Dataset Information

Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif.

ABSTRACT: Antibiotics target key biological processes that include protein synthesis. Bacteria respond by developing resistance, which increases rapidly due to antibiotics overuse. Mupirocin, a clinically used natural antibiotic, inhibits isoleucyl-tRNA synthetase (IleRS), an enzyme that links isoleucine to its tRNA^Ile for protein synthesis. Two IleRSs, mupirocin-sensitive IleRS1 and resistant IleRS2, coexist in bacteria. The latter may also be found in resistant Staphylococcus aureus clinical isolates. Here, we describe the structural basis of mupirocin resistance and unravel a mechanism of hyper-resistance evolved by some IleRS2 proteins. We surprisingly find that an up to 10³-fold increase in resistance originates from alteration of the HIGH motif, a signature motif of the class I aminoacyl-tRNA synthetases to which IleRSs belong. The structural analysis demonstrates how an altered HIGH motif could be adopted in IleRS2 but not IleRS1, providing insight into an elegant mechanism for coevolution of the key catalytic motif and associated antibiotic resistance.

SUBMITTER: Brkic A

PROVIDER: S-EPMC10485003 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif.

Brkic A A Leibundgut M M Jablonska J J Zanki V V Car Z Z Petrovic Perokovic V V Marsavelski A A Ban N N Gruic-Sovulj I I

Nature communications 20230907 1

Antibiotics target key biological processes that include protein synthesis. Bacteria respond by developing resistance, which increases rapidly due to antibiotics overuse. Mupirocin, a clinically used natural antibiotic, inhibits isoleucyl-tRNA synthetase (IleRS), an enzyme that links isoleucine to its tRNA<sup>Ile</sup> for protein synthesis. Two IleRSs, mupirocin-sensitive IleRS1 and resistant IleRS2, coexist in bacteria. The latter may also be found in resistant Staphylococcus aureus clinical ...[more]

PMID: 37679387

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Project description:BackgroundRecent studies point to a great diversity of non-ribosomal peptide synthesis systems with major roles in amino acid and co-factor biosynthesis, secondary metabolism, and post-translational modifications of proteins by peptide tags. The least studied of these systems are those utilizing tRNAs or aminoacyl-tRNA synthetases (AAtRS) in non-ribosomal peptide ligation.ResultsHere we describe novel examples of AAtRS related proteins that are likely to be involved in the synthesis of widely distributed peptide-derived metabolites. Using sensitive sequence profile methods we show that the cyclodipeptide synthases (CDPSs) are members of the HUP class of Rossmannoid domains and are likely to be highly derived versions of the class-I AAtRS catalytic domains. We also identify the first eukaryotic CDPSs in fungi and in animals; they might be involved in immune response in the latter organisms. We also identify a paralogous version of the methionyl-tRNA synthetase, which is widespread in bacteria, and present evidence using contextual information that it might function independently of protein synthesis as a peptide ligase in the formation of a peptide- derived secondary metabolite. This metabolite is likely to be heavily modified through multiple reactions catalyzed by a metal-binding cupin domain and a lysine N6 monooxygenase that are strictly associated with this paralogous methionyl-tRNA synthetase (MtRS). We further identify an analogous system wherein the MtRS has been replaced by more typical peptide ligases with the ATP-grasp or modular condensation-domains.ConclusionsThe prevalence of these predicted biosynthetic pathways in phylogenetically distant, pathogenic or symbiotic bacteria suggests that metabolites synthesized by them might participate in interactions with the host. More generally, these findings point to a complete spectrum of recruitment of AAtRS to various non-ribosomal biosynthetic pathways, ranging from the conventional AAtRS, through closely related paralogous AAtRS dedicated to certain pathways, to highly derived versions of the class-I AAtRS catalytic domain like the CDPSs. Both the conventional AAtRS and their closely related paralogs often provide aminoacylated tRNAs for peptide ligations by MprF/Fem/MurM-type acetyltransferase fold ligases in the synthesis of peptidoglycan, N-end rule modifications of proteins, lipid aminoacylation or biosynthesis of antibiotics, such as valinamycin. Alternatively they might supply aminoacylated tRNAs for other biosynthetic pathways like that for tetrapyrrole or directly function as peptide ligases as in the case of mycothiol and those identified here.

Project description:MotivationSimilarities in core residue packing provide evidence for divergence or convergence not reported using other methods.ResultsWe apply a new method for rapid structure comparison based on Simplicial Neighborhood Analysis of Protein Packing (SNAPP) to the diverse structural classification of proteins (SCOP) alpha/beta-class of protein folds. The procedure identifies inter-residue packing motifs shared by protein pairs from different folds. A threshold of 0.67 A RMSD for all atoms of corresponding residues ensures inclusion of only highly significant similarities comparable with those observed for identical catalytic residues in homologues. Many tertiary packing motifs are shared among the three classical Rossmannoid folds, as well as thousands of other motifs that occur in at least two distinct folds. Merging of neighboring packing motifs facilitated recognition of larger, recurrent substructures or cores. The anti-codon-binding domain of an archeal aminoacyl-tRNA synthetase (aaRS) was discovered to possess a packed core in which eight identical amino acid residues are within 0.55 A RMSD of the comparable structure in the FixJ receiver, a member of the Rossmannoid family that also includes the CheY signaling protein and flavodoxin-like proteins. Further investigation identified close variants of this core in five other Rossmannoid folds, including a functionally relevant core in Class Ia aminoacyl-tRNA synthetases. Although it is possible that the two essentially identical cores in the ProRS anti-codon-binding domain and the FixJ receiver converged to the same structure, the consensus core obtained from the structural and sequence alignments suggests that all the implicated protein folds descended from a simpler ancestral protein in which this core provided nucleotide binding and proto-allosteric functions.AvailabilityPrograms are available at http://staff.vbi.vt.edu/cammer/snapp/download/ImplementationPrograms were written in Perl and c and run under Linux.Contactcammer@vbi.vt.edu.

Dataset Information

Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif.

Publications

Antibiotic hyper-resistance in a class I aminoacyl-tRNA synthetase with altered active site signature motif.

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