first_page settings Order Article Reprints Open AccessFeature PaperReview Reflections on the Origin of Coded Protein Biosynthesis by Juan Carlos Fontecilla-Camps Univ. Grenoble Alpes, CEA, CNRS, IBS Metalloproteins Unit, F-38000 Grenoble, France Biomolecules 2024, 14(5), 518; https://doi.org/10.3390/biom14050518 Submission received: 9 April 2024 / Revised: 23 April 2024 / Accepted: 24 April 2024 / Published: 25 April 2024 (This article belongs to the Section Enzymology) Download keyboard_arrow_down Browse Figures Review Reports Versions Notes Abstract The principle of continuity posits that some central features of primordial biocatalytic mechanisms should still be present in the genetically dependent pathway of protein synthesis, a crucial step in the emergence of life. Key bimolecular reactions of this process are catalyzed by DNA-dependent RNA polymerases, aminoacyl-tRNA synthetases, and ribosomes. Remarkably, none of these biocatalysts contribute chemically active groups to their respective reactions. Instead, structural and functional studies have demonstrated that nucleotidic α-phosphate and β-d-ribosyl 2′ OH and 3′ OH groups can help their own catalysis, a process which, consequently, has been called “substrate-assisted”. Furthermore, upon binding, the substrates significantly lower the entropy of activation, exclude water from these catalysts’ active sites, and are readily positioned for a reaction. This binding mode has been described as an “entropy trap”. The combination of this effect with substrate-assisted catalysis results in reactions that are stereochemically and mechanistically simpler than the ones found in most modern enzymes. This observation is consistent with the way in which primordial catalysts could have operated; it may also explain why, thanks to their complementary reactivities, β-d-ribose and phosphate were naturally selected to be the central components of early coding polymers.