MccE Provides Resistance to Protein Synthesis Inhibitor Microcin C by Acetylating the Processed Form of the Antibiotic

Новикова, М. А.; Kazakov, Teymur; Vondenhoff, Gaston; Semenova, Ekaterina; Rozenski, Jef; Metlytskaya, Anastasija; Zukher, Inna; Tikhonov, Anton; Severinov, Konstantin

doi:10.1074/jbc.m109.080192

Cited by 34 publications

(55 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since ϳ20-foldlarger amounts of RimL were required to recover tRNA Ser aminoacylation in albomycin-inhibited extracts than to achieve full recovery of tRNA Asp aminoacylation in McC-inhibited extracts, processed albomycin is a much poorer RimL substrate than processed McC, in agreement with in vivo data (Fig. 2) and earlier findings with MccE CTD (6). Purified Rim proteins were combined with acetyl-CoA, a donor of acetyl groups, and the rate of production of free CoA generated during the acetylation reaction was determined in the presence of processed McC, DSA, ESA, and LSA as described in Materials and Methods.…”

Section: Resultssupporting

confidence: 81%

“…The results, presented in Table 2, demonstrate that production of CoA from acetyl-CoA was observed with every aaSA tested in the presence of RimL. A similar result was obtained in the presence of MccE CTD , as expected (6). In contrast, no CoA production was detected in reaction mixtures that contained RimI or RimJ.…”

Section: Resultssupporting

confidence: 47%

“…In this respect, RimL appears to be very similar to the C-terminal domain of MccE acetyltransferase encoded by the plasmid-borne McC biosynthesis/immunity gene cluster mcc (6). As is the case with MccE CTD , the nature of the amino acid appears to be unimportant for RimL activity, since all aminoacyl sulfamoyl adenylates containing the primary amine group tested in this work (i.e., Ala, Asp, Gly, Phe, Lys, Glu, Leu, and Ile sulfamoyl adenylates) are efficiently acetylated.…”

Section: Discussionmentioning

confidence: 99%

“…Processed McC generated internally within the producing cell is detoxified by the acetyltransferase activity of the C-terminal domain of the MccE protein (MccE CTD ). MccE CTD acetylates the primary amino group of the aminoacyl moiety of processed McC; acetylated processed McC no longer inhibits AspRS (6). MccE CTD also acetylates (and, therefore, provides resistance to) a wide spectrum of nonhydrolyzable synthetic aminoacyl sulfamoyl adenylates (aaSAs, where "aa" denotes an amino acid in a single-letter code) such as DSA, shown in Fig.…”

mentioning

confidence: 99%

See 3 more Smart Citations

The RimL Transacetylase Provides Resistance to Translation Inhibitor Microcin C

et al. 2014

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 81%

Section: Resultssupporting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

The RimL Transacetylase Provides Resistance to Translation Inhibitor Microcin C

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…CTD acetylates the amino group of processed McC, thus preventing its interaction with (and inhibition of) AspRS (14).…”

Section: C-terminal Domain Of the Mcce Protein Mccementioning

confidence: 99%

The Mechanism of Microcin C Resistance Provided by the MccF Peptidase

Tikhonov

Kazakov

Semenova

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Role of Aminoacyl-tRNA Synthetases in Infectious Diseases and Targets for Therapeutic Development

Dewan

Reader

Forsyth

2013

Topics in Current Chemistry

View full text Add to dashboard Cite

Aminoacyl-tRNA synthetases (AARSs) play a pivotal role in protein synthesis and cell viability. These 22 "housekeeping" enzymes (1 for each standard amino acid plus pyrrolysine and o-phosphoserine) are specifically involved in recognizing and aminoacylating their cognate tRNAs in the cellular pool with the correct amino acid prior to delivery of the charged tRNA to the protein synthesis machinery. Besides serving this canonical function, higher eukaryotic AARSs, some of which are organized in the cytoplasm as a multisynthetase complex of nine enzymes plus additional cellular factors, have also been implicated in a variety of non-canonical roles. AARSs are involved in the regulation of transcription, translation, and various signaling pathways, thereby ensuring cell survival. Based in part on their versatility, AARSs have been recruited by viruses to perform essential functions. For example, host synthetases are packaged into some retroviruses and are required for their replication. Other viruses mimic tRNA-like structures in their genomes, and these motifs are aminoacylated by the host synthetase as part of the viral replication cycle. More recently, it has been shown that certain large DNA viruses infecting animals and other diverse unicellular eukaryotes encode tRNAs, AARSs, and additional components of the protein-synthesis machinery. This chapter will review our current understanding of the role of host AARSs and tRNA-like structures in viruses and discuss their potential as anti-viral drug targets. The identification and development of compounds that target bacterial AARSs, thereby serving as novel antibiotics, will also be discussed. Particular attention will be given to recent work on a number of tRNA-dependent AARS inhibitors and to advances in a new class of natural "pro-drug" antibiotics called Trojan Horse inhibitors. Finally, we will explore how bacteria that naturally produce AARS-targeting antibiotics must protect themselves against cell suicide using naturally antibiotic resistant AARSs, and how horizontal gene transfer of these AARS genes to pathogens may threaten the future use of this class of antibiotics.

show abstract

MccE Provides Resistance to Protein Synthesis Inhibitor Microcin C by Acetylating the Processed Form of the Antibiotic

Cited by 34 publications

References 26 publications

The RimL Transacetylase Provides Resistance to Translation Inhibitor Microcin C

The RimL Transacetylase Provides Resistance to Translation Inhibitor Microcin C

The Mechanism of Microcin C Resistance Provided by the MccF Peptidase

Role of Aminoacyl-tRNA Synthetases in Infectious Diseases and Targets for Therapeutic Development

Contact Info

Product

Resources

About