Journal articles: 'AARS2'

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Lakshmanan, Rahul, Matthew E. Adams, David S. Lynch, Justin A. Kinsella, Rahul Phadke, Jonathan M. Schott, Elaine Murphy, et al. "Redefining the phenotype of ALSP and AARS2 mutation–related leukodystrophy." Neurology Genetics 3, no. 2 (February 15, 2017): e135. http://dx.doi.org/10.1212/nxg.0000000000000135.

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Objective:To provide an overview of the phenotype of 2 clinically, radiologically, and pathologically similar leukodystrophies, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and alanyl-transfer RNA synthetase 2 mutation–related leukodystrophy (AARS2-L), and highlight key differentiating features.Methods:ALSP and AARS2-L cases were identified from the adult-onset leukodystrophy database at our institution. In addition, cases with imaging findings were identified from a literature review. The phenotypic features were determined by combining published cases with those from our database.Results:A combined total of 74 cases of ALSP and 10 cases of AARS2-L with neuroimaging data were identified. The mean age at onset was 42 years in ALSP and 26 years in AARS2-L. Cognitive and motor symptoms were the most common symptoms overall in both. Ovarian failure was exclusive to AARS2-L, present in all known female cases. Both ALSP and AARS2-L showed a confluent, asymmetric, predominantly frontoparietal, periventricular pattern of white matter disease with subcortical U-fiber sparing; pyramidal tract and corpus callosum involvement; and diffusion changes in the white matter which we have termed “deep white matter diffusion dots.” Central atrophy and corpus callosal thinning were prominent in ALSP and disproportionately mild in AARS2-L when present. ALSP also occasionally showed ventricular abnormalities and calcifications in the frontal periventricular white matter, features not seen in AARS2-L. AARS2-L demonstrates white matter rarefaction which suppresses on fluid-attenuated inversion recovery MRI sequences, a feature not seen in ALSP.Conclusions:ALSP and AARS2-L share similar clinical, imaging, and pathologic characteristics with key differentiating features that we have highlighted.

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Axelsen, Tobias Melton, Tzvetelina Lubenova Vammen, Mads Bak, Nelsan Pourhadi, Christian Midtgaard Stenør, and Sabine Grønborg. "Case report: ‘AARS2 leukodystrophy’." Molecular Genetics and Metabolism Reports 28 (September 2021): 100782. http://dx.doi.org/10.1016/j.ymgmr.2021.100782.

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Bhardwaj, Priya, Christoffer Rasmus Vissing, Niels Kjær Stampe, Kasper Rossing, Alex Hørby Christensen, Thomas Hartvig Lindkær Jensen, and Bo Gregers Winkel. "Reassessment of Gene-Elusive Familial Dilated Cardiomyopathy Leading to the Discovery of a Homozygous AARS2 Variant—The Importance of Regular Reassessment of Genetic Findings." Cardiogenetics 11, no. 3 (July 23, 2021): 122–28. http://dx.doi.org/10.3390/cardiogenetics11030013.

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Background: AARS2 encodes the mitochondrial protein alanyl-tRNA synthetase 2 (MT-AlaRS), an important enzyme in oxidative phosphorylation. Variants in AARS2 have previously been associated with infantile cardiomyopathy. Case summary: A 4-year-old girl died of infantile-onset dilated cardiomyopathy (DCM) in 1996. Fifteen years later, her 21-year-old brother was diagnosed with DCM and ultimately underwent heart transplantation. Initial sequencing of 15 genes discovered no pathogenic variants in the brother at the time of his diagnosis. However, 9 years later re-screening in an updated screening panel of 129 genes identified a homozygous AARS2 (c.1774C > T) variant. Sanger sequencing of the deceased girl confirmed her to be homozygous for the AARS2 variant, while both parents and a third sibling were all found to be unaffected heterozygous carriers of the AARS2 variant. Discussion: This report underlines the importance of repeated and extended genetic screening of elusive families with suspected hereditary cardiomyopathies, as our knowledge of disease-causing mutations continuously grows. Although identification of the genetic etiology in the reported family would not have changed the clinical management, the genetic finding allows genetic counselling and holds substantial value in identifying at-risk relatives.

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Dallabona, C., D. Diodato, S. H. Kevelam, T. B. Haack, L. J. Wong, G. S. Salomons, E. Baruffini, et al. "Novel (ovario) leukodystrophy related to AARS2 mutations." Neurology 82, no. 23 (May 7, 2014): 2063–71. http://dx.doi.org/10.1212/wnl.0000000000000497.

