Abstract
In recent years it has become apparent that aminoacyl-tRNAs are not only crucial components involved in protein biosynthesis, but are also used as substrates and amino acid donors in a variety of other important cellular processes, ranging from bacterial cell wall biosynthesis and lipid modification to protein turnover and secondary metabolite assembly. In this review, we focus on tRNA-dependent biosynthetic pathways that generate modified cyclic dipeptides (CDPs). The essential peptide bond-forming catalysts responsible for the initial generation of a CDP-scaffold are referred to as cyclodipeptide synthases (CDPSs) and use loaded tRNAs as their substrates. After initially discussing the phylogenetic distribution and organization of CDPS gene clusters, we will focus on structural and catalytic properties of CDPSs before turning to two recently characterized CDPS-dependent pathways that assemble modified CDPs. Finally, possible applications of CDPSs in the rational design of structural diversity using combinatorial biosynthesis will be discussed before concluding with a short outlook.
Highlights
Aminoacyl-tRNA synthetases represent an ancient and ubiquitous tRNA-utilizing enzyme family that possesses the unique catalytic capability of attaching amino acids to the correct tRNA-adaptors needed during the translational process [1]
Transferases, as well as peptide ligases have been identified in putative cyclodipeptide synthases (CDPSs) gene clusters hinting at a diverse set of modifications that can be introduced into CDPS-dependent cyclic dipeptides [31]
Families among others can be observed. They are usually involved in regulating various processes in response to environmental stimuli like resistance to toxic chemicals and antibiotics, the expression of virulence factors and the adaptation to oxidative stress, which may hint at the biological function of CDPS-dependent modified CDPs [41,42]
Summary
Aminoacyl-tRNA synthetases (aaRSs) represent an ancient and ubiquitous tRNA-utilizing enzyme family that possesses the unique catalytic capability of attaching amino acids to the correct tRNA-adaptors needed during the translational process [1]. They represent the true decoders of the genetic code [2]. Examples where aaRS homologs act as ligases include the formation of mycothiol [9], as well as the aminoacylation of a conserved lysine residue in elongation factor P, which is essential for cell survival [10,11]. We focus on another recently identified homologous enzyme family referred to as cyclodipeptide synthases that shows the largest sequential and functional divergence among all known aaRS homologs
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