3-deoxyglucosone
Encyclopedia
3-Deoxyglucosone is a dicarbonyl sugar that is synthesized through the Maillard reaction
, and is detoxified to 3-deoxyfructose and 2-keto-3-deoxygluconic acid. 3DG is a precursor for the formation of advanced glycation end-products (AGEs): 3DG rapidly reacts with protein amino groups to form AGEs such as imidazolone, pyrraline, N6-(carboxymethyl)lysine and pentosidine
. 3DG as well as AGEs play a role in the modification and cross-linking of long-lived proteins such as crystallin
and collagen
, contributing to diseases such as the vascular complications of diabetes, atherosclerosis
, hypertension
, Alzheimer’s disease inflammation
and aging.
, the early stage of the Maillard reaction. In the intermediate and late stages of glycation, the spontaneous formation of highly reactive compounds such as 3DG may account for the numerous features of diabetic complication as well as aging.
In 1990, the Brown group from Fox Chase Cancer Center
in Philadelphia identified fructose 3-phosphate (F3P) in lenses from diabetic rats. This shows the existence of the only mammalian kinase
that phosphorylates a sugar on a secondary hydroxyl group. F3P is an unstable compound, and the spontaneous decomposition of F3P leads to formation of 3DG. In 2000, the 3-phosphokinase responsible for the formation of F3P was cloned and named fructosamine 3-kinase
(FN3K).
Maillard reaction
The Maillard reaction is a form of nonenzymatic browning similar to caramelization. It results from a chemical reaction between an amino acid and a reducing sugar, usually requiring heat....
, and is detoxified to 3-deoxyfructose and 2-keto-3-deoxygluconic acid. 3DG is a precursor for the formation of advanced glycation end-products (AGEs): 3DG rapidly reacts with protein amino groups to form AGEs such as imidazolone, pyrraline, N6-(carboxymethyl)lysine and pentosidine
Pentosidine
Pentosidine is a biomarker for advanced glycation endproducts, or AGEs. It is a well characterized and easily detected member of this large class of compounds.-Background:...
. 3DG as well as AGEs play a role in the modification and cross-linking of long-lived proteins such as crystallin
Crystallin
In anatomy, a crystallin is a water-soluble structural protein found in the lens and the cornea of the eye accounting for the transparency of the structure. It has also been identified in other places such as the heart, and in aggressive breast cancer tumors....
and collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
, contributing to diseases such as the vascular complications of diabetes, atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, Alzheimer’s disease inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and aging.
Sources
3DG is a highly reactive sugar that is found in high-fructose corn syrup and in many foods. It is also made naturally by the body when excessive sugar is consumed or when a person is diabetic. Glucose reacts non-enzymatically with protein amino groups to initiate glycationGlycation
Glycation is the result of the bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme. All blood sugars are reducing molecules. Glycation may occur either inside the body or outside the body...
, the early stage of the Maillard reaction. In the intermediate and late stages of glycation, the spontaneous formation of highly reactive compounds such as 3DG may account for the numerous features of diabetic complication as well as aging.
In 1990, the Brown group from Fox Chase Cancer Center
Fox Chase Cancer Center
The Fox Chase Cancer Center is a National Cancer Institute-designated Comprehensive Cancer Center research facility and hospital located in the Fox Chase section of Philadelphia, Pennsylvania, United States. The main facilities of the center are located on property adjoining Burholme Park...
in Philadelphia identified fructose 3-phosphate (F3P) in lenses from diabetic rats. This shows the existence of the only mammalian kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
that phosphorylates a sugar on a secondary hydroxyl group. F3P is an unstable compound, and the spontaneous decomposition of F3P leads to formation of 3DG. In 2000, the 3-phosphokinase responsible for the formation of F3P was cloned and named fructosamine 3-kinase
FN3K
Fructosamine-3-kinase is an enzyme that in humans is encoded by the FN3K gene.- Function :FN3K catalyzes phosphorylation of fructosamines formed by glycation, the nonenzymatic reaction of glucose with primary amines followed by Amadori rearrangement...
(FN3K).
