A mechanism for the association of amino acids with their codons and the origin of the genetic code

Abstract

The genetic code has certain regularities that have resisted mechanistic interpretation. These include strong correlations between the first base of codons and the precursor from which the encoded amino acid is synthesized and between the second base of codons and the hydrophobicity of the encoded amino acid. These regularities are even more striking in a projection of the modern code onto a simpler code consisting of doublet codons encoding a set of simple amino acids. These regularities can be explained if, before the emergence of macromolecules, simple amino acids were synthesized in covalent complexes of dinucleotides with ␣-keto acids originating from the reductive tricarboxylic acid cycle or reductive acetate pathway. 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.catalysis ͉ origin of life T he genetic code has many regularities (1), of which only a subset have explanations in terms of tRNA function (2) or robustness against deleterious effects of mutation (3, 4) or errors in translation (3, 5). There is a strong correlation between the first bases of codons and the biosynthetic pathways of the amino acids they encode (1, 6). Codons beginning with C, A, and U encode amino acids synthesized from ␣-ketoglutarate (␣-KG), oxaloacetate (OAA), and pyruvate, respectively. ¶ These correlations are especially striking in light of the structural diversity of amino acids whose codons share a first base. For example, codons for Glu and Pro both begin with C, and those for Cys and Leu begin with U. Codons beginning with G encode amino acids that can be formed by direct reductive amination of a simple ␣-keto acid. These include glycine, alanine, aspartate, and glutamate, which can be formed by reductive amination of glyoxalate, pyruvate, OAA, and ␣-KG, respectively. There is also a long-recognized relationship between the hydrophobicity of the amino acid and the second base of its codon (1). 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.We suggest that both correlations can be explained if, before the emergence of macromolecules, simple amino acids were synthesized from ␣-keto acid precursors covalently attached to dinucleotides that catalyzed the reactions required to synthesize specific amino acids (see Fig. 1). This is a significant departure from previous theories attempting to explain the regularities in the genetic code (3). The ''stereochemical'' hypothesis suggests that binding interactions between amino acids and their codons or anticodons dictated the structure of the genetic code (7-10). The ''coevolution'' hypothesis (6) suggests that the original genetic code specifi...

DNA‐Catalyzed Reductive Amination

“…[2] In the presently reported DNAcatalyzed reaction, the electrophilic reaction partner, which is the dialdehyde formed by NaIO 4 oxidation of a 3′-terminal ribonucleotide, has considerable precedent for electrophilic reactivity. [25] In contrast, although reaction of the guanine nucleobase at its N 2 -amine is experimentally precedented [26,27] and has been proposed as a basis for codons to associate with amino acids during the origin of the genetic code, [28] such nucleophilic reactivity is not extremely common.…”

“…[2] In the presently reported DNAcatalyzed reaction, the electrophilic reaction partner, which is the dialdehyde formed by NaIO 4 oxidation of a 3′-terminal ribonucleotide, has considerable precedent for electrophilic reactivity. [25] In contrast, although reaction of the guanine nucleobase at its N 2 -amine is experimentally precedented [26,27] and has been proposed as a basis for codons to associate with amino acids during the origin of the genetic code, [28] such nucleophilic reactivity is not extremely common.An important mechanistic question is whether the new deoxyribozymes participate in catalysis of the imine formation step involving the N 2 -amine nucleophile, the reduction step involving NaCNBH 3 , or both of these reaction steps. The relatively low general nucleophilicity of the guanine N 2 -amine suggests that its nucleophilic attack into the dialdehyde-oligonucleotide would benefit strongly from DNA catalysis.…”

Energy flow and the organization of life

“…For instance, the citric acid cycle is distinguished as a simple pathway for organosynthesis from CO 2 and reductant, but it is of no apparent significance in networks driven by high concentrations of the reactive molecule formaldehydewhich undergoes aldol condensations to form complex mixtures of diverse sugars [28]. Similarly, the biological amino acids are among the most natural elaborations of citric-acid cycle intermediates in an environment of ammonia and reductant [29]. These amino acids are not distinguished in synthetic reactions from gas-phase free radicals [30], and they are not distinguished in the deepspace photochemistry of interstellar and cometary ices or meteors [31].…”

The origin of modern terrestrial life

“…The amino-acid binding module probably originated first and was later on duplicated to produce the anticodon module (Maizels and Weiner, 1994). From the imagination of scientists, a great variety of scenarios have been proposed to explain the origin of the translation machinery (Schimmel and Henderson, 1994) (Copley et al, 2005) (Taylor, 2006) (Szathmary, 1999) (Wolf and Koonin, 2007). A detailed presentation of these models is beyond the scope of this review.…”