A Novel 4-Oxo-2(E)-nonenal-Derived Modification to Angiotensin II: Oxidative Decarboxylation of N-Terminal Aspartic Acid
A Novel 4-Oxo-2(E)-nonenal-Derived Modification to Angiotensin II: Oxidative Decarboxylation of N-Terminal Aspartic Acid
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DOI：
10.1021/tx800316v
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发表时间：
2008-12-01
影响因子：
4.1
通讯作者：
Oe, Tomoyuki
中科院分区：
文献类型：
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作者：
Lee, Seon Hwa;Goto, Takaaki;Oe, Tomoyuki
4-Oxo-2(E)-nonenal (4-ONE) 是一种源自脂质氢过氧化物的主要双功能亲电子试剂。过去对 4-ONE 衍生的细胞大分子修饰的大量研究得出这样的结论：4-ONE 比 4-羟基-2(E)-壬烯醛 (4-HNE) 对 DNA 和蛋白质更具反应性。本研究发现，4-ONE 不仅介导加合物形成，还介导血管紧张素 (Ang) II 和 des-Ile(5)、His(6)、Pro(7) 和 Phe(8)-Ang II [Ang II (1-4)] 上 N 端天冬氨酸的氧化脱羧。该反应不是由其他脂质过氧化衍生的醛（例如 4-HNE 和反式-4,5-环氧-2(E)-癸烯醛 (4,5-EDE)）介导的。 4-ONE 与 Ang II 或 Ang II (1-4) 的 N 端 α-氨基基团的初始反应导致形成席夫碱中间体。所得中间体经历互变异构和脱羧，然后水解，在 Ang II 和 Ang II (1-4) 的 N 末端提供 α-酮酰胺（丙酮酰胺）部分。通过基质辅助激光解吸电离飞行时间/质谱 (MALDI-TOF/MS) 和源后衰变 (PSD)-TOF/MS 分析并与其真实标准品进行比较，确认了 4-ONE 衍生的丙酮酰胺-Ang II 和 -Ang II (1-4) 的结构。通过用硼氢化钠还原，导致添加两个氢原子，证实了 N 末端存在酮基。然后将 4-ONE 对 Ang II 上 N 端天冬氨酸的反应性与 5'-磷酸吡哆醛 (PLP) 的反应性进行比较，PLP 是一种众所周知的醛，可有效地将 N 端天冬氨酸残基转化为丙酮酸残基。结果表明，4-ONE 衍生的丙酮酰胺-Ang II 快速形成，并且 4-ONE 在其生理浓度下具有更高的反应性。这表明含有 N 末端天冬氨酸的肽或蛋白质可以很容易地与脂质氢过氧化物衍生的 4-ONE 反应形成丙酮酰胺，从而调节其生物功能。
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-Ile(5), His(6), Pro(7), and Phe(8)-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 alpha-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 alpha-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.