Small amphipathic amino acids imprint the active site of extant E. coli aminoacyl-tRNA synthetases

Abstract

The genetic code defines one of life's most critical processes, protein synthesis. The rules of the genetic code were deciphered decades ago. However, questions remain with regard to the emergence of the translation machinery. It is widely accepted that amino acids (L-AAs) preceded translation components such as aminoacyl-tRNA synthetases (aaRSs), tRNA and ribosomes. We believe that connections exist between L-AAs and extant aaRSs. Moreover, these connections enable the chronology of L-AAs to be determined. We hypothesize that primordial L-AAs effectively "imprinted" the active site(s) of aaRSs during the establishment of the genetic code. Moreover, the imprints confer "memory" into aaRSs active sites that present as misactivation (promiscuity) because imprinting effectively supersedes selectivity. Taking the hypothesis further, we expect that primordial L-AAs will be activated by multiple aaRSs whereas more recent L-AAs will not. The data show that nine amino acids are activated by two or more noncognate aaRSs; we consider these L-AAs to be primordial. Primordial L-AAs are compared with other hypothesized ancient amino acids identified from alternate methods. Computational docking assays using E. coli LeuRS offer insight into identifying pivotal synthetase catalytic site residues that influence the activation of primordial amino acids. Somewhat surprisingly, L-Cys and L-Met are selected by the largest number of noncognate aaRSs (six and three). It is tempting to surmise that the activity of the sulfur containing amino acids are due to these residues being relics of the Thioester World.

Keywords: Amino acids; Aminoacyl-tRNA synthetases (aaRSs); Genetic code; Thioester world.