3-Deoxyglucosone

3-Deoxyglucosone

Names
IUPAC name (4S,5R)-4,5,6-Trihydroxy-2-oxohexanal
Other names 3-Deoxy-D-erythro-hexosulose; 2-Keto-3-deoxyglucose; 3-Deoxy-D-erythro-hexos-2-ulose; 3-Deoxy-D-erythro-hexosulose; 3-Deoxy-D-glucosone; D-3-Deoxyglucosone
Identifiers
CAS Number	4084-27-9
ChEBI	CHEBI:60777
ChemSpider	102799
Jmol interactive 3D	Image Image
PubChem	114839
InChI InChI=1S/C6H10O5/c7-2-4(9)1-5(10)6(11)3-8/h2,5-6,8,10-11H,1,3H2/t5-,6+/m0/s1 Key: ZGCHLOWZNKRZSN-NTSWFWBYSA-N InChI=1/C6H10O5/c7-2-4(9)1-5(10)6(11)3-8/h2,5-6,8,10-11H,1,3H2/t5-,6+/m0/s1 Key: ZGCHLOWZNKRZSN-NTSWFWBYBM
SMILES C(C(C(CO)O)O)C(=O)C=O O=C(C=O)C[C@H](O)[C@H](O)CO
Properties
Chemical formula	C6H10O5
Molar mass	162.14 g·mol^−1
Density	1.406 g/ml
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

3-Deoxyglucosone (3DG) is a dicarbonyl sugar that is synthesized through the Maillard reaction,^[1] and is metabolized 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^[2] and collagen,^[3] contributing to diseases such as the vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, inflammation, 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 glycation, 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.^[4] 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).^[5]

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, particularly 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 nephropathy were found to have elevated plasma levels of 3DG compared with other diabetics.^[6][7][8]
• Glycated diet, which elevates systemic 3DG levels, leads to diabetes-like tubular and glomerular kidney pathology^[9] and increased oxidative stress. Diabetic humans also show increased oxidative stress.^[10]
• Increased 3DG is correlated to increased glomerular basement membrane width.^[11]
• Aminoguanidine (AG), an agent that detoxifies 3DG pharmacologically via formation of rapidly excreted covalent derivatives,^[12] has been shown to reduce AGE associated retinal, neural, arterial, and renal pathologies in animal models.^{[13][14][15][16]} The problem with AG is that it is toxic in the quantities needed for efficacy.
• 3DG induces reactive oxygen species (ROS) that contribute to the development of diabetic complications.^[17] Specifically, 3DG induces heparin-binding epidermal growth factor, a smooth muscle mitogen that is abundant in atherosclerotic plaques. This observation suggests that an increase in 3DG may trigger atherogenesis in diabetes.^[18][19]
• 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.^[20][21]
• 3DG inactivates aldehyde reductase.^[22] 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.^[23]
• 3DG induces ROS, resulting in oxidative DNA damage.^[24] 3DG can be internalized by cells and internalized 3DG is responsible for the production of intracellular oxidative stress.^[25]
• 3DG is a teratogenic factor in diabetic embryopathy, leading to embryo malformation.^[26] 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^[27] and is toxic to cultured cortical neurons^[28] and PC12 cells.^[29] 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.^[30]
• 3DG glycates and crosslinks proteins leading to a complex mixture of compounds called advanced glycation end-products (AGEs).^[31][32] AGEs have been postulated to contribute to the development of a range of diabetic complications including nephropathy, retinopathy, and neuropathy.^[33] Elevated levels of 3DG-modified proteins are found in diabetic versus control rat kidneys.^[34] In hyperglycemia, production of 3DG provides an amplification loop to sustain AGE generation, oxidative stress, and vascular activation.^[35]
• Hemoglobin-AGE levels are elevated in diabetic individuals^[36] 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.^[37] 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.^[38][39]
• 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.^[40] 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.^[38]

References

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