Regulation of an Auxiliary, Antibiotic-Resistant Tryptophanyl-tRNA Synthetase Gene via Ribosome-Mediated Transcriptional Attenuation

Vecchione, James J.; Sello, Jason K.

doi:10.1128/jb.00290-10

Cited by 7 publications

(2 citation statements)

References 43 publications

(86 reference statements)

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“…26,000 cases of duplicated aaRS in organisms of the three domains of life only a handful have been empirically characterized. In these few cases, duplicated aaRSs were shown to have evolved distinct expression profiles ( 8 , 56 , 57 ) substrate specificity ( 58 – 63 ) susceptibility to antibiotics ( 9 , 64 , 65 ) or thermal stability ( 66 ). In general, it is proposed that the asymmetric properties of duplicated proteins provide a selective advantage, a better fitness or a higher robustness to the host organism ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

Trans-oligomerization of duplicated aminoacyl-tRNA synthetases maintains genetic code fidelity under stress

et al. 2015

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Aminoacyl-tRNA synthetases (aaRSs) play a key role in deciphering the genetic message by producing charged tRNAs and are equipped with proofreading mechanisms to ensure correct pairing of tRNAs with their cognate amino acid. Duplicated aaRSs are very frequent in Nature, with 25,913 cases observed in 26,837 genomes. The oligomeric nature of many aaRSs raises the question of how the functioning and oligomerization of duplicated enzymes is organized. We characterized this issue in a model prokaryotic organism that expresses two different threonyl-tRNA synthetases, responsible for Thr-tRNAThr synthesis: one accurate and constitutively expressed (T1) and another (T2) with impaired proofreading activity that also generates mischarged Ser-tRNAThr. Low zinc promotes dissociation of dimeric T1 into monomers deprived of aminoacylation activity and simultaneous induction of T2, which is active for aminoacylation under low zinc. T2 either forms homodimers or heterodimerizes with T1 subunits that provide essential proofreading activity in trans. These findings evidence that in organisms with duplicated genes, cells can orchestrate the assemblage of aaRSs oligomers that meet the necessities of the cell in each situation. We propose that controlled oligomerization of duplicated aaRSs is an adaptive mechanism that can potentially be expanded to the plethora of organisms with duplicated oligomeric aaRSs.

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Section: Discussionmentioning

confidence: 99%

Trans-oligomerization of duplicated aminoacyl-tRNA synthetases maintains genetic code fidelity under stress

et al. 2015

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“…TrpRS2 confers resistance to both chuangxinmycin and indolmycin, antibiotics produced by other species that inhibit TrpRS1 (Kitabatake et al ., 2002; Vecchione & Sello, 2009). The two trpRS genes are also differentially expressed, with the sensitive trpRS2 expressed constitutively and trpRS1 transcriptionally activated by indolmycin (Kitabatake et al ., 2002; Vecchione & Sello, 2010). The second MetRS2 of S. pneumoniae and the IleRS2 of S. aureus that impart drug‐resistance capacity to these organisms have been found to have homologs in the Gram‐positive bacterium Bacillus anthracis , the causative agent of anthrax (Brown et al ., 2003).…”

Section: The Case Of Aminoacyl‐trna Synthetases (Aars)mentioning

confidence: 99%

Multilevel populations and the evolution of antibiotic resistance through horizontal gene transfer

2011

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Horizontal gene transfer (HGT) can create diversity in the genetic repertoire of a lineage. Successful gene transfer likely occurs more frequently between more closely related organisms, leading to the formation of higher-level exchange groups that in some respects are comparable to single-species populations. Genes that appear fixed in a single species can be replaced through distant homologs or iso-functional analogs acquired through HGT. These genes may originate from other species or they may be acquired by an individual strain from the species pan-genome. Because of their similarity to alleles in a population, we label these gene variants that are exchanged between related species as homeoalleles. In a case study, we show that biased gene transfer plays an important role in the evolution of aminoacyl-tRNA synthetases (aaRS). Many microorganisms make use of these genes against naturally occurring antibiotics. We suggest that the resistance against naturally occurring antibiotics is the likely driving force behind the frequent switching between divergent aaRS types and the reason for the maintenance of these homeoalleles in higher-level exchange groups. Resistance to naturally occurring antibiotics may lead to the maintenance of different types of aminoacyl-tRNA synthetases in Bacteria through gene transfer.

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

Dewan

Reader

Forsyth

2013

Topics in Current Chemistry

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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.

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Regulation of an Auxiliary, Antibiotic-Resistant Tryptophanyl-tRNA Synthetase Gene via Ribosome-Mediated Transcriptional Attenuation

Cited by 7 publications

References 43 publications

Trans-oligomerization of duplicated aminoacyl-tRNA synthetases maintains genetic code fidelity under stress

Trans-oligomerization of duplicated aminoacyl-tRNA synthetases maintains genetic code fidelity under stress

Multilevel populations and the evolution of antibiotic resistance through horizontal gene transfer

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

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