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 pK_a values of DMBI protonation (pK_{a 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.

Graphical abstract

中文翻译：

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氰基和水钴胺素的内消旋溴化促进其通过谷胱甘肽加工成 Co(II) 物质

_{氰钴胺 (CNCbl) 是维生素 B 12}的一种药用形式，对谷胱甘肽 (GSH) 具有抗性，并通过还原脱氰化进行细胞内加工，产生由 CblC 蛋白介导的 Co(II) 形式的 Cbl (Cbl(II)) 。CblC 蛋白质结构的改变可能会抑制 CNCbl 加工。在这里，我们表明，在 CNCbl 咕啉环的 C10 位引入溴原子有利于其与 GSH 的反应，导致 Cbl(II) 的形成和氰化物解离。在中性介质中，C10-Br-CNCbl 和 GSH 之间的反应通过反应物的络合进行，进一步导致二甲基苯并咪唑 (DMBI) 取代以及电子从 GSH 转移到 Co(III)-离子。GSH 硫醇基去质子化后反应加速。与未修饰的 CNCbl 相比，解释 C10-Br-CNCbl 对 GSH 具有更高反应性的关键因素是介观溴化时 CNCbl 双电子还原的电极电位增加以及 DMBI 的显着不稳定化（通过比较它们与氰化物的反应表明）和 DMBI 质子化的 p K _a值（p K _{a base-off}）。在 Corrin 的 C10 位上溴化的水钴胺素 (H 2 OCbl) 通过 GSH 络合和随后该复合物与第二个 GSH 分子的反应与 GSH 反应生成 Cbl(II)，而未修饰的 H 2 OCbl 则生成谷胱甘肽_{-Cbl ，}其抵抗 GSH 的进一步还原。

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