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.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kim, S., You, S. & Hwang, D. Aminoacyl-tRNA synthetases and tumorigenesis: more than housekeeping. Nat. Rev. Cancer 11, 708–718 (2011). This is a comprehensive and analytical Review on the relationship between ARSs and cancer.
Yao, P. & Fox, P. L. Aminoacyl-tRNA synthetases in medicine and disease. EMBO Mol. Med. 5, 332–343 (2013).
Fang, P. & Guo, M. Evolutionary limitation and opportunities for developing tRNA synthetase inhibitors with 5-binding-mode classification. Life (Basel) 5, (1703–1725 (2015).
Hurdle, J. G., O’Neill, A. J. & Chopra, I. Prospects for aminoacyl-tRNA synthetase inhibitors as new antimicrobial agents. Antimicrob. Agents Chemother. 49, 4821–4833 (2005).
Schimmel, P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis. Nat. Rev. Mol. Cell Biol. 19, 45–58 (2018).
Bullwinkle, T. J. & Ibba, M. Emergence and evolution. Top. Curr. Chem. 344, 43–87 (2014).
Perona, J. J. & Gruic-Sovulj, I. Synthetic and editing mechanisms of aminoacyl-tRNA synthetases. Top. Curr. Chem. 344, 1–41 (2014).
Giege, R. & Springer, M. Aminoacyl-tRNA synthetases in the bacterial world. EcoSal Plus https://doi.org/10.1128/ecosalplus.ESP-0002-2016 (2016).
Lee, J. W. et al. Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature 443, 50–55 (2006).
Ribas de Pouplana, L. & Schimmel, P. Aminoacyl-tRNA synthetases: potential markers of genetic code development. Trends Biochem. Sci. 26, 591–596 (2001). This study presents the route of catalytic evolution of ARSs.
Eriani, G., Delarue, M., Poch, O., Gangloff, J. & Moras, D. Partition of tRNA synthetases into two classes based on mutually exclusive sets of sequence motifs. Nature 347, 203–206 (1990).
Newberry, K. J., Hou, Y. M. & Perona, J. J. Structural origins of amino acid selection without editing by cysteinyl-tRNA synthetase. EMBO J. 21, 2778–2787 (2002).
Nureki, O. et al. Architectures of class-defining and specific domains of glutamyl-tRNA synthetase. Science 267, 1958–1965 (1995).
Brick, P., Bhat, T. N. & Blow, D. M. Structure of tyrosyl-tRNA synthetase refined at 2.3 A resolution. Interaction of the enzyme with the tyrosyl adenylate intermediate. J. Mol. Biol. 208, 83–98 (1989).
Schmidt, E. & Schimmel, P. Residues in a class I tRNA synthetase which determine selectivity of amino acid recognition in the context of tRNA. Biochemistry 34, 11204–11210 (1995).
Palencia, A. et al. Structural dynamics of the aminoacylation and proofreading functional cycle of bacterial leucyl-tRNA synthetase. Nat. Struct. Mol. Biol. 19, 677–684 (2012).
Guo, M. et al. The C-Ala domain brings together editing and aminoacylation functions on one tRNA. Science 325, 744–747 (2009).
Delagoutte, B., Moras, D. & Cavarelli, J. tRNA aminoacylation by arginyl-tRNA synthetase: induced conformations during substrates binding. EMBO J. 19, 5599–5610 (2000).
Beuning, P. J. & Musier-Forsyth, K. Species-specific differences in amino acid editing by class II prolyl-tRNA synthetase. J. Biol. Chem. 276, 30779–30785 (2001).
Guo, M., Yang, X. L. & Schimmel, P. New functions of aminoacyl-tRNA synthetases beyond translation. Nat. Rev. Mol. Cell Biol. 11, 668–674 (2010). This Review discusses the non-catalytic evolution of ARSs and AIMPs.
Fournier, G. P., Andam, C. P., Alm, E. J. & Gogarten, J. P. Molecular evolution of aminoacyl tRNA synthetase proteins in the early history of life. Orig. Life Evol. Biosph. 41, 621–632 (2011).
Beebe, K., Ribas De Pouplana, L. & Schimmel, P. Elucidation of tRNA-dependent editing by a class II tRNA synthetase and significance for cell viability. EMBO J. 22, 668–675 (2003).
Sasaki, H. M. et al. Structural and mutational studies of the amino acid-editing domain from archaeal/eukaryal phenylalanyl-tRNA synthetase. Proc. Natl Acad. Sci. USA 103, 14744–14749 (2006).
Guo, M. & Yang, X. L. Architecture and metamorphosis. Top. Curr. Chem. 344, 89–118 (2014).
Schimmel, P. & Ribas De Pouplana, L. Footprints of aminoacyl-tRNA synthetases are everywhere. Trends Biochem. Sci. 25, 207–209 (2000).
Cen, S., Javanbakht, H., Niu, M. & Kleiman, L. Ability of wild-type and mutant lysyl-tRNA synthetase to facilitate tRNA(Lys) incorporation into human immunodeficiency virus type 1. J. Virol. 78, 1595–1601 (2004).
