also by immunoblotting with specific monoclonal antibodies. MG-glycated proteins undergo cellular proteolysis and release MG-H1 free adduct for excretion. MG-H1 residues have been found in proteins of animals, plants, bacteria, fungi and protoctista. MG-H1 is often the major advanced glycation endproduct in proteins of tissues and body fluids, increasing in diabetes and associated vascular complications, renal failure, cirrhosis, Alzheimer's disease, arthritis, Parkinson's disease and ageing. Glyoxalase 1 and aldo-keto reductase 1B1 metabolise >99% MG to innocuous products and thereby protect the proteome, providing an enzymatic defence against MG-mediated glycation. Proteins susceptible to MG modification with related functional impairment are called the "dicarbonyl proteome" (DCP). DCP includes albumin, haemoglobin, transcription factors, mitochondrial proteins, extracellular matrix proteins, lens crystallins and other proteins. DCP component proteins are linked to mitochondrial dysfunction in diabetes and ageing, oxidative stress, dyslipidemia, cell detachment and anoikis and apoptosis. Biochemical and physiological susceptibility of a protein to modification by MG and sensitivity of biochemical pathways and physiological systems to related functional impairment under challenge of physiologically relevant increases in MG exposure are key concepts. Improved understanding of the DCP will likely have profound importance for human health, longevity and treatment of disease.

Methylglyoxal suppresses human colon cancer cell lines and tumor growth in a mouse model by impairing glycolytic metabolism of cancer cells associated with down-regulation of c-Myc expression

“…13 (5) activation of the p38-MAPK, p42/44-MAPK signaling pathway, causing a rapid cytochrome c release and triggering the caspase cascade apoptotic pathway; 12,14 and (6) reduction of tumor migration via restoration of the transcriptional activities of wild-type p53. 15 Moreover, AG abolished the MG-induced anti-tumor effects by acting as a scavenger, reacting rapidly with MG. 30 Cancer cells favor the aerobic glycolytic pathway and generate energy predominantly by increasing their rate of glycolysis.…”

“…24 MG is an intermediate metabolite of glucose. 5 We postulate that MG induces its anti-tumor effects through disruption of cancer metabolism and glycolysis. Our results demonstrating that MG reduced glucose consumption and lactate production and impaired ATP supply in human colon cancer cells are supported by other reports in which MG has been shown to inhibit glycolysis through targeting lactate dehydrogenase (LDH) and glyceraldehyde 3-phosphate dehydrogenase (G3PDH).…”

“…4 It is formed through various metabolic routes via both enzymatic and non-enzymatic pathways, predominantly the glycolytic pathway. 5 MG is produced in only small amounts under normal conditions, but its expression is greatly increased in hyperglycemic disorders such as diabetes. 6,7 It is catalyzed mainly by the glyoxalase system and is converted to D-lactate.…”

Restoration of Glyoxalase Enzyme Activity Precludes Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease

“…1 The activity of the glyoxalase (GLO) enzyme system is vital to mitigation of the dicarbonyl component of oxidative stress. 2 Dicarbonyls are neurotoxic at almost every biomolecular level. MG forms advanced glycation end products (AGEs) with proteins, leading to protein misfolding.…”

Key steps from the “RNA World” to the “DNA World”

“…We have previously reported a remarkable stereoselective reaction of methylglyoxal (MG, pyruvaldehyde) with α-aminoazaheterocycles, as 2-aminopyridine, the nucleic base adenine and adenine nucleosides, leading in high yield to cyclic adducts in water under mild conditions at 50 to 70° C (Figure 8) [26][27]. On another hand, the reactions of MG with the guanidinine function of arginine residues in proteins are considered to be involved in diabete complications because of the MG production by degradation of glucose in vivo [28][29][30]. The formations of fluorescent 3-hydroxypyrimidine biomarkers called Argpyrimidines and of MG adducts from arginine residues have been independently demonstrated in vivo and/or in vitro from the corresponding amino acid derivatives ( Figure 9) but were not related [31][32][33].…”