An Unusual Co(I)--H Interaction: Structural and Mechanistic Ramifications for Methyltransferases

The cob(II)alamin cob(I)alamin (Co$^{2+}$/Co$^{1+})$ reduction is a common chemical event in a broad family of cytoplasmic methyltransferases and ATP:corrinoid adenosyltransferases, respectively. Despite its broad and general chemical appeal, the Co$^{2+}$/Co$^{1+}$ reduction continues to remain one of the least understood aspects of corrinoid chemistry. This is due in part to the inaccessible redox chemistry of Co$^{2+}$/Co$^{1+}$ couple under cellular conditions i.e., the reduction potential of cob(II)alamin (-500 mV vs SHE) is more negative than that of the common physiological reductants (-280 mV to -440 mV vs SHE) present in the cellular environments. To gain better understanding about the Co$^{2+}$/Co$^{1+}$ reduction, we have utilized the density functional theory and quantum mechanics/molecular mechanics (QM/MM) computational methods. The calculations indicate that cob(I)alamin, a ubiquitous B$_{12}$ intermediate, is not square planar as has been commonly accepted, but a square pyramidal species due to the unusual hydrogen bonding interaction between the Co$^{1+}$ ion and its axial ligands (\textit{Angew. Chem. Int. Ed.} \textbf{2011}, \textit{50}, 8702-8705; \textit{Inorg. Chem. }\textbf{2012}, \textit{51}, 5533-5538). The Co$^{1+}$--H interaction exerts an anodic shift of 100 mV vs SHE upon the reduction potential of the Co$^{2+}$/Co$^{1+}$ couple, which explains why this redox process is observed inside transferases. Building upon these new insights, an alternate mechanism for the enzyme-bound Co$^{2+}$/Co$^{1+}$ redox process is suggested that is mediated by the square pyramidal cob(I)alamin rather than its commonly accepted square planar analogue.