Kim, D. G. et al. Interaction of two translational components, lysyl-tRNA synthetase and p40/37LRP, in plasma membrane promotes laminin-dependent cell migration. FASEB J. 26, 4142–4159 (2012).
Kim, D. G. et al. Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction. Nat. Chem. Biol. 10, 29–34 (2014).
Fu, Y. et al. Structure of the ArgRS-GlnRS-AIMP1 complex and its implications for mammalian translation. Proc. Natl Acad. Sci. USA 111, 15084–15089 (2014).
Wakasugi, K. & Schimmel, P. Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science 284, 147–151 (1999). This study demonstrates the function of secreted YRSs working as cytokines.
Park, S. G., Choi, E. C. & Kim, S. Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMPs): a triad for cellular homeostasis. IUBMB Life 62, 296–302 (2010).
Kim, D., Kwon, N. H. & Kim, S. Association of aminoacyl-tRNA synthetases with cancer. Top. Curr. Chem. 344, 207–245 (2014).
Cho, H. Y. et al. Assembly of multi-tRNA synthetase complex via heterotetrameric glutathione transferase-homology domains. J. Biol. Chem. 290, 29313–29328 (2015).
Arif, A. et al. Two-site phosphorylation of EPRS coordinates multimodal regulation of noncanonical translational control activity. Mol. Cell 35, 164–180 (2009). This study demonstrates the role of phosphorylation on the relocalization and novel function of EPRS.
Jia, J., Arif, A., Ray, P. S. & Fox, P. L. WHEP domains direct noncanonical function of glutamyl-Prolyl tRNA synthetase in translational control of gene expression. Mol. Cell 29, 679–690 (2008).
Sajish, M. et al. Trp-tRNA synthetase bridges DNA-PKcs to PARP-1 to link IFN-gamma and p53 signaling. Nat. Chem. Biol. 8, 547–554 (2012).
Ahn, Y. H. et al. Secreted tryptophanyl-tRNA synthetase as a primary defence system against infection. Nat. Microbiol. 2, 16191 (2016).
Han, J. M. et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410–424 (2012).
Bonfils, G. et al. Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol. Cell. 46, 105–110 (2012).
Xu, X. et al. Unique domain appended to vertebrate tRNA synthetase is essential for vascular development. Nat. Commun. 3, 681 (2012).
Lo, W. S. et al. Human tRNA synthetase catalytic nulls with diverse functions. Science 345, 328–332 (2014). This study presents the diverse splicing variants of ARSs identified by omics studies.
Choi, J. W. et al. Cancer-associated splicing variant of tumor suppressor AIMP2/p38: pathological implication in tumorigenesis. PLOS Genet. 7, e1001351 (2011).
Xu, Z. et al. Internally deleted human tRNA synthetase suggests evolutionary pressure for repurposing. Structure 20, 1470–1477 (2012).
Kanaji, T. et al. Tyrosyl-tRNA synthetase stimulates thrombopoietin-independent hematopoiesis accelerating recovery from thrombocytopenia. Proc. Natl Acad. Sci. USA 115, E8228–E8235 (2018).
Tolstrup, A. B., Bejder, A., Fleckner, J. & Justesen, J. Transcriptional regulation of the interferon-gamma-inducible tryptophanyl-tRNA synthetase includes alternative splicing. J. Biol. Chem. 270, 397–403 (1995).
Kim, J. E. et al. An elongation factor-associating domain is inserted into human cysteinyl-tRNA synthetase by alternative splicing. Nucleic Acids Res. 28, 2866–2872 (2000).
Yao, P. et al. Coding region polyadenylation generates a truncated tRNA synthetase that counters translation repression. Cell 149, 88–100 (2012).
Kim, D. G. et al. Oncogenic mutation of AIMP2/p38 inhibits its tumor-suppressive interaction with Smurf2. Cancer Res. 76, 3422–3436 (2016).
Ofir-Birin, Y. et al. Structural switch of lysyl-tRNA synthetase between translation and transcription. Mol. Cell. 49, 30–42 (2013).
Nam, S. H. et al. Lysyl-tRNA synthetase-expressing colon spheroids induce M2 macrophage polarization to promote metastasis. J. Clin. Invest. 128, 5034–5055 (2018).
Arif, A. et al. EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature 542, 357–361 (2017).
Lee, E. Y. et al. Infection-specific phosphorylation of glutamyl-prolyl tRNA synthetase induces antiviral immunity. Nat. Immunol. 17, 1252–1262 (2016).
Kwon, N. H. et al. Dual role of methionyl-tRNA synthetase in the regulation of translation and tumor suppressor activity of aminoacyl-tRNA synthetase-interacting multifunctional protein-3. Proc. Natl Acad. Sci. USA 108, 19635–19640 (2011).
Lee, J. Y. et al. Promiscuous methionyl-tRNA synthetase mediates adaptive mistranslation to protect cells against oxidative stress. J. Cell Sci. 127, 4234–4245 (2014).
Luo, S. & Levine, R. L. Methionine in proteins defends against oxidative stress. FASEB J. 23, 464–472 (2009).
