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We investigated the reaction between glutathionylcobalamin (GSCbl), a tight complex of cobalamin with glutathione (GSH), and nitroxyl (HNO) produced upon decomposition of Angeli's salt using ultraviolet-visible spectroscopy and 1H NMR. The reaction in neutral and alkaline media leads to formation of nitrosylcobalamin (NOCbl). Simulation of the kinetic traces using the ChemMech program package suggested that the mechanism of the process involves complexation between HNO and GSCbl and further decomposition of the complex into the products. The complex participates in an acid-base equilibrium (pKa = 8.9), and the deprotonated form decomposes to NOCbl more rapidly than the protonated species. At pH 7.4, the reaction of HNO with GSCbl proceeds ca.103-times more slowly than with free GSH. GSCbl can react directly with the monoprotonated anion of Angeli's salt (HN2O3−) to produce nitrocobalamin (NO2Cbl). The reaction between GSCbl and HN2O3− is insignificant in an alkaline medium and is accelerated upon acidification of the medium. The critical step of the process is the complexation between GSCbl and HN2O3−. The produced complex is involved in an acid-base equilibrium (pKa = 8.1): the protonated form can be transformed to NO2Cbl and GSNHO−, whereas the deprotonated species decompose to initial reactants. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Besides its use in medicine, vitamin B12 (cobalamin) and its derivatives have found in numerous applications as catalysts. However, studies related to the activation of oxidants via cobalamin are scant. In this work, we showed how the addition of aquacobalamin (H2OCbl) accelerates the destruction of azo-dye Orange II by peroxymonosulfate (HSO5−) in aqueous solutions. In neutral and weakly alkaline media, the process is initiated by the modification of the corrin macrocycle with HSO5−, which requires the preliminary deprotonation of the aqua-ligand in H2OCbl to give hydroxocobalamin, producing 5,6-dioxo-5,6-secocobalamin or its isomer (14,15-dioxo-14,15-secocobalamin). In acidic solutions, where the concentration of hydroxocobalamin is negligible, the formation of dioxo-seco-species is not observed, and the reaction between H2OCbl and HSO5− results in slow chromophore bleaching. Using terephthalic acid, we demonstrated the formation of hydroxyl radicals in the mixture of H2OCbl with HSO5−, whereas the generation of sulfate radicals was proved by comparing the effects of ethanol and nitrobenzene on Orange II destruction using the H2OCbl/HSO5− system. The reaction mechanism includes the binding of HSO5− to the Co(III) ion of dioxo-secocobalamin, which results in its deprotonation and the labilization of the O-O bond, leading to the formation of sulfate and hydroxyl radicals which further react with Orange II. [ABSTRACT FROM AUTHOR]

[Display omitted] • Efficient synthesis methods for meso-brominated aquacyanocobinamide and aquahydroxocobinamide. • meso-Bromination alters the aerobic stability of NOCbi in the presence of ligands. • Slower NO release from the meso-brominated NOCbi suggests milder hypotensive effects. • meso-Modification represents a valuable tool for modifying the properties of corrinoids as NO donors. This study explores the modification of nitrosylcobinamide, explicitly focusing on meso-bromination, and its impact on the dissociation rate of nitric oxide (NO). meso-Brominated aquahydroxocobinamide was efficiently synthesized from meso-brominated cyanocobalamin via hydrolysis, followed by decyanation step. Its reaction with Angeli's salt produces meso-brominated nitrosylcobinamide (NOCbi-Br). NOCbi-Br exhibits stability in the presence of dioxygen comparable to that of the unmodified NOCbi in neutral aqueous solutions. However, in the presence of L-histidine the oxidation of NOCbi-Br by dioxygen is significantly slower than unmodified NOCbi, indicating potential differences in ligand affinities. Furthermore, the rate constant for NO release from NOCbi-Br was lower than that of unmodified NOCbi, suggesting that meso-bromination strengthens the Co(II)–NO bond. These findings underscore the utility of meso-modification in tailoring the properties of corrinoids as nitric oxide donors, with potential implications for therapeutic applications. [ABSTRACT FROM AUTHOR]

Here, we report results of spectrophotometric, spectrofluorimetric, and ultrafiltration studies on the reaction between cobinamides (viz. aquahydroxo-, nitro-, aquacyano- and dicyanocobinamides; Cbi) and bovine serum albumin (BSA), and reactivity of formed complexes toward cyanide. (H2O)(HO−)Cbi binds BSA at almost equimolar ratio predominantly via amino group of lysine side chains. The mechanism of the reaction involves two steps, i.e. the coordination of amino group on Co(III), and further stabilization of the generated complex. The reaction of (H2O)(NO2−)Cbi with BSA is similar with that involving (H2O)(HO−)Cbi, and both complexes bind cyanide significantly slower than free (H2O)(HO−)Cbi and (H2O)(NO2−)Cbi. (H2O)(CN−)Cbi binds BSA predominantly via aminogroup as well, however, its coordination proceeds substantially faster and less tightly than in the case of (H2O)(HO−)Cbi. Binding of (H2O)(CN−)Cbi and (H2O)(HO−)Cbi occurs at different sites of BSA as was indicated by spectrofluorimetric titration. Reaction of the complex between (H2O)(CN−)Cbi and BSA with cyanide proceeds much faster than in the case of the complex between (H2O)(HO−)Cbi and BSA. (CN−)2Cbi is partially decyanated by BSA, however, its binding by BSA is relatively low. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]