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Parra, Sahyli Perez, Stephan H. Heckers, William R. Wilcox, Colin David Mcknight, and H. A. Jinnah. "The emerging neurological spectrum of AARS2-associated disorders." Parkinsonism & Related Disorders 93 (December 2021): 50–54. http://dx.doi.org/10.1016/j.parkreldis.2021.10.031.

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van der Knaap, Marjo S., and Truus E. M. Abbink. "Ovarioleukodystrophy: Vanishing white matter versus AARS2-related ovarioleukodystrophy." Clinical Neurology and Neurosurgery 171 (August 2018): 195. http://dx.doi.org/10.1016/j.clineuro.2018.06.024.

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Szpisjak, Laszlo, Nora Zsindely, Jozsef I. Engelhardt, Laszlo Vecsei, Gabor G. Kovacs, and Peter Klivenyi. "Novel AARS2 gene mutation producing leukodystrophy: a case report." Journal of Human Genetics 62, no. 2 (October 13, 2016): 329–33. http://dx.doi.org/10.1038/jhg.2016.126.

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Kuo, Molly E., Anthony Antonellis, and Vikram G. Shakkottai. "Alanyl-tRNA Synthetase 2 (AARS2)-Related Ataxia Without Leukoencephalopathy." Cerebellum 19, no. 1 (November 9, 2019): 154–60. http://dx.doi.org/10.1007/s12311-019-01080-y.

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Taglia, I., I. Di Donato, S. Bianchi, A. Cerase, L. Monti, R. Marconi, A. Orrico, A. Rufa, A. Federico, and M. T. Dotti. "AARS2-related ovarioleukodystrophy: Clinical and neuroimaging features of three new cases." Acta Neurologica Scandinavica 138, no. 4 (May 10, 2018): 278–83. http://dx.doi.org/10.1111/ane.12954.

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10

Bruwer, Zandrè, Nihal Al Riyami, Tamima Al Dughaishi, Fathiya Al Murshedi, Abeer Al Sayegh, Adila Al Kindy, Douja Meftah, et al. "Inborn errors of metabolism in a cohort of pregnancies with non-immune hydrops fetalis: a single center experience." Journal of Perinatal Medicine 46, no. 9 (November 27, 2018): 968–74. http://dx.doi.org/10.1515/jpm-2017-0124.

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Abstract Objective: The purpose of this study was to determine the frequency of non-immune hydrops fetalis (NIHF) among all pregnancies referred for prenatal care at Sultan Qaboos University Hospital (SQUH) during the study period and to evaluate the underlying etiologies of NIH. Study design: All pregnancies referred to SQUH between February 2014 and December 2015 were identified, and all pregnancies meeting the diagnosis of NIHF were included in this study. All cases of NIHF referred to our center during this period underwent standard systematic diagnostic work-up that included biochemical and molecular studies in addition to the standard investigations for hydrops fetalis. Clinical characteristics and results of the diagnostic work-up were retrospectively reviewed. Results: A total of 3234 pregnancies were referred for prenatal care at SQUH during the study period, and 12 pregnancies were affected by NIHF. An underlying diagnosis was established in nine cases, and the majority of cases (7/9) were caused by inborn errors of metabolism (IEM). These included a novel homozygous variant in the AARS2 gene (5/7) and two cases of galactosialidosis (2/7). Conclusion: IEM was a major cause of NIHF in this cohort. The AARS2 variant accounts for a significant number of cases with NIHF in this cohort of Omani patients.

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Saga, Yusuke, Moeka Kawashima, Shiho Sakai, Kaori Yamazaki, Misato Kaneko, Moeka Takahashi, Natsuko Sato, et al. "Plant-Specific Domains and Fragmented Sequences Imply Non-Canonical Functions in Plant Aminoacyl-tRNA Synthetases." Genes 11, no. 9 (September 7, 2020): 1056. http://dx.doi.org/10.3390/genes11091056.

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Aminoacyl-tRNA synthetases (aaRSs) play essential roles in protein translation. In addition, numerous aaRSs (mostly in vertebrates) have also been discovered to possess a range of non-canonical functions. Very few studies have been conducted to elucidate or characterize non-canonical functions of plant aaRSs. A genome-wide search for aaRS genes in Arabidopsis thaliana revealed a total of 59 aaRS genes. Among them, asparaginyl-tRNA synthetase (AsnRS) was found to possess a WHEP domain inserted into the catalytic domain in a plant-specific manner. This insertion was observed only in the cytosolic isoform. In addition, a long stretch of sequence that exhibited weak homology with histidine ammonia lyase (HAL) was found at the N-terminus of histidyl-tRNA synthetase (HisRS). This HAL-like domain has only been seen in plant HisRS, and only in cytosolic isoforms. Additionally, a number of genes lacking minor or major portions of the full-length aaRS sequence were found. These genes encode 14 aaRS fragments that lack key active site sequences and are likely catalytically null. These identified genes that encode plant-specific additional domains or aaRS fragment sequences are candidates for aaRSs possessing non-canonical functions.

