Abstract
Hypochlorous acid (HOCl) is a potent oxidant generated by myeloperoxidase (MPO), which is an abundant enzyme used for defense against microbes. We examined the potential role of HOCl in corrin ring destruction and subsequent formation of cyanogen chloride (CNCl) from dicyanocobinamide ((CN)2-Cbi). Stopped-flow analysis revealed that the reaction consists of at least three observable steps, including at least two sequential transient intermediates prior to corrin ring destruction. The first two steps were attributed to sequential replacement of the two cyanide ligands with hypochlorite, while the third step was the destruction of the corrin ring. The formation of (OCl)(CN)-Cbi and its conversion to (OCl)2-Cbi was fitted to a first order rate equation with second order rate constants of 0.002 and 0.0002 µM−1s−1, respectively. The significantly lower rate of the second step compared to the first suggests that the replacement of the first cyanide molecule by hypochlorite causes an alteration in the ligand trans effects changing the affinity and/or accessibility of Co toward hypochlorite. Plots of the apparent rate constants as a function of HOCl concentration for all the three steps were linear with Y-intercepts close to zero, indicating that HOCl binds in an irreversible one-step mechanism. Collectively, these results illustrate functional differences in the corrin ring environments toward binding of diatomic ligands.
Highlights
Cyanogen chloride (CNCl, CAS 506-77-4) is a disinfectant byproduct found in drinking water treated with free chlorine and chloramines at concentrations ranging from 0.45–0.8 mg/L [1,2]
We showed that hypochlorous acid (HOCl) mediates (CN)2-Cbi corrin ring destruction and subsequent liberation of toxic cyanogen chloride (CNCl)
Corrin ring destruction occurs through a mechanism that initially involved the sequential replacement of the Cbi and (CN)- groups by OClmolecules
Summary
Cyanogen chloride (CNCl, CAS 506-77-4) is a disinfectant byproduct found in drinking water treated with free chlorine and chloramines at concentrations ranging from 0.45–0.8 mg/L [1,2]. Prolonged exposure can cause permanent brain damage, muscle paralysis, coma, and death [4]. The ability of these molecules to react with sulfhydryl compounds such as protein thiols and reduced glutathione (GSH) causes the toxicity elicited in biological systems [6]. They are known to block the electron transport chain by inhibiting mitochondrial cytochrome C oxidase, initiating a fatal series of events by decreased oxidative metabolism and oxygen utilization [7]. We have shown that significant amounts of CNCl/ CN- are liberated by mixing cyanocobalamin (Cbl), the most common supplemental form of vitamin B12, with HOCl through a mechanism that involves disruption of axial coordination of the Co atom and cleavage of the corrin ring [8]
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