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meso-Bromination of cyano- and aquacobalamins facilitates their processing into Co(II)-species by glutathione

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Abstract

Cyanocobalamin (CNCbl), a medicinal form of vitamin B12, is resistant to glutathione (GSH), and undergoes intracellular processing via reductive decyanation producing the Co(II)-form of Cbl (Cbl(II)) mediated by the CblC-protein. Alteration of the CblC-protein structure might inhibit CNCbl processing. Here, we showed that introducing a bromine atom to the C10-position of the CNCbl corrin ring facilitates its reaction with GSH leading to the formation of Cbl(II) and cyanide dissociation. In a neutral medium, the reaction between C10-Br-CNCbl and GSH proceeds via the complexation of the reactants further leading to dimethylbenzimidazole (DMBI) substitution and electron transfer from GSH to the Co(III)-ion. The reaction is accelerated upon the GSH thiol group deprotonation. The key factors explaining the higher reactivity of C10-Br-CNCbl compared with unmodified CNCbl towards GSH are increasing the electrode potential of CNCbl two-electron reduction upon meso-bromination and the substantial labilization of DMBI, which was shown by comparing their reactions with cyanide and the pKa values of DMBI protonation (pKa base-off). Aquacobalamin (H2OCbl) brominated at the C10-position of the corrin reacts with GSH to give Cbl(II) via GSH complexation and subsequent reaction of this complex with a second GSH molecule, whereas unmodified H2OCbl generates glutathionyl-Cbl, which is resistant to further reduction by GSH.

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Abbreviations

C10-Br-CNCbl:

CNCbl brominated at C10-position of corrin ring

C10-Br-H2OCbl:

H2OCbl brominated at C10-position of corrin ring

Cbi:

Cobinamide

Cbl:

Cobalamin

CNCbl:

Cyanocobalamin

DMBI:

5,6-Dimethylbenzimidazole

GSCbl:

Glutathionylcobalamin

GSH:

Glutathione

H2OCbl:

Aquacobalamin

C10-Br-SO3Cbl:

Sulfitocobalamin brominated at C10-position of corrin ring

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Acknowledgements

This research was funded by the Russian Science Foundation (Project no. 19-73-00147) to IAD. MALDI-mass-spectrometry experiments were carried out using the resources of the Center for Shared Use of Scientific Equipment of the ISUCT (with the support of the Ministry of Science and Higher Education of Russia, Grant No. 075-15-2021-671).

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Authors and Affiliations

  1. Department of Food Chemistry, Ivanovo State University of Chemistry and Technology, Sheremetevskiy Str. 7, 153000, Ivanovo, Russia

    Ilia A. Dereven’kov, Vladimir S. Osokin, Nikita A. Ershov & Sergei V. Makarov

  2. G.A. Krestov Institute of Solution Chemistry, Russian Academy of Sciences, 153045, Ivanovo, Russia

    Ilya A. Khodov & Valentina V. Sobornova

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  1. Ilia A. Dereven’kov
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  2. Vladimir S. Osokin
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  6. Sergei V. Makarov
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IAD was responsible for investigation, funding acquisition, and writing—original draft preparation. VSO, IAK, VVS, and NAE were responsible for investigation. SVM was responsible for supervision, and writing—review & editing.

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Correspondence to Ilia A. Dereven’kov.

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Dereven’kov, I.A., Osokin, V.S., Khodov, I.A. et al. meso-Bromination of cyano- and aquacobalamins facilitates their processing into Co(II)-species by glutathione. J Biol Inorg Chem 28, 571–581 (2023). https://doi.org/10.1007/s00775-023-02009-x

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