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Peragallo, Jason H., Stephanie Keller, Marjo S. van der Knaap, Bruno P. Soares, and Suma P. Shankar. "Retinopathy and optic atrophy: Expanding the phenotypic spectrum of pathogenic variants in the AARS2 gene." Ophthalmic Genetics 39, no. 1 (August 18, 2017): 99–102. http://dx.doi.org/10.1080/13816810.2017.1350723.

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Sharaf, Gruber, Jiroutová, and Oborník. "Characterization of Aminoacyl-tRNA Synthetases in Chromerids." Genes 10, no. 8 (July 31, 2019): 582. http://dx.doi.org/10.3390/genes10080582.

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Aminoacyl-tRNA synthetases (AaRSs) are enzymes that catalyze the ligation of tRNAs to amino acids. There are AaRSs specific for each amino acid in the cell. Each cellular compartment in which translation takes place (the cytosol, mitochondria, and plastids in most cases), needs the full set of AaRSs; however, individual AaRSs can function in multiple compartments due to dual (or even multiple) targeting of nuclear-encoded proteins to various destinations in the cell. We searched the genomes of the chromerids, Chromera velia and Vitrella brassicaformis, for AaRS genes: 48 genes encoding AaRSs were identified in C. velia, while only 39 AaRS genes were found in V. brassicaformis. In the latter alga, ArgRS and GluRS were each encoded by a single gene occurring in a single copy; only PheRS was found in three genes, while the remaining AaRSs were encoded by two genes. In contrast, there were nine cases for which C. velia contained three genes of a given AaRS (45% of the AaRSs), all of them representing duplicated genes, except AsnRS and PheRS, which are more likely pseudoparalogs (acquired via horizontal or endosymbiotic gene transfer). Targeting predictions indicated that AaRSs are not (or not exclusively), in most cases, used in the cellular compartment from which their gene originates. The molecular phylogenies of the AaRSs are variable between the specific types, and similar between the two investigated chromerids. While genes with eukaryotic origin are more frequently retained, there is no clear pattern of orthologous pairs between C. velia and V. brassicaformis.

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Wang, Justin, Ingrid Vallee, Aditi Dutta, Yu Wang, Zhongying Mo, Ze Liu, Haissi Cui, Andrew I. Su, and Xiang-Lei Yang. "Multi-Omics Database Analysis of Aminoacyl-tRNA Synthetases in Cancer." Genes 11, no. 11 (November 22, 2020): 1384. http://dx.doi.org/10.3390/genes11111384.

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Aminoacyl-tRNA synthetases (aaRSs) are key enzymes in the mRNA translation machinery, yet they possess numerous non-canonical functions developed during the evolution of complex organisms. The aaRSs and aaRS-interacting multi-functional proteins (AIMPs) are continually being implicated in tumorigenesis, but these connections are often limited in scope, focusing on specific aaRSs in distinct cancer subtypes. Here, we analyze publicly available genomic and transcriptomic data on human cytoplasmic and mitochondrial aaRSs across many cancer types. As high-throughput technologies have improved exponentially, large-scale projects have systematically quantified genetic alteration and expression from thousands of cancer patient samples. One such project is the Cancer Genome Atlas (TCGA), which processed over 20,000 primary cancer and matched normal samples from 33 cancer types. The wealth of knowledge provided from this undertaking has streamlined the identification of cancer drivers and suppressors. We examined aaRS expression data produced by the TCGA project and combined this with patient survival data to recognize trends in aaRSs’ impact on cancer both molecularly and prognostically. We further compared these trends to an established tumor suppressor and a proto-oncogene. We observed apparent upregulation of many tRNA synthetase genes with aggressive cancer types, yet, at the individual gene level, some aaRSs resemble a tumor suppressor while others show similarities to an oncogene. This study provides an unbiased, overarching perspective on the relationship of aaRSs with cancers and identifies certain aaRS family members as promising therapeutic targets or potential leads for developing biological therapy for cancer.

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Hamatani, Mio, Naoto Jingami, Yoshinori Tsurusaki, Shino Shimada, Keiko Shimojima, Megumi Asada-Utsugi, Kenji Yoshinaga, et al. "The first Japanese case of leukodystrophy with ovarian failure arising from novel compound heterozygous AARS2 mutations." Journal of Human Genetics 61, no. 10 (June 2, 2016): 899–902. http://dx.doi.org/10.1038/jhg.2016.64.

