3-Deoxyglucosone

3-Deoxyglucosone (3DG) is a sugar that is notable because it is a marker for diabetes. 3DG reacts with protein to form advanced glycation end-products (AGEs), which contribute to diseases such as the vascular complications of diabetes, atherosclerosis, hypertension, Alzheimer's disease, inflammation, and aging.[1]

3-Deoxyglucosone
Names
IUPAC name
3-Deoxy-D-erythro-hexos-2-ulose
Systematic 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-hexosulose; 3-Deoxy-D-glucosone; D-3-Deoxyglucosone
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.241.539
UNII
  • 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 checkY
    Key: ZGCHLOWZNKRZSN-NTSWFWBYSA-N checkY
  • 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
  • C(C(C(CO)O)O)C(=O)C=O
  • O=C(C=O)C[C@H](O)[C@H](O)CO
Properties
C6H10O5
Molar mass 162.141 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).
☒N verify (what is checkY☒N ?)
Infobox references

Biosynthesis
4-Imidazolone arise from the condensation of arginine residues and 3-deoxyglucosone (R = CH2CH(OH)CH(OH)CH2OH).[2]

3DG is made naturally via the Maillard reaction. It forms after glucose reacts with primary amino groups of lysine or arginine found in proteins. Because of the increased concentration of the reactant glucose, more 3DG forms with excessive blood sugar levels, as in uncontrolled diabetes. Glucose reacts non-enzymatically with protein amino groups to initiate glycation. The formation of 3DG may account for the numerous complications of diabetes as well as aging.[1]

3DG arises also via the degradation of fructose 3-phosphate (F3P).[3] 3DG plays a central role in the development of diabetic complications via the action of fructosamine-3-kinase.

Biochemistry

As a dicarbonyl sugar, i.e. one with the grouping R-C(O)-C(O)-R, 3DG is highly reactive toward amine groups. Amines are common in amino acids as well as some nucleic acids. The products from the reaction of 3DG with protein amino groups are called advanced glycation end-products (AGEs). AGEs include imidazolones, 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.[1]

3DG has a variety of potential biological effects, particularly when it is present at elevated concentrations in diabetic states:

  • Diabetics with nephropathy were found to have elevated plasma levels of 3DG compared with other diabetics.[4][5][1]
  • Glycated diet, which elevates systemic 3DG levels, leads to diabetes-like tubular and glomerular kidney pathology.[6]
  • Increased 3DG is correlated to increased glomerular basement membrane width.[7]
  • 3DG inactivates aldehyde reductase.[8] 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.[9]
  • 3DG is a teratogenic factor in diabetic embryopathy, leading to embryo malformation.[10] 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[11] and is toxic to cultured cortical neurons[12] and PC12 cells.[13]

3DG and ROS

3DG induces reactive oxygen species (ROS) that contribute to the development of diabetic complications.[14] 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.[15][16] 3DG also inactivates some 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.[17][18] Diabetic humans show increased oxidative stress.[19] 3DG-induced ROS result in oxidative DNA damage.[20] 3DG can be internalized by cells and internalized 3DG is responsible for the production of intracellular oxidative stress.[21]

Detoxification

Although of uncertain medical significance, a variety of compounds react with 3DG, possibly deactivating it. One such agent is aminoguanidine (AG).[22] AG reduces AGE associated retinal, neural, arterial, and renal pathologies in animal models.[23][24][25][26] The problem with AG is that it is toxic in the quantities needed for efficacy.

Additional reading
  • Delpierre G, Rider MH, Collard F, Stroobant V, Vanstapel F, Santos H, Van Schaftingen E (October 2000). "Identification, cloning, and heterologous expression of a mammalian fructosamine-3-kinase". Diabetes. 49 (10): 1627–34. doi:10.2337/diabetes.49.10.1627. PMID 11016445.
  • Baynes JW, Thorpe SR, Murtiashaw MH (1984). "[8] Nonenzymatic glucosylation of lysine residues in albumin". Nonenzymatic glucosylation of lysine residues in albumin. Methods in Enzymology. Vol. 106. pp. 88–98. doi:10.1016/0076-6879(84)06010-9. ISBN 978-0-12-182006-0. PMID 6436646.
  • Dyer DG, Blackledge JA, Thorpe SR, Baynes JW (June 1991). "Formation of pentosidine during nonenzymatic browning of proteins by glucose. Identification of glucose and other carbohydrates as possible precursors of pentosidine in vivo". The Journal of Biological Chemistry. 266 (18): 11654–60. doi:10.1016/S0021-9258(18)99007-1. PMID 1904867.
  • Rahbar S, Kumar Yernini K, Scott S, Gonzales N, Lalezari I (September 1999). "Novel inhibitors of advanced glycation endproducts". Biochemical and Biophysical Research Communications. 262 (3): 651–6. doi:10.1006/bbrc.1999.1275. PMID 10471380.
  • Yan SF, Ramasamy R, Naka Y, Schmidt AM (December 2003). "Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond". Circulation Research. 93 (12): 1159–69. doi:10.1161/01.RES.0000103862.26506.3D. PMID 14670831.*

