Abstract
Peptide-nucleotide antibiotic microcin C (McC) is produced by some Escherichia coli strains. Inside a sensitive cell, McC is processed, releasing a nonhydrolyzable analog of aspartyl-adenylate, which inhibits aspartyl-tRNA synthetase. The product of mccE, a gene from the plasmid-borne McC biosynthetic cluster, acetylates processed McC, converting it into a nontoxic compound. MccE is homologous to chromosomally encoded acetyltransferases RimI, RimJ, and RimL, which acetylate, correspondingly, the N termini of ribosomal proteins S18, S5, and L12. Here, we show that E. coli RimL, but not other Rim acetyltransferases, provides a basal level of resistance to McC and various toxic nonhydrolyzable aminoacyl adenylates. RimL acts by acetylating processed McC, which along with ribosomal protein L12 should be considered a natural RimL substrate. When overproduced, RimL also makes cells resistant to albomycin, an antibiotic that upon intracellular processing gives rise to a seryl-thioribosyl pyrimidine that targets seryl-tRNA synthetase. We further show that E. coli YhhY, a protein related to Rim acetyltransferases but without a known function, is also able to detoxify several nonhydrolyzable aminoacyl adenylates but not processed McC. We propose that RimL and YhhY protect bacteria from various toxic aminoacyl nucleotides, either exogenous or those generated inside the cell during normal metabolism.
Highlights
Peptide-nucleotide antibiotic microcin C (McC) is produced by some Escherichia coli strains
Processed McC is a nonhydrolyzable analog of aspartyl-adenylate (Fig. 1), an intermediate of a tRNAAsp aminoacylation reaction catalyzed by aspartyl-tRNA synthetase (AspRS) [5]
Susceptibilities of mutant strains to (i) McC, (ii) McC(1120), an 1,120-Da McC maturation intermediate lacking the propylamine modification [11], (iii) two aminoacyl sulfamoyl adenylates active against E. coli (aspartyl sulfamoyl adenylate DSA and leucil sulfamoyl adenylate (LSA) [12], (iv) two synthetic McC(1120) analogs with an MRTGNA peptide (“X”) corresponding to the first six amino acids of McC heptapeptide coupled to DSA and LSA [12], and (v) albomycin were determined
Summary
Peptide-nucleotide antibiotic microcin C (McC) is produced by some Escherichia coli strains. We show that E. coli RimL, but not other Rim acetyltransferases, provides a basal level of resistance to McC and various toxic nonhydrolyzable aminoacyl adenylates. We further show that E. coli YhhY, a protein related to Rim acetyltransferases but without a known function, is able to detoxify several nonhydrolyzable aminoacyl adenylates but not processed McC. Processed McC is a nonhydrolyzable analog of aspartyl-adenylate (Fig. 1), an intermediate of a tRNAAsp aminoacylation reaction catalyzed by aspartyl-tRNA synthetase (AspRS) [5]. Processed McC generated internally within the producing cell is detoxified by the acetyltransferase activity of the C-terminal domain of the MccE protein (MccECTD). We demonstrate that an additional E. coli NAT, the product of the yhhY gene, acetylates some nonhydrolyzable aminoacyl adenylates (but not processed McC) and increases cellular resistance to these compounds
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