A novel 4-oxo-2(E)-nonenal-derived modification to angiotensin II: Oxidative decarboxylation of N-terminal aspartic acid

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4-Oxo-2(E)-nonenal (4-ONE) is a major bifunctional electrophile derived from lipid hydroperoxides. A substantial amount of past research on 4-ONE-derived modifications to cellular macromolecules has led to the conclusion that 4-ONE is more reactive toward DNA and protein than 4-hydroxy-2(E)-nonenal (4-HNE). In this study, a novel discovery was made that 4-ONE mediates not only adduct formation but also oxidative decarboxylation of N-terminal aspartic acid on angiotensin (Ang) II and des-Ile5, His6, Pro 7, and Phe8-Ang II [Ang II (1-4)]. This reaction was not mediated by other lipid peroxidation-derived aldehydes such as 4-HNE and trans-4,5-epoxy-2(E)-decenal (4,5-EDE). The initial reaction of 4-ONE with an N-terminal R-amino group of Ang II or Ang II (1-4) resulted in the formation of a Schiff base intermediate. The resulting intermediate underwent tautomerization and decarboxylation followed by hydrolysis to provide an α-keto amide (pyruvamide) moiety at the N terminus of Ang II and Ang II (1-4). The structures of 4-ONE-derived pyruvamide-Ang II and -Ang II (1-4) were confirmed by matrix-assisted laser desorption ionization-time-of-flight/mass spectrometry (MALDI-TOF/MS) and postsource decay (PSD)-TOF/MS analyses and by comparisons to their authentic standards. The presence of a ketone group on the N terminus was confirmed by reduction with sodium borohydride, which resulted in the addition of two hydrogen atoms. Reactivity of 4-ONE toward N-terminal aspartic acid on Ang II was then compared with that of pyridoxal 5′-phosphate (PLP), a well-known aldehyde that efficiently converts N-terminal aspartic acid residue to pyruvate residue. The results indicated a rapid formation of 4-ONE-derived pyruvamide-Ang II and a higher reactivity of 4-ONE at its physiological concentration. This suggests that peptides or proteins containing N-terminal aspartic acid can readily react with lipid hydroperoxide-derived 4-ONE to form pyruvamides, which could modulate their biological functions.

Original languageEnglish
Pages (from-to)2237-2244
Number of pages8
JournalChemical Research in Toxicology
Issue number12
Publication statusPublished - 2008 Dec 15

ASJC Scopus subject areas

  • Toxicology


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