The Alanine World Model for the Development of the Amino Acid Repertoire in Protein Biosynthesis

Abstract

A central question in the evolution of the modern translation machinery is the origin and chemical ethology of the amino acids prescribed by the genetic code. The RNA World hypothesis postulates that templated protein synthesis has emerged in the transition from RNA to the Protein World. The sequence of these events and principles behind the acquisition of amino acids to this process remain elusive. Here we describe a model for this process by following the scheme previously proposed by Hartman and Smith, which suggests gradual expansion of the coding space as GC–GCA–GCAU genetic code. We point out a correlation of this scheme with the hierarchy of the protein folding. The model follows the sequence of steps in the process of the amino acid recruitment and fits well with the co-evolution and coenzyme handle theories. While the starting set (GC-phase) was responsible for the nucleotide biosynthesis processes, in the second phase alanine-based amino acids (GCA-phase) were recruited from the core metabolism, thereby providing a standard secondary structure, the α-helix. In the final phase (GCAU-phase), the amino acids were appended to the already existing architecture, enabling tertiary fold and membrane interactions. The whole scheme indicates strongly that the choice for the alanine core was done at the GCA-phase, while glycine and proline remained rudiments from the GC-phase. We suggest that the Protein World should rather be considered the Alanine World, as it predominantly relies on the alanine as the core chemical scaffold.

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

“…The unique features created by proline residues in proteins justify the essential role of proline in biochemistry. Moreover, our recent theory suggests that proline was one of the first amino acids recruited for protein translation [ 22 ]. This suggests that the proteome originally evolved around proline as its universal constituent, which makes the proteome-wide replacement of proline a challenging task.…”

“…Furthermore, such an evolution model suggests that the first protein-biosynthesis-generated structures are based on variable backbone elements; proline (cyclic and chiral), glycine (acyclic and achiral) or alanine (acyclic and chiral). Subsequent acquisition of the functional side-chains for this repertoire led to the recruitment of amino acids that are essentially derived from alanine, leading to the α-helix-dominated protein world as we know it [ 22 ]. For this reason, most amino acids in proteins can be exchanged for alanine by point mutations while leaving the secondary structure intact.…”

The Combinatorial Fusion Cascade to Generate the Standard Genetic Code

“…The gradual expansion of the coding space as GC–GCA–GCAU genetic code was proposed by Hartman and Smith [ 15 ]. Kubyshkin and Budisa supported this hypothesis, demonstrating the correlation of this scheme with the hierarchy of the protein folding [ 16 ].…”

Break the template boundary: Test of different protein scaffolds by genetic code expansion resulted in NADPH-dependent secondary amine catalysis

“…[11][12][13] Indeed, proline and its derivatives (e.g., prolyl-RNA) have been proposed to play roles in the prebiotic world catalyzing the formation of crucial building blocks such as carbohydrates and nucleotides. [14][15][16] Given the reactivity of secondary amines, their incorporation into protein scaffolds can generate catalytically active entities which have strong potentials to be transformed into highly active and selective arti cial enzymes.…”