Oxidative deamination of lysine residues by polyphenols generates an equilibrium of aldehyde and 2-piperidinol products

Kosuke Yamaguchi,Masanori Itakura,Roma Kitazawa,Sei-Young Lim,Koji Nagata,Takahiro Shibata,Mitsugu Akagawa,Koji Uchida

doi:10.1016/j.jbc.2021.101035

Kosuke Yamaguchi, Masanori Itakura + Show 6 more

Open Access

https://doi.org/10.1016/j.jbc.2021.101035

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Abstract

Polyphenols, especially catechol-type polyphenols, exhibit lysyl oxidase–like activity and mediate oxidative deamination of lysine residues in proteins. Previous studies have shown that polyphenol-mediated oxidative deamination of lysine residues can be associated with altered electrical properties of proteins and increased crossreactivity with natural immunoglobulin M antibodies. This interaction suggested that oxidized proteins could act as innate antigens and elicit an innate immune response. However, the structural basis for oxidatively deaminated lysine residues remains unclear. In the present study, to establish the chemistry of lysine oxidation, we characterized oxidation products obtained via incubation of the lysine analog N-biotinyl-5-aminopentylamine with eggshell membranes containing lysyl oxidase and identified a unique six-membered ring 2-piperidinol derivative equilibrated with a ring-open product (aldehyde) as the major product. By monitoring these aldehyde–2-piperidinol products, we evaluated the lysyl oxidase–like activity of polyphenols. We also observed that this reaction was mediated by some polyphenols, especially o-diphenolic-type polyphenols, in the presence of copper ions. Interestingly, the natural immunoglobulin M monoclonal antibody recognized these aldehyde–2-piperidinol products as an innate epitope. These findings establish the existence of a dynamic equilibrium of oxidized lysine and provide important insights into the chemopreventive function of dietary polyphenols for chronic diseases.

Highlights

Oxidative modification of proteins is associated with agerelated pathologies, such as atherosclerosis, neurodegenerative disorders, and cataracts [1, 2]
To gain structural insights into the polyphenol-mediated oxidation of lysine residues, the lysine analog (Bt-APA) (Fig. 2A) was incubated with hen’s eggshell membrane (ESM) containing lysyl oxidase in 0.1 M sodium phosphate buffer for 48 h, and the reaction mixtures were analyzed by LC–MS
To demonstrate that the 2-piperidinol structure is generally formed by oxidative modification of lysine residues, a lysinecontaining dipeptide, Nα-benzoylglycyl-lysine, was incubated with ESM in 0.1 M sodium phosphate buffer for 48 h, and the products were analyzed by LC–MS

Summary

Introduction

Oxidative modification of proteins is associated with agerelated pathologies, such as atherosclerosis, neurodegenerative disorders, and cataracts [1, 2]. To gain structural insights into the polyphenol-mediated oxidation of lysine residues, the lysine analog (Bt-APA) (Fig. 2A) was incubated with hen’s ESM containing lysyl oxidase in 0.1 M sodium phosphate buffer for 48 h, and the reaction mixtures were analyzed by LC–MS.

Results

Conclusion