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Mechanism of cyanocobalamin chlorination by hypochlorous acid

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Abstract

Hypochlorous acid (HOCl) is a strong oxidant produced by myeloperoxidase. Previous work suggested that HOCl modifies the corrin ring of cobalamins to yield chlorinated species via mechanisms that are incompletely understood. Herein, we report a mechanistic study on the reaction between cyanocobalamin (CNCbl, vitamin B12) and HOCl. Under weakly acidic, neutral and weakly alkaline conditions, the reaction produces the c-lactone derivative of CNCbl chlorinated at the C10-position of corrin ring (C10–Cl–CNCbl-c-lactone). Formation of C10–Cl–CNCbl-c-lactone was not observed at pH ≥ 9.9. The chlorination of CNCbl by HOCl proceeds via two pathways involving one and two HOCl molecules: the reaction is initiated by the very fast formation of a complex between CNCbl and HOCl, which either undergoes slow transformation to chlorinated species, or rapidly reacts with a second HOCl molecule to produce C10–Cl–CNCbl. Subsequent reaction of C10–Cl–CNCbl with HOCl proceeds rapidly toward lactone ring formation by H-atom abstraction at position C8. This work uncovered mechanisms and products of the reaction of a biologically active and therapeutically used cobalamin, CNCbl and the endogenous oxidant HOCl. Binding and reactivity studies of C10–Cl–CNCbl and C10–Cl–CNCbl-c-lactone with relevant proteins of the cobalamin pathway and with cultured cells are necessary to elucidate the potential physiological effects of these species.

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Scheme 1.

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Abbreviations

C10–Cl–CNCbl:

CNCbl chlorinated at C10-position of corrin ring

C10–Cl–CNCbl-c-lactone:

C-lactone derivative of C10–Cl–CNCbl

Cbl:

Cobalamin

CNCbl:

Cyanocobalamin

GSCbl:

Glutathionylcobalamin

H2OCbl:

Aquacobalamin

HSQC:

Heteronuclear single quantum coherence

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Acknowledgements

This work was supported by the Russian Science Foundation (Project no. 19-73-00147) to IAD. The authors thank researcher D.V. Tyurin of the Shared Scientific Resource Center, Ivanovo State University of Chemistry and Technology, Ivanovo, Russia, for his help in analyzing the products of the reaction between cyanocobalamin and hypochlorous acid using MALDI-mass-spectrometry. The NMR spectroscopy experiment was performed using the molecular fluid spectroscopy facility (http://www.ckp-rf.ru/usu/503933/) of G.A. Krestov Institute of Solution Chemistry of the Russian Academy of Sciences (ISC RAS) (Russia).

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Authors and Affiliations

  1. Ivanovo State University of Chemistry and Technology, Sheremetevskiy Str. 7, 153000, Ivanovo, Russian Federation

    Ilia A. Dereven’kov, Vladimir S. Osokin, Sergei V. Makarov & Oskar I. Koifman

  2. Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center-University of Freiburg, 79106, Freiburg, Germany

    Luciana Hannibal

  3. G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, Akademicheskaya Str. 1, 153045, Ivanovo, Russian Federation

    Ilya A. Khodov

Authors
  1. Ilia A. Dereven’kov
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  2. Vladimir S. Osokin
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  3. Luciana Hannibal
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  4. Sergei V. Makarov
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  5. Ilya A. Khodov
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  6. Oskar I. Koifman
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Correspondence to Ilia A. Dereven’kov.

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Raw data on mass-spectrometry and 2D-NMR results presented in our study are available to colleagues upon reasonable request. All requests should be directed to the corresponding author. The authors declare no conflict of interest.

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Dereven’kov, I.A., Osokin, V.S., Hannibal, L. et al. Mechanism of cyanocobalamin chlorination by hypochlorous acid. J Biol Inorg Chem 26, 427–434 (2021). https://doi.org/10.1007/s00775-021-01869-5

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