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- Seon Hwa Lee
- Department of Bio-analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan
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- Hyunsook Kyung
- Department of Bio-analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan
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- Ryo Yokota
- Department of Bio-analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan
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- Takaaki Goto
- Department of Bio-analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan
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- Tomoyuki Oe
- Department of Bio-analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai 980-8578, Japan
書誌事項
- 公開日
- 2014-02-25
- 資源種別
- journal article
- DOI
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- 10.1021/tx400469x
- 公開者
- American Chemical Society (ACS)
この論文をさがす
説明
We have previously reported that N-terminal α-ketoamide peptides can be formed through 4-oxo-2(E)-nonenal (ONE)-derived oxidative decarboxylation of aspartic acid (Asp), which converts angiotensin (Ang) II (DRVYIHPF) to pyruvamide-Ang II (Ang P, CH3COCONH-RVYIHPF). The pyruvamide group significantly inhibits Ang P binding to the Ang II type 1 receptor, which mediates the major biological effects of Ang II. In the present study, we found that ONE can also introduce an α-ketoamide moiety at the N-terminus of peptides containing N-terminal residues other than Asp. Subsequent investigation of alternative biosynthetic pathways for N-terminal α-ketoamide peptides revealed that hydroxyl radical-mediated formation is a much more efficient route. The proposed mechanism involves initial abstraction of the N-terminal α-hydrogen and hydrolysis of the ketimine intermediate. The resulting N-terminal α-ketoamide is then converted to the D- and L-amino acids by nonenzymatic transamination in the presence of pyridoxamine (PM). The formation of the epimeric N-terminus depended on the incubation time and the concentration of PM, and increased further upon the addition of Cu(II) ions. A conversion of approximately 60% after three days of incubation was observed for Ang P. We propose that the reaction intermediate contains a prochiral α-carbon and is stabilized by the chelate effect of Cu(II) ions. The ONE- and hydroxyl radical-derived formation of N-terminal α-ketoamide and its transamination in the presence of PM were also observed in amyloid β 1-11 (DAEFRHDSGYE), where the N-terminal Asp was converted to epimeric alanine. This suggests that these N-terminal modifications could occur in vivo and modulate the biological functions of peptides and proteins.
収録刊行物
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- Chemical Research in Toxicology
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Chemical Research in Toxicology 27 (4), 637-648, 2014-02-25
American Chemical Society (ACS)
