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

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Book cover Aminoacyl-tRNA Synthetases in Biology and Medicine

Part of the book series: Topics in Current Chemistry ((TOPCURRCHEM,volume 344))

Abstract

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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Abbreviations

AA-AMP:

Aminoacyl adenylate

AARS:

Aminoacyl-tRNA synthetase

CA:

Capsid

CA-CTD:

Capsid C-terminal domain

cDNA:

Complementary DNA

EPRS:

Glutaminyl-prolyl-tRNA synthetase

HIV-1:

Human immunodeficiency virus-1

IFN-γ:

Interferon-γ

IleRS:

Isoleucyl-tRNA synthetase

LeuRS:

Leucyl-tRNA synthetase

LysRS:

Lysyl-tRNA synthetase

MetRS:

Methionyl-tRNA synthetase

mRNA:

Messenger RNA

MSC:

Multi-synthetase complex

PBS:

Primer binding site

PheRS:

Phenylalanyl-tRNA synthetase

RSV:

Rous sarcoma virus

SerRS:

Seryl-tRNA synthetase

ThrRS:

Threonyl-tRNA synthetase

TLE:

tRNA-like element

TLS:

tRNA-like structure

tRNA:

Transfer RNA

TrpRS:

Tryptophanyl-tRNA synthetase

TYMV:

Turnip yellow mosaic virus

TyrRS:

Tyrosyl-tRNA synthetase

ValRS:

Valyl-tRNA synthetase

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Acknowledgements

The authors acknowledge funding from National Institutes of Health Grants GM049928 and AI077387 (to K.M.-F.) and National Science Foundation Grant MCB-1158488 (to J.S.R.).

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  1. Department of Chemistry and Biochemistry, Ohio State Biochemistry Program, Center for RNA Biology, and Center for Retroviral Research, The Ohio State University, Columbus, OH, 43210, USA

    Varun Dewan & Karin-Musier Forsyth

  2. Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, 27514, USA

    John Reader

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Correspondence to Karin-Musier Forsyth .

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  1. Department of Molecular Medicine and Biopharmaceutical Sciences, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Korea, Republic of (South Korea)

    Sunghoon Kim

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Dewan, V., Reader, J., Forsyth, KM. (2013). Role of Aminoacyl-tRNA Synthetases in Infectious Diseases and Targets for Therapeutic Development. In: Kim, S. (eds) Aminoacyl-tRNA Synthetases in Biology and Medicine. Topics in Current Chemistry, vol 344. Springer, Dordrecht. https://doi.org/10.1007/128_2013_425

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