Abstract:The antibiotic valanimycin is a naturally occurring azoxy compound produced by Streptomyces viridifaciens MG456-hF10. Precursor incorporation experiments showed that valanimycin is derived from L-valine and L-serine via the intermediacy of isobutylamine and isobutylhydroxylamine. Enzymatic and genetic investigations led to the cloning and sequencing of the valanimycin biosynthetic gene cluster, which was found to contain 14 genes. A novel feature of the valanimycin biosynthetic gene cluster is the presence of … Show more
“…It is worth mentioning that aminoacyl-tRNAs function as donors of activated amino acids outside the protein synthesis as well (e.g., in porphyrin or phospholipid synthesis, peptidoglycan crosslinking; 30-32). Recently, it was shown that VlmL, a dedicated seryl-tRNA synthetase, and Ser-tRNA Ser participate in the biosynthesis of valanimycin, azoxy antibiotic produced by Streptomyces viridifaciens (8). Aminoacyl-CPs synthesized by aa:CP ligases may represent a substitute for aa-tRNAs as amino acid donors in such processes outside the protein biosynthesis.…”
Section: Discussionmentioning
confidence: 99%
“…Additional SerRSs, encoded by duplicated serS genes in two Streptomyces species, are required for antibiotic production (8) or resistance (9). These duplicated SerRSs are significantly divergent from canonical housekeeping bacterial SerRSs, but in both cases they have retained their canonical tRNA aminoacylating activity.…”
Aminoacyl-tRNA synthetases (aaRSs) are ancient and evolutionary conserved enzymes catalyzing the formation of aminoacyl-tRNAs, that are used as substrates for ribosomal protein biosynthesis. In addition to full length aaRS genes, genomes of many organisms are sprinkled with truncated genes encoding single-domain aaRSlike proteins, which often have relinquished their canonical role in genetic code translation. We have identified the genes for putative seryl-tRNA synthetase homologs widespread in bacterial genomes and characterized three of them biochemically and structurally. The proteins encoded are homologous to the catalytic domain of highly diverged, atypical seryl-tRNA synthetases (aSerRSs) found only in methanogenic archaea and are deprived of the tRNA-binding domain. Remarkably, in comparison to SerRSs, aSerRS homologs display different and relaxed amino acid specificity. aSerRS homologs lack canonical tRNA aminoacylating activity and instead transfer activated amino acid to phosphopantetheine prosthetic group of putative carrier proteins, whose genes were identified in the genomic surroundings of aSerRS homologs. Detailed kinetic analysis confirmed that aSerRS homologs aminoacylate these carrier proteins efficiently and specifically. Accordingly, aSerRS homologs were renamed amino acid:[carrier protein] ligases (AMP forming). The enzymatic activity of aSerRS homologs is reminiscent of adenylation domains in nonribosomal peptide synthesis, and thus they represent an intriguing link between programmable ribosomal protein biosynthesis and template-independent nonribosomal peptide synthesis.
“…It is worth mentioning that aminoacyl-tRNAs function as donors of activated amino acids outside the protein synthesis as well (e.g., in porphyrin or phospholipid synthesis, peptidoglycan crosslinking; 30-32). Recently, it was shown that VlmL, a dedicated seryl-tRNA synthetase, and Ser-tRNA Ser participate in the biosynthesis of valanimycin, azoxy antibiotic produced by Streptomyces viridifaciens (8). Aminoacyl-CPs synthesized by aa:CP ligases may represent a substitute for aa-tRNAs as amino acid donors in such processes outside the protein biosynthesis.…”
Section: Discussionmentioning
confidence: 99%
“…Additional SerRSs, encoded by duplicated serS genes in two Streptomyces species, are required for antibiotic production (8) or resistance (9). These duplicated SerRSs are significantly divergent from canonical housekeeping bacterial SerRSs, but in both cases they have retained their canonical tRNA aminoacylating activity.…”
Aminoacyl-tRNA synthetases (aaRSs) are ancient and evolutionary conserved enzymes catalyzing the formation of aminoacyl-tRNAs, that are used as substrates for ribosomal protein biosynthesis. In addition to full length aaRS genes, genomes of many organisms are sprinkled with truncated genes encoding single-domain aaRSlike proteins, which often have relinquished their canonical role in genetic code translation. We have identified the genes for putative seryl-tRNA synthetase homologs widespread in bacterial genomes and characterized three of them biochemically and structurally. The proteins encoded are homologous to the catalytic domain of highly diverged, atypical seryl-tRNA synthetases (aSerRSs) found only in methanogenic archaea and are deprived of the tRNA-binding domain. Remarkably, in comparison to SerRSs, aSerRS homologs display different and relaxed amino acid specificity. aSerRS homologs lack canonical tRNA aminoacylating activity and instead transfer activated amino acid to phosphopantetheine prosthetic group of putative carrier proteins, whose genes were identified in the genomic surroundings of aSerRS homologs. Detailed kinetic analysis confirmed that aSerRS homologs aminoacylate these carrier proteins efficiently and specifically. Accordingly, aSerRS homologs were renamed amino acid:[carrier protein] ligases (AMP forming). The enzymatic activity of aSerRS homologs is reminiscent of adenylation domains in nonribosomal peptide synthesis, and thus they represent an intriguing link between programmable ribosomal protein biosynthesis and template-independent nonribosomal peptide synthesis.
