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Glycoxidative damage to human DNA: Neo-antigenic epitopes on DNA molecule could be a possible reason for autoimmune response in type 1 diabetes.

Authors
  • Ahmad, Saheem
  • Shahab, Uzma
  • Habib, Safia
  • Salman Khan, M
  • Alam, Khursheed
  • Ali, Asif
Type
Published Article
Journal
Glycobiology
Publisher
Oxford University Press
Publication Date
Mar 01, 2014
Volume
24
Issue
3
Pages
281–291
Identifiers
DOI: 10.1093/glycob/cwt109
PMID: 24347633
Source
Medline
Keywords
License
Unknown

Abstract

Advanced glycation end-products (AGEs) are known to be mutagenic, diabetogenic and vascular disease risk factors. Methylglyoxal (MG) is a dicarbonyl species that reacts with biological macromolecule (proteins, DNA and lipids) to give AGEs. Nonenzymatic glycation of MG with lysine (Lys) in the presence of copper (Cu(2+)) is reported to generate reactive oxygen species (ROS) capable of causing DNA damage. We show that DNA modification in MG-Lys-Cu(2+) system results in the generation of strand breaks, base modification, hyperchromicity and increased fluorescence intensity. Superoxide generation in the MG-Lys system was found to be significantly higher when compared with that in the MG and Lys alone. Moreover, d-penicillamine and pyridoxal phosphate significantly inhibited the formation of glycation products. The presence of a major DNA glycation adduct, N(2)-carboxyethyl-2'-deoxyguanosine (CEdG), was detected by high performance liquid chromatography (HPLC) and confirmed by nuclear magnetic resonance (NMR). As reported earlier, modified DNA (MG-Lys-Cu(2+)-DNA) was highly immunogenic in experimental animals. Furthermore, induced anti-MG-Lys-Cu(2+)-DNA antibodies were effective probe for detecting glycoxidative lesions in human genomic DNA of type I diabetes patients. Our results clearly imply that interaction of MG-Lys and Cu(2+) leads to the formation of AGEs and also the production of potent ROS, capable of causing DNA damage, thereby playing an important role in diabetes mellitus.

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