Importance of iron as the metal ion in peptide deformylase: a biomimetic computational study

Peptide deformylase (PDF), a metalloamidase which catalyzes a deformylation step during eubacterial protein biosynthesis, shows a peculiar preference for Fe as its active site metal ion (in particular, as opposed to Zn, which is far more common among this class of enzymes). In order to explore the origin of this preference, density functional theory (DFT) calculations have been carried out using a biomimetic heteroscorpionate N2Sthiolate ligand system (L) and the metal centers Fe, Zn, and Co. Comparison of computed ML(formate) complexes to crystal structures of PDF–formate complexes illustrates the viability of the biomimetic ligand for investigating the PDF chemistry. pKa calculations on [ML(H2O)] ? complexes show that the metal centers are effective Lewis acids in activating the water molecule to allow formation of a nucleophilic hydroxide ligand. Computed oxidation potentials predict the ML(OH) and ML(formate) complexes not to be unstable with respect to oxidation. However, while each of the metal centers was therefore seen to be suitable for PDF chemistry, examination of the entire deformylation reaction showed Fe to be uniquely suited to PDF. The deformylation reaction was thermodynamically and kinetically optimal with Fe as the metal center. This is attributed to the charge transfer that occurs from the thiolate ligand to the Fe center during the reaction and to the relative coordinative flexibility of Fe that allows for facile interconversion between tetraand pentacoordination, leading to greater activation of the substrate carbonyl at the nucleophilic attack transition state.