Iron mediates catalysis of nucleic acid processing enzymes: support for Fe(II) as a cofactor before the great oxidation event

Life originated in an anoxic, Fe(2+)-rich environment. We hypothesize that on early Earth, Fe(2+) was a ubiquitous cofactor for nucleic acids, with roles in RNA folding and catalysis as well as in processing of nucleic acids by protein enzymes. In this model, Mg(2+) replaced Fe(2+) as the primary cofactor for nucleic acids in parallel with known metal substitutions of metalloproteins, driven by the Great Oxidation Event. To test predictions of this model, we assay the ability of nucleic acid processing enzymes, including a DNA polymerase, an RNA polymerase and a DNA ligase, to use Fe(2+) in place of Mg(2+) as a cofactor during catalysis. Results show that Fe(2+) can indeed substitute for Mg(2+) in catalytic function of these enzymes. Additionally, we use calculations to unravel differences in energetics, structures and reactivities of relevant Mg(2+) and Fe(2+) complexes. Computation explains why Fe(2+) can be a more potent cofactor than Mg(2+) in a variety of folding and catalytic functions. We propose that the rise of O(2) on Earth drove a Fe(2+) to Mg(2+) substitution in proteins and nucleic acids, a hypothesis consistent with a general model in which some modern biochemical systems retain latent abilities to revert to primordial Fe(2+)-based states when exposed to pre-GOE conditions.