Otani, A. et al. A fragment of human TrpRS as a potent antagonist of ocular angiogenesis. Proc. Natl Acad. Sci. USA 99, 178–183 (2002).
Tzima, E. et al. VE-cadherin links tRNA synthetase cytokine to anti-angiogenic function. J. Biol. Chem. 280, 2405–2408 (2005).
Vo, M. N., Yang, X. L. & Schimmel, P. Dissociating quaternary structure regulates cell-signaling functions of a secreted human tRNA synthetase. J. Biol. Chem. 286, 11563–11568 (2011).
Kim, S. B. et al. Caspase-8 controls the secretion of inflammatory lysyl-tRNA synthetase in exosomes from cancer cells. J. Cell. Biol. 216, 2201–2216 (2017).
Vo, M. N. et al. ANKRD16 prevents neuron loss caused by an editing-defective tRNA synthetase. Nature 557, 510–515 (2018).
Zhou, Q. et al. Orthogonal use of a human tRNA synthetase active site to achieve multifunctionality. Nat. Struct. Mol. Biol. 17, 57–61 (2010).
Sajish, M. & Schimmel, P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 519, 370–373 (2015).
Uhlen, M. et al. A pathology atlas of the human cancer transcriptome. Science 357, eaan2507 (2017).
Park, B. J. et al. The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR. Cell 120, 209–221 (2005).
Park, B. J. et al. AIMP3 haploinsufficiency disrupts oncogene-induced p53 activation and genomic stability. Cancer Res. 66, 6913–6918 (2006).
Choi, J. W., Um, J. Y., Kundu, J. K., Surh, Y. J. & Kim, S. Multidirectional tumor-suppressive activity of AIMP2/p38 and the enhanced susceptibility of AIMP2 heterozygous mice to carcinogenesis. Carcinogenesis 30, 1638–1644 (2009).
Thul, P. J. & Lindskog, C. The human protein atlas: a spatial map of the human proteome. Protein Sci. 27, 233–244 (2018).
Kim, E. Y., Jung, J. Y., Kim, A., Kim, K. & Chang, Y. S. Methionyl-tRNA synthetase overexpression is associated with poor clinical outcomes in non-small cell lung cancer. BMC Cancer 17, 467 (2017).
Forus, A., Florenes, V. A., Maelandsmo, G. M., Fodstad, O. & Myklebost, O. The protooncogene CHOP/GADD153, involved in growth arrest and DNA damage response, is amplified in a subset of human sarcomas. Cancer Genet. Cytogenet. 78, 165–171 (1994).
Nilbert, M., Rydholm, A., Mitelman, F., Meltzer, P. S. & Mandahl, N. Characterization of the 12q13-15 amplicon in soft tissue tumors. Cancer Genet. Cytogenet. 83, 32–36 (1995).
Palmer, J. L., Masui, S., Pritchard, S., Kalousek, D. K. & Sorensen, P. H. Cytogenetic and molecular genetic analysis of a pediatric pleomorphic sarcoma reveals similarities to adult malignant fibrous histiocytoma. Cancer Genet. Cytogenet. 95, 141–147 (1997).
Reifenberger, G. et al. Refined mapping of 12q13-q15 amplicons in human malignant gliomas suggests CDK4/SAS and MDM2 as independent amplification targets. Cancer Res. 56, 5141–5145 (1996).
Vellaichamy, A. et al. Proteomic interrogation of androgen action in prostate cancer cells reveals roles of aminoacyl tRNA synthetases. PLOS ONE 4, e7075 (2009).
Wellman, T. L. et al. Threonyl-tRNA synthetase overexpression correlates with angiogenic markers and progression of human ovarian cancer. BMC Cancer 14, 620 (2014).
Jeong, S. J. et al. Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration. Exp. Mol. Med. 50, e424 (2018).
Lee, C. W. et al. Overexpressed tryptophanyl-tRNA synthetase, an angiostatic protein, enhances oral cancer cell invasiveness. Oncotarget 6, 21979–21992 (2015).
Chi, L. M. et al. Enhanced interferon signaling pathway in oral cancer revealed by quantitative proteome analysis of microdissected specimens using 16O/18O labeling and integrated two-dimensional LC-ESI-MALDI tandem MS. Mol. Cell. Proteomics 8, 1453–1474 (2009).
Liu, J., Shue, E., Ewalt, K. L. & Schimmel, P. A new gamma-interferon-inducible promoter and splice variants of an anti-angiogenic human tRNA synthetase. Nucleic Acids Res. 32, 719–727 (2004).
Turpaev, K. T. et al. Alternative processing of the tryptophanyl-tRNA synthetase mRNA from interferon-treated human cells. Eur. J. Biochem. 240, 732–737 (1996).
Koscielny, G. et al. Open Targets: a platform for therapeutic target identification and validation. Nucleic Acids Res. 45, D985–D994 (2017).
Santos-Cortez, R. L. et al. Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89. Am. J. Hum. Genet. 93, 132–140 (2013).
Garbern, J. Y. Pelizaeus-Merzbacher disease: genetic and cellular pathogenesis. Cell. Mol. Life Sci. 64, 50–65 (2007).
