Protection of Catalytic Cofactors by Polypeptides as a Driver for the Emergence of Primordial Enzymes Gutiérrez Rus, Luis Ignacio Gámiz Arco, María Gloria Gavira Gallardo, José Antonio Risso, Valeria Alejandra Sánchez Ruiz, José Manuel Enzymes catalyze the chemical reactions of life. For nearly half of known enzymes, catalysis requires the binding of small molecules known as cofactors. Polypeptide-cofactor complexes likely formed at a primordial stage and became starting points for the evolution of many efficient enzymes. Yet, evolution has no foresight so the driver for the primordial complex formation is unknown. Here, we use a resurrected ancestral TIM-barrel protein to identify one potential driver. Heme binding at a flexible region of the ancestral structure yields a peroxidation catalyst with enhanced efficiency when compared to free heme. This enhancement, however, does not arise from proteinmediated promotion of catalysis. Rather, it reflects the protection of bound heme from common degradation processes and a resulting longer lifetime and higher effective concentration for the catalyst. Protection of catalytic cofactors by polypeptides emerges as a general mechanism to enhance catalysis and may have plausibly benefited primordial polypeptide-cofactor associations. 2023-07-27T08:29:08Z 2023-07-27T08:29:08Z 2023-05-26 journal article Luis I Gutierrez-Rus and others, Protection of Catalytic Cofactors by Polypeptides as a Driver for the Emergence of Primordial Enzymes, Molecular Biology and Evolution, Volume 40, Issue 6, June 2023, msad126, [https://doi.org/10.1093/molbev/msad126] https://hdl.handle.net/10481/84039 10.1093/molbev/msad126 eng http://creativecommons.org/licenses/by-nc/4.0/ open access Atribución-NoComercial 4.0 Internacional Oxford academy