The genetic code sectored via tRNA charging errors, and the code progressed toward closure and universality because of evolution of aminoacyl-tRNA synthetase (aaRS) fidelity and translational fidelity mechanisms. Class I and class II aaRS folds are identified as homologs. From sequence alignments, a structurally conserved Zn-binding domain common to class I and class II aaRS was identified. A model for the class I and class II aaRS alternate folding pathways is posited. Five mechanisms toward code closure are highlighted: 1) aaRS proofreading to remove mischarged amino acids from tRNA; 2) accurate aaRS active site specification of amino acid substrates; 3) aaRS-tRNA anticodon recognition; 4) conformational coupling proofreading of the anticodon-codon interaction; and 5) deamination of tRNA wobble adenine to inosine. In tRNA anticodons there is strong wobble sequence preference that results in a broader spectrum of contacts to synonymous mRNA codon wobble bases. Adenine is excluded from the anticodon wobble position of tRNA unless it is modified to inosine. Uracil is generally preferred to cytosine in the tRNA anticodon wobble position. Because of wobble ambiguity when tRNA reads mRNA, the maximal coding capacity of the three nucleotide code read by tRNA is 31 amino acids + stops.
Keywords: The last universal common cellular ancestor; aminoacyl-tRNA synthetases; anticodon wobble preference; class I and class II aaRS homology; cloverleaf tRNA; standard genetic code; synonymous anticodons; tRNA wobble inosine.