References
  1. Niwa, Toshimitsu (1999). "3-Deoxyglucosone: Metabolism, analysis, biological activity, and clinical implication". Journal of Chromatography B: Biomedical Sciences and Applications. 731 (1): 23–36. doi:10.1016/S0378-4347(99)00113-9. PMID 10491986.
  2. Bellier, Justine; Nokin, Marie-Julie; Lardé, Eva; Karoyan, Philippe; Peulen, Olivier; Castronovo, Vincent; Bellahcène, Akeila (2019). "Methylglyoxal, a Potent Inducer of AGEs, Connects between Diabetes and Cancer". Diabetes Research and Clinical Practice. 148: 200–211. doi:10.1016/j.diabres.2019.01.002. PMID 30664892. S2CID 58631777.
  3. Szwergold BS, Kappler F, Brown TR (January 1990). "Identification of fructose 3-phosphate in the lens of diabetic rats". Science. 247 (4941): 451–4. Bibcode:1990Sci...247..451S. doi:10.1126/science.2300805. PMID 2300805.
  4. Kusunoki H, Miyata S, Ohara T, Liu BF, Uriuhara A, Kojima H, Suzuki K, Miyazaki H, Yamashita Y, Inaba K, Kasuga M (June 2003). "Relation between serum 3-deoxyglucosone and development of diabetic microangiopathy". Diabetes Care. 26 (6): 1889–94. doi:10.2337/diacare.26.6.1889. PMID 12766129.
  5. Wells-Knecht KJ, Lyons TJ, McCance DR, Thorpe SR, Feather MS, Baynes JW (September 1994). "3-Deoxyfructose concentrations are increased in human plasma and urine in diabetes". Diabetes. 43 (9): 1152–6. doi:10.2337/diabetes.43.9.1152. PMID 8070616.
  6. Kappler F, Schwartz ML, Su B, Tobia AM, Brown T (2001). "DYN 12, a small molecule inhibitor of the enzyme amadorase, lowers plasma 3-deoxyglucosone levels in diabetic rats". Diabetes Technology & Therapeutics. 3 (4): 609–16. doi:10.1089/15209150152811234. PMID 11911173.
  7. Beisswenger PJ, Drummond KS, Nelson RG, Howell SK, Szwergold BS, Mauer M (November 2005). "Susceptibility to diabetic nephropathy is related to dicarbonyl and oxidative stress". Diabetes. 54 (11): 3274–81. doi:10.2337/diabetes.54.11.3274. PMID 16249455.
  8. Takahashi M, Lu YB, Myint T, Fujii J, Wada Y, Taniguchi N (January 1995). "In vivo glycation of aldehyde reductase, a major 3-deoxyglucosone reducing enzyme: identification of glycation sites". Biochemistry. 34 (4): 1433–8. doi:10.1021/bi00004a038. PMID 7827091.
  9. Lal S, Kappler F, Walker M, Orchard TJ, Beisswenger PJ, Szwergold BS, Brown TR (June 1997). "Quantitation of 3-deoxyglucosone levels in human plasma". Archives of Biochemistry and Biophysics. 342 (2): 254–60. doi:10.1006/abbi.1997.0117. PMID 9186486.
  10. Eriksson UJ, Wentzel P, Minhas HS, Thornalley PJ (December 1998). "Teratogenicity of 3-deoxyglucosone and diabetic embryopathy". Diabetes. 47 (12): 1960–6. doi:10.2337/diabetes.47.12.1960. PMID 9836531.
  11. Okado A, Kawasaki Y, Hasuike Y, Takahashi M, Teshima T, Fujii J, Taniguchi N (August 1996). "Induction of apoptotic cell death by methylglyoxal and 3-deoxyglucosone in macrophage-derived cell lines". Biochemical and Biophysical Research Communications. 225 (1): 219–24. doi:10.1006/bbrc.1996.1157. PMID 8769121.
  12. Kikuchi S, Shinpo K, Moriwaka F, Makita Z, Miyata T, Tashiro K (July 1999). "Neurotoxicity of methylglyoxal and 3-deoxyglucosone on cultured cortical neurons: synergism between glycation and oxidative stress, possibly involved in neurodegenerative diseases". Journal of Neuroscience Research. 57 (2): 280–9. doi:10.1002/(SICI)1097-4547(19990715)57:2<280::AID-JNR14>3.0.CO;2-U. PMID 10398306. S2CID 39613521.
  13. Suzuki K, Koh YH, Mizuno H, Hamaoka R, Taniguchi N (February 1998). "Overexpression of aldehyde reductase protects PC12 cells from the cytotoxicity of methylglyoxal or 3-deoxyglucosone". Journal of Biochemistry. 123 (2): 353–7. doi:10.1093/oxfordjournals.jbchem.a021944. PMID 9538214.