Nafisinia, M. et al. Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease. Eur. J. Hum. Genet. 25, 1134–1141 (2017).
Mendes, M. I. et al. Bi-allelic mutations in EPRS, encoding the glutamyl-prolyl-aminoacyl-tRNA Synthetase, cause a hypomyelinating leukodystrophy. Am. J. Hum. Genet. 102, 676–684 (2018).
Wolf, N. I. et al. Mutations in RARS cause hypomyelination. Ann. Neurol. 76, 134–139 (2014).
Shukla, A. et al. Homozygosity for a nonsense variant in AIMP2 is associated with a progressive neurodevelopmental disorder with microcephaly, seizures, and spastic quadriparesis. J. Hum. Genet. 63, 19–25 (2018).
Iqbal, Z. et al. Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration. Eur. J. Hum. Genet. 24, 392–399 (2016).
Zhu, X. et al. MSC p43 required for axonal development in motor neurons. Proc. Natl Acad. Sci. USA 106, 15944–15949 (2009).
Xu, H., Malinin, N. L., Awasthi, N., Schwarz, R. E. & Schwarz, M. A. The N terminus of pro-endothelial monocyte-activating polypeptide II (EMAP II) regulates its binding with the C terminus, arginyl-tRNA synthetase, and neurofilament light protein. J. Biol. Chem. 290, 9753–9766 (2015).
Simons, C. et al. Loss-of-function alanyl-tRNA synthetase mutations cause an autosomal-recessive early-onset epileptic encephalopathy with persistent myelination defect. Am. J. Hum. Genet. 96, 675–681 (2015).
Casey, J. P. et al. Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS. J. Inherit. Metab. Dis. 38, 1085–1092 (2015).
van Meel, E. et al. Rare recessive loss-of-function methionyl-tRNA synthetase mutations presenting as a multi-organ phenotype. BMC Med. Genet. 14, 106 (2013).
Kopajtich, R. et al. Biallelic IARS mutations cause growth retardation with prenatal onset, intellectual disability, muscular hypotonia, and infantile hepatopathy. Am. J. Hum. Genet. 99, 414–422 (2016).
Puffenberger, E. G. et al. Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLOS ONE 7, e28936 (2012).
Zhang, X. et al. Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am. J. Hum. Genet. 94, 547–558 (2014).
Xu, Z. et al. Bi-allelic mutations in phe-tRNA synthetase associated with a multi-system pulmonary disease support non-translational function. Am. J. Hum. Genet. 103, 100–114 (2018).
Antonellis, A. et al. Compound heterozygosity for loss-of-function FARSB variants in a patient with classic features of recessive aminoacyl-tRNA synthetase-related disease. Hum. Mutat. 39, 834–840 (2018).
Sissler, M., Gonzalez-Serrano, L. E. & Westhof, E. Recent advances in mitochondrial aminoacyl-tRNA synthetases and disease. Trends Mol. Med. 23, 693–708 (2017).
Schwenzer, H., Zoll, J., Florentz, C. & Sissler, M. Pathogenic implications of human mitochondrial aminoacyl-tRNA synthetases. Top. Curr. Chem. 344, 247–292 (2014).
Datt, M. & Sharma, A. Evolutionary and structural annotation of disease-associated mutations in human aminoacyl-tRNA synthetases. BMC Genomics 15, 1063 (2014).
Motley, W. W., Talbot, K. & Fischbeck, K. H. GARS axonopathy: not every neuron’s cup of tRNA. Trends Neurosci. 33, 59–66 (2010).
Storkebaum, E. Peripheral neuropathy via mutant tRNA synthetases: Inhibition of protein translation provides a possible explanation. Bioessays 38, 818–829 (2016).
He, W. et al. CMT2D neuropathy is linked to the neomorphic binding activity of glycyl-tRNA synthetase. Nature 526, 710–714 (2015). This study demonstrates the gain-of-function mutation in GRS and its role in disease development.
Schwarz, Q. et al. Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. Genes Dev. 18, 2822–2834 (2004).
Mo, Z. et al. Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy. Nat. Commun. 9, 1007 (2018).
Sleigh, J. N. et al. Trk receptor signaling and sensory neuron fate are perturbed in human neuropathy caused by Gars mutations. Proc. Natl Acad. Sci. USA 114, E3324–E3333 (2017).
Kunst, C. B., Mezey, E., Brownstein, M. J. & Patterson, D. Mutations in SOD1 associated with amyotrophic lateral sclerosis cause novel protein interactions. Nat. Genet. 15, 91–94 (1997).
Kawamata, H., Magrane, J., Kunst, C., King, M. P. & Manfredi, G. Lysyl-tRNA synthetase is a target for mutant SOD1 toxicity in mitochondria. J. Biol. Chem. 283, 28321–28328 (2008).
Kwon, N. H. et al. Stabilization of cyclin-dependent kinase 4 by methionyl-tRNA synthetase in p16INK4a-negative cancer. ACS Pharmacol. Transl Sci. 1, 21–31 (2018). This study describes the little effect of reduced level of MRS on translation under normal conditions and the novel function of MRS in cell cycle regulation.
Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).
Lee, Y. et al. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat. Neurosci. 16, 1392–1400 (2013). This study demonstrates the gain of function of AIMP2 mediated by the mutation in its binding partners and its relationship to disease phenotype.
Ko, H. S. et al. Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death. J. Neurosci. 25, 7968–7978 (2005).
David, K. K., Andrabi, S. A., Dawson, T. M. & Dawson, V. L. Parthanatos, a messenger of death. Front. Biosci. (Landmark Ed.) 14, 1116–1128 (2009).
Choi, J. W. et al. AIMP2 promotes TNFalpha-dependent apoptosis via ubiquitin-mediated degradation of TRAF2. J. Cell Sci. 122, 2710–2715 (2009).
Choi, J. W. et al. Splicing variant of AIMP2 as an effective target against chemoresistant ovarian cancer. J. Mol. Cell. Biol. 4, 164–173 (2012).
Oh, A. Y. et al. Inhibiting DX2-p14/ARF interaction exerts antitumor effects in lung cancer and delays tumor progression. Cancer Res. 76, 4791–4804 (2016).
Lega, J. C. et al. The clinical phenotype associated with myositis-specific and associated autoantibodies: a meta-analysis revisiting the so-called antisynthetase syndrome. Autoimmun. Rev. 13, 883–891 (2014).
Cavagna, L. et al. Serum Jo-1 autoantibody and isolated arthritis in the antisynthetase syndrome: review of the literature and report of the experience of AENEAS Collaborative Group. Clin. Rev. Allergy Immunol. 52, 71–80 (2017).
Zhou, J. J. et al. Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis. J. Biol. Chem. 289, 19269–19275 (2014).
Park, M. C. et al. Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis. Proc. Natl Acad. Sci. USA 109, E640–E647 (2012).
Fischer, A. et al. Anti-synthetase syndrome in ANA and anti-Jo-1 negative patients presenting with idiopathic interstitial pneumonia. Respir. Med. 103, 1719–1724 (2009).
Hughes, J. & Mellows, G. Interaction of pseudomonic acid A with Escherichia coli B isoleucyl-tRNA synthetase. Biochem. J. 191, 209–219 (1980).
Elewski, B. E. et al. Efficacy and safety of tavaborole topical solution, 5%, a novel boron-based antifungal agent, for the treatment of toenail onychomycosis: results from 2 randomized phase-III studies. J. Am. Acad. Dermatol. 73, 62–69 (2015). This study presents the results from two clinical trials assessing AN2690.
Hui, X. et al. In vitro penetration of a novel oxaborole antifungal (AN2690) into the human nail plate. J. Pharm. Sci. 96, 2622–2631 (2007).
Rock, F. L. et al. An antifungal agent inhibits an aminoacyl-tRNA synthetase by trapping tRNA in the editing site. Science 316, 1759–1761 (2007).
Yao, P. et al. Unique residues crucial for optimal editing in yeast cytoplasmic Leucyl-tRNA synthetase are revealed by using a novel knockout yeast strain. J. Biol. Chem. 283, 22591–22600 (2008).
Pang, Y. L. & Martinis, S. A. A paradigm shift for the amino acid editing mechanism of human cytoplasmic leucyl-tRNA synthetase. Biochemistry 48, 8958–8964 (2009).
Palencia, A. et al. Cryptosporidium and toxoplasma parasites are inhibited by a benzoxaborole targeting leucyl-tRNA synthetase. Antimicrob. Agents Chemother. 60, 5817–5827 (2016).
Li, X. et al. Discovery of a potent and specific M. tuberculosis leucyl-tRNA synthetase inhibitor: (S)-3-(aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3 H)-ol (GSK656). J. Med. Chem. 60, 8011–8026 (2017).
Hernandez, V. et al. Discovery of a novel class of boron-based antibacterials with activity against gram-negative bacteria. Antimicrob. Agents Chemother. 57, 1394–1403 (2013).
Kato, N. et al. Diversity-oriented synthesis yields novel multistage antimalarial inhibitors. Nature 538, 344–349 (2016).
Keller, T. L. et al. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat. Chem. Biol. 8, 311–317 (2012).
Zhou, H., Sun, L., Yang, X. L. & Schimmel, P. ATP-directed capture of bioactive herbal-based medicine on human tRNA synthetase. Nature 494, 121–124 (2013). This study demonstrates the binding mode of halofuginone in PRS.
Sundrud, M. S. et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324, 1334–1338 (2009).
Park, J. S. et al. Inhibition of prolyl-tRNA Synthetase as a novel mediator of cardiac fibrosis [abstract]. Am. Heart Associ. 136 (Suppl. 1), A24036 (2017).
Fang, P. et al. Structural basis for full-spectrum inhibition of translational functions on a tRNA synthetase. Nat. Commun. 6, 6402 (2015). This study shows the structure-based interaction between borrelidin and TRS.
Wang, X., Lan, H., Li, J., Su, Y. & Xu, L. Muc1 promotes migration and lung metastasis of melanoma cells. Am. J. Cancer Res. 5, 2590–2604 (2015).
