Roles of tRNA in cell wall biosynthesis

Abstract

Recent research into various aspects of bacterial metabolism such as cell wall and antibiotic synthesis, degradation pathways, cellular stress, and amino acid biosynthesis has elucidated roles of aminoacyl-transfer ribonucleic acid (aa-tRNA) outside of translation. Although the two enzyme families responsible for cell wall modifications, aminoacyl-phosphatidylglycerol synthases (aaPGSs) and Fem, were discovered some time ago, they have recently become of intense interest for their roles in the antimicrobial resistance of pathogenic microorganisms. The addition of positively charged amino acids to phosphatidylglycerol (PG) by aaPGSs neutralizes the lipid bilayer making the bacteria less susceptible to positively charged antimicrobial agents. Fem transferases utilize aa-tRNA to form peptide bridges that link strands of peptidoglycan. These bridges vary among the bacterial species in which they are present and play a role in resistance to antibiotics that target the cell wall. Additionally, the formation of truncated peptides results in shorter peptide bridges and loss of branched linkages which makes bacteria more susceptible to antimicrobials. A greater understanding of the structure and substrate specificity of this diverse enzymatic family is necessary to aid current efforts in designing potential bactericidal agents. These two enzyme families are linked only by the substrate with which they modify the cell wall, aa-tRNA; their structure, cell wall modification processes and the physiological changes they impart on the bacterium differ greatly.

Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances

“…Depending on the bacterial species, the connecting peptide can be made of Gly, Ala, Ser, or Thr. These aa are sequentially added to the cytoplasmic precursor of peptidoglycan (i.e., UDP-N-acetyl-muramyl-pentapeptide) by distinct Fem proteins (for review see [3,43]). This pathway is an alternate route to the direct bridging of peptidoglycan chains, and uses a set of penicillin binding proteins exhibiting a low affinity for β-lactam antibiotics (e.g., protein mecA in methicillin resistant S. aureus ).…”

The Structure of FemXWv in Complex with a Peptidyl‐RNA Conjugate: Mechanism of Aminoacyl Transfer from Ala‐tRNAAla to Peptidoglycan Precursors

“…[1,2] The latter enzymes are attractive targets for drug development, as they have no counterpart in mammalian cells and perform essential steps in cell-wall assembly in important multidrug-resistant pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis. [1,2] The latter enzymes are attractive targets for drug development, as they have no counterpart in mammalian cells and perform essential steps in cell-wall assembly in important multidrug-resistant pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecalis.…”

Cameo appearances of aminoacyl-tRNA in natural product biosynthesis

“…The cell wall biosynthesis enzyme FemX from Weissella viridescens catalyzes the formation of branched peptide chains by conjugating the ε-amino group of lysine in UDP-MurNAc pentapeptide with l -Ala from Ala-tRNA Ala (Figure 2b) [28]. Other members of the FemABX family catalyze similar reactions but use different aa-tRNA substrates [9]. The following subsections will highlight the MprF/FemX homologs that are involved in biosynthesis of a diverse set of natural products.…”

“…Considering that aa-tRNAs have profound importance for the cell as the link between mRNA and peptide formation at the ribosome, it is intriguing that aa-tRNA is also accepted as a substrate for enzymes involved in cell wall biosynthesis, antibiotic resistance, porphyrin biosynthesis, protein degradation pathways, and antibiotic biosynthesis [2–6]. These topics are covered in a number of comprehensive recent reviews [7–9]; this review will focus on the use of aa-tRNA in natural product biosynthesis. The realization that aa-tRNA is used in these processes started in 2008, with this review emphasizing studies published in the period 2014–2016.…”