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Project Progress

The genetic code was elucidated forty years ago. Despite decades of effort, a satisfactory explanation why certain amino acids are assigned to certain codons has not been developed. A collaboration with Dr. Harold Morowitz of George Mason University and Dr. Eric Smith of the Santa Fe Institute has led to the proposal of a novel mechanism for the association of amino acids with their codons and the origin of the genetic code. This work was recently published in Proceedings of the National Academy of Sciences.

The genetic code has many regularities, of which only a subset have explanations in terms of tRNA function or robustness against deleterious effects of mutation or errors in translation. There is a strong correlation between the first bases of codons and the biosynthetic pathways of the amino acids they encode. Codons beginning with C, A, and U encode amino acids synthesized from α-ketoglutarate, oxaloacetate, and pyruvate, respectively. There is also a long-recognized relationship between the hydrophobicity of the amino acid and the second base of its codon. Codons having U as the second base are associated with the most hydrophobic amino acids, and those having A as the second base are associated with the most hydrophilic amino acids. These regularities can be explained if, before the emergence of macromolecules, simple amino acids were synthesized in covalent complexes of dinucleotides with α-keto acids originating from the reductive tricarboxylic acid cycle or reductive acetate pathway (see Figure 1). The bases and phosphates of the dinucleotide are proposed to have enhanced the rates of synthetic reactions leading to amino acids in a small-molecule reaction network that preceded the RNA translation apparatus, but created an association between amino acids and the first two bases of their codons that was retained when translation emerged later in evolution.

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