Funahashi, Y. et al. Establishment of a quantitative mouse dorsal air sac model and its application to evaluate a new angiogenesis inhibitor. Oncol. Res. 11, 319–329 (1999).
Taft, R. J. et al. Mutations in DARS cause hypomyelination with brain stem and spinal cord involvement and leg spasticity. Am. J. Hum. Genet. 92, 774–780 (2013).
Hu, J. et al. Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nat. Biotechnol. 31, 522–529 (2013).
Dobbelstein, M. & Moll, U. Targeting tumour-supportive cellular machineries in anticancer drug development. Nat. Rev. Drug Discov. 13, 179–196 (2014).
Luo, J., Solimini, N. L. & Elledge, S. J. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823–837 (2009).
Kim, J. H. et al. Control of leucine-dependent mTORC1 pathway through chemical intervention of leucyl-tRNA synthetase and RagD interaction. Nat. Commun. 8, 732 (2017). This study demonstrates how LRS inhibitors regulate mTORC1 signalling.
Bae, S. et al. in 2018 Fall International Convention of The Pharmaceutical Society of Korea P6-72 (The Pharmaceutical Society of Korea, 2018).
Son, S. H., Park, M. C. & Kim, S. Extracellular activities of aminoacyl-tRNA synthetases: new mediators for cell-cell communication. Top. Curr. Chem. 344, 145–166 (2014).
aTyr Pharma. ATYR1923: about ATYR1923. aTyrPharma https://www.atyrpharma.com/programs/atyr1923/ (2019).
aTyr Pharma. Interstitial lung disease and the immune system: introduction to the iMod.Fc program. aTyrPharma https://investors.atyrpharma.com/static-files/f5cf2a36-e7a2-4bcb-8cac-189b08dc5f89 (2017).
Australian New Zealand Clinical Trials Registry. A randomized, double-blind, placebo-controlled study to investigate the safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics of single doses of intravenous ATYR1923 in healthy volunteers (registration number: ACTRN12617001446358). ANZCTR https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373652 (2018).
Albericio, F. & Kruger, H. G. Therapeutic peptides. Future Med. Chem. 4, 1527–1531 (2012).
Fosgerau, K. & Hoffmann, T. Peptide therapeutics: current status and future directions. Drug. Discov. Today 20, 122–128 (2015).
Han, J. M., Myung, H. & Kim, S. Antitumor activity and pharmacokinetic properties of ARS-interacting multi-functional protein 1 (AIMP1/p43). Cancer Lett. 287, 157–164 (2010).
Lee, Y. S. et al. Antitumor activity of the novel human cytokine AIMP1 in an in vivo tumor model. Mol. Cells 21, 213–217 (2006).
Park, S. G. et al. Dose-dependent biphasic activity of tRNA synthetase-associating factor, p43, in angiogenesis. J. Biol. Chem. 277, 45243–45248 (2002).
Park, S. G. et al. Hormonal activity of AIMP1/p43 for glucose homeostasis. Proc. Natl Acad. Sci. USA 103, 14913–14918 (2006).
Park, S. G. et al. The novel cytokine p43 stimulates dermal fibroblast proliferation and wound repair. Am. J. Pathol. 166, 387–398 (2005).
Kim, S. Y. et al. ARS-interacting multi-functional protein 1 induces proliferation of human bone marrow-derived mesenchymal stem cells by accumulation of beta-catenin via fibroblast growth factor receptor 2-mediated activation of Akt. Stem Cells Dev. 22, 2630–2640 (2013).
Kwon, H. S. et al. Identification of CD23 as a functional receptor for the proinflammatory cytokine AIMP1/p43. J. Cell Sci. 125, 4620–4629 (2012).
Hong, S. H. et al. The antibody atliximab attenuates collagen-induced arthritis by neutralizing AIMP1, an inflammatory cytokine that enhances osteoclastogenesis. Biomaterials 44, 45–54 (2015).
Pines, M. & Spector, I. Halofuginone - the multifaceted molecule. Molecules 20, 573–594 (2015).
Neenan, T. X., Burrier, R. E. & Kim, S. Biocon’s target factory. Nat. Biotechnol. 36, 791–797 (2018).
Beebe, K., Waas, W., Druzina, Z., Guo, M. & Schimmel, P. A universal plate format for increased throughput of assays that monitor multiple aminoacyl transfer RNA synthetase activities. Anal. Biochem. 368, 111–121 (2007).
Cestari, I. & Stuart, K. A spectrophotometric assay for quantitative measurement of aminoacyl-tRNA synthetase activity. J. Biomol. Screen. 18, 490–497 (2013).
Lloyd, A. J., Thomann, H. U., Ibba, M. & Soll, D. A broadly applicable continuous spectrophotometric assay for measuring aminoacyl-tRNA synthetase activity. Nucleic Acids Res. 23, 2886–2892 (1995).
Wu, M. X. & Hill, K. A. A continuous spectrophotometric assay for the aminoacylation of transfer RNA by alanyl-transfer RNA synthetase. Anal. Biochem. 211, 320–323 (1993).
