| Autor: |
Shuck SC; Department of Molecular Medicine, City of Hope and Beckman Research Institute , Duarte, California 91010, United States., Wuenschell GE; Department of Molecular Medicine, City of Hope and Beckman Research Institute , Duarte, California 91010, United States., Termini JS; Department of Molecular Medicine, City of Hope and Beckman Research Institute , Duarte, California 91010, United States. |
| Jazyk: |
angličtina |
| Zdroj: |
Chemical research in toxicology [Chem Res Toxicol] 2018 Feb 19; Vol. 31 (2), pp. 105-115. Date of Electronic Publication: 2018 Jan 31. |
| DOI: |
10.1021/acs.chemrestox.7b00274 |
| Abstrakt: |
Methylglyoxal (MG) is a highly reactive electrophile produced endogenously as a byproduct of glucose metabolism and protein catabolism and exogenously as a food contaminant. MG reacts spontaneously with proteins, lipids, and nucleic acids to form advanced glycation end products (AGEs), modifying or inhibiting their function. Protein AGEs are associated with pathological complications of diabetes, cancer, and neurodegenerative diseases, while the physiological impact of DNA, RNA, and lipid AGE formation is less well explored. Conflicting reports in the literature on the biologically significant DNA-AGE product distribution and mechanisms of formation prompted a re-examination of the reaction products of MG with dG, oligonucleotides, and plasmid DNA under varying conditions of MG:dG stoichiometry, pH, and reaction time. Major products identified using sequential mass fragmentation and authentic standards were N 2 -(1-carboxyethyl)-2'-dG (CEdG), N 2 -(1-carboxyethyl)-7-1-hydroxy-2-oxopropyl-dG (MG-CEdG), and 1,N 2 -(1,2-dihydroxy-2-methyl)ethano-2'-dG (cMG-dG). CEdG and MG-CEdG were observed in all DNA substrates, although cMG-dG was not detected to any significant extent in oligomeric or polymeric DNA. Product analyses of reactions under conditions of diminished water activity as well as results from H 2 18 O labeling indicated that MG hydration equilibria plays an important role in controlling product distribution. In contrast to previous reports, our data support independent mechanisms of formation of CEdG and cMG-dG, with the latter kinetic product undergoing reversible formation under physiological conditions. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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