Aminoacyl-tRNA synthetases as therapeutic targets

Abstract

Aminoacyl-tRNA synthetases (ARSs) are essential enzymes for protein synthesis with evolutionarily conserved enzymatic mechanisms. Despite their similarity across organisms, scientists have been able to generate effective anti-infective agents based on the structural differences in the catalytic clefts of ARSs from pathogens and humans. However, recent genomic, proteomic and functionomic advances have unveiled unexpected disease-associated mutations and altered expression, secretion and interactions in human ARSs, revealing hidden biological functions beyond their catalytic roles in protein synthesis. These studies have also brought to light their potential as a rich and unexplored source for new therapeutic targets and agents through multiple avenues, including direct targeting of the catalytic sites, controlling disease-associated protein–protein interactions and developing novel biologics from the secreted ARS proteins or their parts. This Review addresses the emerging biology and therapeutic applications of human ARSs in diseases including autoimmune and rare diseases, and cancer.

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Fig. 1: Catalysis and architecture of the ARS catalytic site.
Fig. 2: The metamorphosis of ARSs for functional expansion.
Fig. 3: Disease specificity of ARSN.
Fig. 4: Multiple routes for drug development from unique ARS activities.
Fig. 5: ARSN in human body fluids.

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Acknowledgements

This work was supported by NRF-M3A6A4-2010-0029785 (S.K.), NRF-2015M3A6A4065724 (N.H.K.) and NRF-2017M3A9F7079378 (N.H.K.) from the National Research Foundation, the Ministry of Science and ICT (MSIT) of Korea and by the US National Institutes of Health (NIH) P01 HL029582 (P.L.F.). The authors thank B. S. Kang (Kyungbuk University) for drawing the architecture of class I and class II catalytic sites. They also thank J. Y. Lee (Buck Institute) for collecting data for secreted ARSN in human body fluids.

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Contributions

P.L.F. provided substantial contribution to discussion of the content and reviewed and edited the manuscript before submission. N.H.K and S.K. contributed equally to all aspects of the article.

Corresponding author

Correspondence to Sunghoon Kim.

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Competing interests

S.K. has financial interest in aTyr and Curebio, and N.H.K. has financial interest in Oncotag Diagnostics, although none specifically related to this Review.

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The Human Protein Atlas: https://www.proteinatlas.org

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Urine Proteomics: http://www.urineproteomics.org

Supplementary information

Glossary

Polyketide

A type of secondary metabolite that either contains alternating carbonyl and methylene groups or is derived from precursors that contain such alternating groups.

Rossmann fold

A super-secondary structure composed of a series of alternating β-strand and α-helical segments that commonly appears in a variety of nucleotide binding proteins.

WHEP domains

Helix-turn-helix domains whose name comes from the first letters of tryptophanyl-tRNA synthetase (WRS), histidyl-tRNA synthetase (HRS) and glutamyl-prolyl-tRNA synthetase (EPRS), in which WHEP domains were first discovered.

Isoacceptors

In the context of this review, the different tRNA species that bind to alternate codons for the same amino acid residue.

Angiostatic factor

A substance that inhibits angiogenesis.

Megakaryopoiesis

A complex process in the bone marrow that ends with platelet formation from commitment of pluripotent haematopoietic stem cells.

PDZ-binding motif

A specific C-terminal motif that is usually approximately four or five residues in length and interacts with PDZ domains that are found in anchoring proteins.

Hypomyelinating leukodystrophy

(HLD). An autosomal recessive neurodegenerative disorder characterized by infant or childhood onset of progressive motor decline.

Frameshift

A shift of translation from one reading frame to another, generally caused by an addition or deletion in the nucleic acid sequence.

Early infantile epileptic encephalopathy

A debilitating progressive neurological disorder that involves intractable seizures and severe mental retardation.

Compound heterozygous missense mutation

A condition in which a gene has two different point mutations resulting in single amino acid change in both alleles.

Charcot–Marie–Tooth (CMT) disease

One of the hereditary motor and sensory neuropathies, a group of varied inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body.

Rhombomere

Any of the nine segments of the embryonic neural tube.

Lewy-body inclusions

Abnormal aggregates of protein that develop inside nerve cells contributing to disorders including Parkinson disease.

Scleroderma

A rare autoimmune connective tissue disease that can affect skin, joints, tendons and internal organs.

Coefficient of variation

A standardized measure of dispersion of a probability distribution or frequency distribution, defined as the ratio of the standard deviation to the mean.

Z′ factor

A measure of statistical effect size proposed for use in high-throughput screening.

NanoLuc luciferase

An engineered small luciferase derived from a deep sea luminous shrimp, which reveals stable, bright and sustained luminescence.

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Kwon, N.H., Fox, P.L. & Kim, S. Aminoacyl-tRNA synthetases as therapeutic targets. Nat Rev Drug Discov 18, 629–650 (2019). https://doi.org/10.1038/s41573-019-0026-3

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