“…The GNAT fold was recently identified in many more tRNA-dependent transferases in Streptomyces species, which utilize specific aa-tRNAs for synthesis of broad-spectrum antibiotics. For instance, the protein VlmA utilizes Ser-tRNA Ser for synthesis of the antibiotic valanimycin 45 ; DhpH and DhpK utilize Gly-tRNA Gly and Leu-tRNA Leu for biosynthesis of tripeptide phosphonate 46 ; the protein PacB utilizes Ala-tRNA Ala in the biosynthetic pathway for pacidamycin 47 ; FzmI uses Val-tRNA Val for synthesis of fosfazinomycin 48 ; Orf11 uses Gly-tRNA Gly for the synthesis of a streptothricin-related antibiotic. 49
10.1080/15476286.2017.1356980-f0003Figure 3.Role of aa-tRNA transferases exhibiting a GNAT fold.…”
Section: The Cytosolic Domain Of Aapgs Exhibits a Gcn5-like Acetyltramentioning
ABSTRACTtRNA-dependent addition of amino acids to lipids on the outer surface of the bacterial membrane results in decreased effectiveness of antimicrobials such as cationic antimicrobial peptides (CAMPs) that target the membrane, and increased virulence of several pathogenic species. After a brief introduction to CAMPs and the various bacterial resistance mechanisms used to counteract these compounds, this review focuses on recent advances in tRNA-dependent pathways for lipid modification in bacteria. Phenotypes associated with amino acid lipid modifications and regulation of their expression will also be discussed.
“…The released nucleoside is a potent inhibitor of SerRS, so a divergent SerRS resistant to the inhibitor encoded by albomycin biosynthetic cluster protects the producer from self-poisoning . [36] On the other hand, a duplicated SerRS within the valanimycin biosynthesis cluster from Streptomyces viridifaciens apparently provides building blocks for valanimycin synthesis, since it was shown that seryl-tRNA Ser is one of the valanimycin precursors [37] and SerRS gene inactivation diminishes the antibiotic production. [38] It is noteworthy that in both examples of albomycin and valanimycin biosynthesis, duplicated SerRSs still play their aboriginal role -tRNA Ser serylation.…”
Abstract:For a long time seryl-tRNA synthetases (SerRSs) stood as an archetypal, canonical aminoacyl-tRNA synthetases (aaRS), exhibiting only basic tRNA aminoacylation activity and with no moonlighting functions beyond protein biosynthesis. The picture has changed substantially in recent years after the discovery that SerRSs play an important role in antibiotic production and resistance and act as a regulatory factor in vascular development, as well as after the discovery of mitochondrial morphogenesis factor homologous to SerRS in insects. In this review we summarize the recent research results from our laboratory, which advance the understanding of seryl-tRNA synthetases and further paint the dynamic picture of unexpected SerRS activities. SerRS from archaeon Methanothermobacter thermautotrophicus was shown to interact with the large ribosomal subunit and it was postulated to contribute to a more efficient translation by the"tRNA channeling" hypothesis. Discovery of the atypical SerRS in a small number of methanogenic archaea led to the discovery of a new family of enzymes in numerous bacteria -amino acid:[carrier protein] ligases (aa:CP ligases). These SerRS homologues resigned tRNA aminoacylation activity, and instead adopted carrier proteins as the acceptors of activated amino acids. The crystal structure of the aa:CP ligase complex with the carrier protein revealed that the interactions between two macromolecules are incomparable to tRNA binding by the aaRS and consequently represent a true evolutionary invention. Kinetic investigations of SerRSs and the accuracy of amino acid selection revealed that SerRSs possess pre-transfer proofreading activity, challenging the widely accepted presumption that hydrolytic proofreading activity must reside in an additional, separate editing domain, not present in SerRSs. Finally, the plant tRNA serylation system is discussed, which is particularly interesting due to the fact that protein biosynthesis takes place in three cellular compartments: cytosol, mitochondria and chloroplasts. Plant cytosolic SerRSs showed broad tRNA Ser specificity and flexibility, unlike SerRSs from other organisms. High fidelity of SerRS dually targeted to mitochondria and chloroplasts indicated its importance in plant organellar quality control.
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