Brennan, J. D., Hogue, C. W., Rajendran, B., Willis, K. J. & Szabo, A. G. Preparation of enantiomerically pure L-7-azatryptophan by an enzymatic method and its application to the development of a fluorimetric activity assay for tryptophanyl-tRNA synthetase. Anal. Biochem. 252, 260–270 (1997).
Kong, J. et al. High-throughput screening for protein synthesis inhibitors targeting aminoacyl-tRNA synthetases. SLAS Discov. 23, 174–182 (2018).
Cochrane, R. V. K., Norquay, A. K. & Vederas, J. C. Natural products and their derivatives as tRNA synthetase inhibitors and antimicrobial agents. Medchemcomm 7, 1535–1545 (2016).
Han, J. M. et al. Identification of gp96 as a novel target for treatment of autoimmune disease in mice. PLOS ONE 5, e9792 (2010).
Kong, J., Kim, D. G., Ahn, H., Kwon, N. H. & Kim, S. in 26th tRNA Conference P52 (Biocon, 2016).
Arkin, M. R., Tang, Y. & Wells, J. A. Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem. Biol. 21, 1102–1114 (2014).
Shin, S. M. et al. Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration. Nat. Commun. 8, 15090 (2017).
Che Nordin, M. A. & Teow, S. Y. Review of current cell-penetrating antibody developments for HIV-1 therapy. Molecules 23, 335 (2018).
Irwin, M. J., Nyborg, J., Reid, B. R. & Blow, D. M. The crystal structure of tyrosyl-transfer RNA synthetase at 2–7 A resolution. J. Mol. Biol. 105, 577–586 (1976).
Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101–114 (2017).
Jia, J. et al. Mechanisms of drug combinations: interaction and network perspectives. Nat. Rev. Drug Discov. 8, 111–128 (2009).
Holohan, C., Van Schaeybroeck, S., Longley, D. B. & Johnston, P. G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13, 714–726 (2013).
Marston, H. D., Dixon, D. M., Knisely, J. M., Palmore, T. N. & Fauci, A. S. Antimicrobial resistance. JAMA 316, 1193–1204 (2016).
O’Dwyer, K. et al. Bacterial resistance to leucyl-tRNA synthetase inhibitor GSK2251052 develops during treatment of complicated urinary tract infections. Antimicrob. Agents Chemother. 59, 289–298 (2015).
Zeng, R. et al. Inhibition of mini-TyrRS-induced angiogenesis response in endothelial cells by VE-cadherin-dependent mini-TrpRS. Heart Vessels 27, 193–201 (2012).
Dewan, V., Reader, J. & Forsyth, K. M. Role of aminoacyl-tRNA synthetases in infectious diseases and targets for therapeutic development. Top. Curr. Chem. 344, 293–329 (2014).
Nakama, T., Nureki, O. & Yokoyama, S. Structural basis for the recognition of isoleucyl-adenylate and an antibiotic, mupirocin, by isoleucyl-tRNA synthetase. J. Biol. Chem. 276, 47387–47393 (2001).
Hoepfner, D. et al. Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA synthetase by the fungal secondary metabolite cladosporin. Cell Host Microbe 11, 654–663 (2012).
Fang, P. et al. Structural basis for specific inhibition of tRNA synthetase by an ATP competitive inhibitor. Chem. Biol. 22, 734–744 (2015).
Mirando, A. C. et al. Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor. Sci. Rep. 5, 13160 (2015).
Woolard, J. et al. Borrelidin modulates the alternative splicing of VEGF in favour of anti-angiogenic isoforms. Chem. Sci. 2011, 273–278 (2011).
Novoa, E. M. et al. Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo. Proc. Natl Acad. Sci. USA 111, E5508–E5517 (2014). This study demonstrates the optimization process of borrelidin with reduced toxicity and enhanced efficacy.
Sugawara, A. et al. Borrelidin analogues with antimalarial activity: design, synthesis and biological evaluation against Plasmodium falciparum parasites. Bioorg. Med. Chem. Lett. 23, 2302–2305 (2013).
Kim, J. H., Han, J. M. & Kim, S. Protein-protein interactions and multi-component complexes of aminoacyl-tRNA synthetases. Top. Curr. Chem. 344, 119–144 (2014).
Lee, S. W., Cho, B. H., Park, S. G. & Kim, S. Aminoacyl-tRNA synthetase complexes: beyond translation. J. Cell Sci. 117, 3725–3734 (2004).
McLaughlin, H. M. et al. A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N). Hum. Mutat. 33, 244–253 (2012).
Zhao, Z. et al. Alanyl-tRNA synthetase mutation in a family with dominant distal hereditary motor neuropathy. Neurology 78, 1644–1649 (2012).
Motley, W. W. et al. A novel AARS mutation in a family with dominant myeloneuropathy. Neurology 84, 2040–2047 (2015).
Nakayama, T. et al. Deficient activity of alanyl-tRNA synthetase underlies an autosomal recessive syndrome of progressive microcephaly, hypomyelination, and epileptic encephalopathy. Hum. Mutat. 38, 1348–1354 (2017).