Biological activity and clinical implication
Emerging data indicate that 3DG plays a central role in the development of diabetic complications via FN3K action. 3DG has a variety of potential biological effects of 3DG, in particular, when it is present at elevated concentrations in diabetic states:- Diabetic humans have elevated levels of 3DG and 3-deoxyfructose (3DF) in plasma and urine as compared with non-diabetic individuals. Development of diabetic complications is accelerated in patients with extremely high levels of 3DG in their serum. Diabetics with nephropathyNephropathyNephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.-Causes:Causes of nephropathy include administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its salts...
were found to have elevated plasma levels of 3DG compared with other diabetics. - Glycated diet, which elevates systemic 3DG levels, leads to diabetes-like tubular and glomerular kidney pathology and increased oxidative stress. Diabetic humans also show increased oxidative stress.
- Increased 3DG is correlated to increased glomerular basement membraneBasement membraneThe basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...
width. - Aminoguanidine (AG), an agent that detoxifies 3DG pharmacologically via formation of rapidly excreted covalent derivatives, has been shown to reduce AGE associated retinal, neural, arterial, and renal pathologies in animal models. The problem with AG is that it is toxic in the quantities needed for efficacy.
- 3DG induces reactive oxygen speciesReactive oxygen speciesReactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
(ROS) that contribute to the development of diabetic complications. Specifically, 3DG induces heparin-binding epidermal growth factor, a smooth muscle mitogenMitogenA mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of a protein.Mitogenesis is the induction of mitosis, typically via a mitogen....
that is abundant in atherosclerotic plaques. This observation suggests that an increase in 3DG may trigger atherogenesis in diabetes. - 3DG inactivates some of the most important enzymes that protect cells from ROS. For example, glutathione peroxidase, a central antioxidant enzyme that uses glutathione to remove ROS, and glutathione reductase, which regenerates glutathione, are both inactivated by 3DG.
- 3DG inactivates aldehyde reductase. Aldehyde reductase is the cellular enzyme that protects the body from 3DG. Detoxification of 3DG to 3-deoxyfructose (3DF) is impaired in diabetic humans since their ratio of 3DG to 3DF in urine and plasma differs significantly from non-diabetic individuals.
- 3DG induces ROS, resulting in oxidative DNA damage. 3DG can be internalized by cells and internalized 3DG is responsible for the production of intracellular oxidative stress.
- 3DG is a teratogenic factor in diabetic embryopathy, leading to embryo malformation. This appears to arise from 3DG accumulation, which leads to superoxide-mediated embryopathy. Women with pre-existing diabetes or severe diabetes that develops during pregnancy are between 3 and 4 times more likely than other women to give birth to infants with birth defects.
- 3DG induces apoptosis in macrophage-derived cell lines and is toxic to cultured cortical neurons and PC12 cells. A recent study on the cause of amyotropic lateral sclerosis, a form of motor neuron disease, has suggested that accumulation of 3DG can lead to neurotoxicity because of ROS generation.
- 3DG glycates and crosslinks proteins leading to a complex mixture of compounds called advanced glycation end-products (AGEs). AGEs have been postulated to contribute to the development of a range of diabetic complications including nephropathy, retinopathy, and neuropathy. Elevated levels of 3DG-modified proteins are found in diabetic versus control rat kidneys. In hyperglycemia, production of 3DG provides an amplification loop to sustain AGE generation, oxidative stressOxidative stressOxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
, and vascular activation. - Hemoglobin-AGE levels are elevated in diabetic individuals and other AGE proteins have been shown in experimental models to accumulate with time, increasing from 5-50 fold over periods of 5–20 weeks in the retina, lens and renal cortex of diabetic rats. The inhibition of AGE formation reduced the extent of nephropathy in diabetic rats. Therefore, substances that inhibit AGE formation may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGE-mediated disease.
- AGEs have specific cellular receptors; the best-characterized are those called RAGE. The activation of cellular RAGE on endothelium, mononuclear phagocytes, and lymphocytes triggers the generation of free radicals and the expression of inflammatory gene mediators. Such increases in oxidative stress lead to the activation of the transcription factor NF-κB and promote the expression of NF-κB regulated genes that have been associated with atherosclerosis.