  14. Araki A (September 1997). "[Oxidative stress and diabetes mellitus: a possible role of alpha-dicarbonyl compounds in free radical formation]". Nihon Ronen Igakkai Zasshi. Japanese Journal of Geriatrics. 34 (9): 716–20. PMID 9430981.
  15. Taniguchi N, Kaneto H, Asahi M, Takahashi M, Wenyi C, Higashiyama S, Fujii J, Suzuki K, Kayanoki Y (July 1996). "Involvement of glycation and oxidative stress in diabetic macroangiopathy". Diabetes. 45 Suppl 3: S81-3. doi:10.2337/diab.45.3.s81. PMID 8674900. S2CID 21268446.
  16. Che W, Asahi M, Takahashi M, Kaneto H, Okado A, Higashiyama S, Taniguchi N (July 1997). "Selective induction of heparin-binding epidermal growth factor-like growth factor by methylglyoxal and 3-deoxyglucosone in rat aortic smooth muscle cells. The involvement of reactive oxygen species formation and a possible implication for atherogenesis in diabetes". The Journal of Biological Chemistry. 272 (29): 18453–9. doi:10.1074/jbc.272.29.18453. PMID 9218489.
  17. Vander Jagt DL, Hunsaker LA, Vander Jagt TJ, Gomez MS, Gonzales DM, Deck LM, Royer RE (April 1997). "Inactivation of glutathione reductase by 4-hydroxynonenal and other endogenous aldehydes". Biochemical Pharmacology. 53 (8): 1133–40. doi:10.1016/S0006-2952(97)00090-7. PMID 9175718.
  18. Niwa T, Tsukushi S (February 2001). "3-deoxyglucosone and AGEs in uremic complications: inactivation of glutathione peroxidase by 3-deoxyglucosone". Kidney International Supplements. 78: S37-41. doi:10.1046/j.1523-1755.2001.59780037.x. PMID 11168980.
  19. Feillet-Coudray C, Choné F, Michel F, Rock E, Thiéblot P, Rayssiguier Y, Tauveron I, Mazur A (October 2002). "Divergence in plasmatic and urinary isoprostane levels in type 2 diabetes". Clinica Chimica Acta; International Journal of Clinical Chemistry. 324 (1–2): 25–30. doi:10.1016/S0009-8981(02)00213-9. PMID 12204421.
  20. Shimoi K, Okitsu A, Green MH, Lowe JE, Ohta T, Kaji K, Terato H, Ide H, Kinae N (September 2001). "Oxidative DNA damage induced by high glucose and its suppression in human umbilical vein endothelial cells". Mutation Research. 480–481: 371–8. doi:10.1016/S0027-5107(01)00196-8. PMID 11506829.
  21. Sakiyama H, Takahashi M, Yamamoto T, Teshima T, Lee SH, Miyamoto Y, Misonou Y, Taniguchi N (February 2006). "The internalization and metabolism of 3-deoxyglucosone in human umbilical vein endothelial cells". Journal of Biochemistry. 139 (2): 245–53. doi:10.1093/jb/mvj017. PMID 16452312.
  22. Brownlee M (June 1994). "Lilly Lecture 1993. Glycation and diabetic complications". Diabetes. 43 (6): 836–41. doi:10.2337/diab.43.6.836. PMID 8194672. S2CID 84490567.
  23. Ellis EN, Good BH (October 1991). "Prevention of glomerular basement membrane thickening by aminoguanidine in experimental diabetes mellitus". Metabolism. 40 (10): 1016–9. doi:10.1016/0026-0495(91)90122-D. PMID 1943726.
  24. Soulis-Liparota T, Cooper M, Papazoglou D, Clarke B, Jerums G (October 1991). "Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat". Diabetes. 40 (10): 1328–34. doi:10.2337/diabetes.40.10.1328. PMID 1834497.
  25. Edelstein D, Brownlee M (January 1992). "Aminoguanidine ameliorates albuminuria in diabetic hypertensive rats". Diabetologia. 35 (1): 96–7. doi:10.1007/BF00400859. PMID 1541387.
  26. Brownlee M, Vlassara H, Kooney A, Ulrich P, Cerami A (June 1986). "Aminoguanidine prevents diabetes-induced arterial wall protein cross-linking". Science. 232 (4758): 1629–32. Bibcode:1986Sci...232.1629B. doi:10.1126/science.3487117. PMID 3487117.
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