Vester, A. et al. A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo. Hum. Mutat. 34, 191–199 (2013).
McLaughlin, H. M. et al. Compound heterozygosity for loss-of-function lysyl-tRNA synthetase mutations in a patient with peripheral neuropathy. Am. J. Hum. Genet. 87, 560–566 (2010).
Hadchouel, A. et al. Biallelic mutations of methionyl-tRNA synthetase cause a specific type of pulmonary alveolar proteinosis prevalent on reunion island. Am. J. Hum. Genet. 96, 826–831 (2015).
Musante, L. et al. Mutations of the aminoacyl-tRNA-synthetases SARS and WARS2 are implicated in the etiology of autosomal recessive intellectual disability. Hum. Mutat. 38, 621–636 (2017).
Stephen, J. et al. Loss of function mutations in VARS encoding cytoplasmic valyl-tRNA synthetase cause microcephaly, seizures, and progressive cerebral atrophy. Hum. Genet. 137, 293–303 (2018).
Khan, S. Recent advances in the biology and drug targeting of malaria parasite aminoacyl-tRNA synthetases. Malar. J. 15, 203 (2016).
Van de Vijver, P. et al. Synthetic microcin C analogs targeting different aminoacyl-tRNA synthetases. J. Bacteriol. 191, 6273–6280 (2009).
Petraitis, V. et al. Efficacy of PLD-118, a novel inhibitor of candida isoleucyl-tRNA synthetase, against experimental oropharyngeal and esophageal candidiasis caused by fluconazole-resistant C. albicans. Antimicrob. Agents Chemother. 48, 3959–3967 (2004).
Cochrane, R. V. et al. Production of new cladosporin analogues by reconstitution of the polyketide synthases responsible for the biosynthesis of this antimalarial agent. Angew. Chem. Int. Ed. Engl. 55, 664–668 (2016).
Yoon, S. et al. Discovery of leucyladenylate sulfamates as novel leucyl-tRNA synthetase (LRS)-targeted mammalian target of rapamycin complex 1 (mTORC1) inhibitors. J. Med. Chem. 59, 10322–10328 (2016).
Sonoiki, E. et al. Antimalarial benzoxaboroles target Plasmodium falciparum leucyl-tRNA synthetase. Antimicrob. Agents Chemother. 60, 4886–4895 (2016).
Bharathkumar, H. et al. Screening of quinoline, 1,3-benzoxazine, and 1,3-oxazine-based small molecules against isolated methionyl-tRNA synthetase and A549 and HCT116 cancer cells including an in silico binding mode analysis. Org. Biomol. Chem. 13, 9381–9387 (2015).
Nayak, S. U. et al. Safety, tolerability, systemic exposure, and metabolism of CRS3123, a methionyl-tRNA synthetase inhibitor developed for treatment of Clostridium difficile, in a phase 1 study. Antimicrob. Agents Chemother. 61, e02760-16 (2017).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02106338 (2016).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT01551004 (2017).
Yu, Z., Vodanovic-Jankovic, S., Kron, M. & Shen, B. New WS9326A congeners from Streptomyces sp. 9078 inhibiting Brugia malayi asparaginyl-tRNA synthetase. Org. Lett. 14, 4946–4949 (2012).
Shibata, A. et al. Discovery and pharmacological characterization of a new class of prolyl-tRNA synthetase inhibitor for anti-fibrosis therapy. PLOS ONE 12, e0186587 (2017).
Lin, Z. et al. Total synthesis and antimicrobial evaluation of natural albomycins against clinical pathogens. Nat. Commun. 9, 3445 (2018).
Brown, P. et al. Synthetic analogues of SB-219383. Novel C-glycosyl peptides as inhibitors of tyrosyl tRNA synthetase. Bioorg. Med. Chem. Lett. 11, 711–714 (2001).
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.
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.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
aTyr Pharma: http://www.atyrpharma.com
Bioxiness Pharmaceuticals: http://bioxiness.com/en
Clinical Trials website: www.clinicaltrials.gov
Exosome protein, RNA and lipid database: http://exocarta.org
Max-Planck Unified Proteome Database: http://www.mapuproteome.com/
Open Targets Platform: https://www.targetvalidation.org
The Human Protein Atlas: https://www.proteinatlas.org
The Online Mendelian Inheritance in Man (OMIM) database: https://omim.org/
Urinary Protein Biomarker Database: http://upbd.bmicc.cn
Urine Proteomics: http://www.urineproteomics.org
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.
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.
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.
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.
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.
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.
About this article
Cite this article
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
Liver International (2021)
Re-discovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis
Journal of Biological Chemistry (2021)
Structural Insights into the Binding of Natural Pyrimidine-Based Inhibitors of Class II Aminoacyl-tRNA Synthetases
ACS Chemical Biology (2020)
Synthesis and Structure–Activity Relationships of Arylsulfonamides as AIMP2-DX2 Inhibitors for the Development of a Novel Anticancer Therapy
Journal of Medicinal Chemistry (2020)
Cell Death & Disease (2020)