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Woese, Carl R., Gary J. Olsen, Michael Ibba, and Dieter Söll. "Aminoacyl-tRNA Synthetases, the Genetic Code, and the Evolutionary Process." Microbiology and Molecular Biology Reviews 64, no. 1 (March 1, 2000): 202–36. http://dx.doi.org/10.1128/mmbr.64.1.202-236.2000.

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SUMMARY The aminoacyl-tRNA synthetases (AARSs) and their relationship to the genetic code are examined from the evolutionary perspective. Despite a loose correlation between codon assignments and AARS evolutionary relationships, the code is far too highly structured to have been ordered merely through the evolutionary wanderings of these enzymes. Nevertheless, the AARSs are very informative about the evolutionary process. Examination of the phylogenetic trees for each of the AARSs reveals the following. (i) Their evolutionary relationships mostly conform to established organismal phylogeny: a strong distinction exists between bacterial- and archaeal-type AARSs. (ii) Although the evolutionary profiles of the individual AARSs might be expected to be similar in general respects, they are not. It is argued that these differences in profiles reflect the stages in the evolutionary process when the taxonomic distributions of the individual AARSs became fixed, not the nature of the individual enzymes. (iii) Horizontal transfer of AARS genes between Bacteria and Archaea is asymmetric: transfer of archaeal AARSs to the Bacteria is more prevalent than the reverse, which is seen only for the “gemini group.” (iv) The most far-ranging transfers of AARS genes have tended to occur in the distant evolutionary past, before or during formation of the primary organismal domains. These findings are also used to refine the theory that at the evolutionary stage represented by the root of the universal phylogenetic tree, cells were far more primitive than their modern counterparts and thus exchanged genetic material in far less restricted ways, in effect evolving in a communal sense.

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Crnković, Ana, Oscar Vargas-Rodriguez, and Dieter Söll. "Plasticity and Constraints of tRNA Aminoacylation Define Directed Evolution of Aminoacyl-tRNA Synthetases." International Journal of Molecular Sciences 20, no. 9 (May 9, 2019): 2294. http://dx.doi.org/10.3390/ijms20092294.

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Genetic incorporation of noncanonical amino acids (ncAAs) has become a powerful tool to enhance existing functions or introduce new ones into proteins through expanded chemistry. This technology relies on the process of nonsense suppression, which is made possible by directing aminoacyl-tRNA synthetases (aaRSs) to attach an ncAA onto a cognate suppressor tRNA. However, different mechanisms govern aaRS specificity toward its natural amino acid (AA) substrate and hinder the engineering of aaRSs for applications beyond the incorporation of a single l-α-AA. Directed evolution of aaRSs therefore faces two interlinked challenges: the removal of the affinity for cognate AA and improvement of ncAA acylation. Here we review aspects of AA recognition that directly influence the feasibility and success of aaRS engineering toward d- and β-AAs incorporation into proteins in vivo. Emerging directed evolution methods are described and evaluated on the basis of aaRS active site plasticity and its inherent constraints.

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Wang, Danqing, Meng Yu, Wei Zhang, Zhaoxia Wang, and Yun Yuan. "AARS2 Compound Heterozygous Variants in a Case of Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia." Journal of Neuropathology & Experimental Neurology 77, no. 11 (September 3, 2018): 997–1000. http://dx.doi.org/10.1093/jnen/nly087.

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Zhou, Yiran, Beili Chen, Lin Li, Hong Pan, Beihong Liu, Tengyan Li, Ruyi Wang, Xu Ma, Binbin Wang, and Yunxia Cao. "Novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation in a consanguineous Chinese family with premature ovarian insufficiency." Fertility and Sterility 112, no. 3 (September 2019): 569–76. http://dx.doi.org/10.1016/j.fertnstert.2019.05.005.

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Pang, Luping, Stephen D. Weeks, and Arthur Van Aerschot. "Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery." International Journal of Molecular Sciences 22, no. 4 (February 10, 2021): 1750. http://dx.doi.org/10.3390/ijms22041750.

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Aminoacyl-tRNA synthetases (aaRSs) catalyze the esterification of tRNA with a cognate amino acid and are essential enzymes in all three kingdoms of life. Due to their important role in the translation of the genetic code, aaRSs have been recognized as suitable targets for the development of small molecule anti-infectives. In this review, following a concise discussion of aaRS catalytic and proof-reading activities, the various inhibitory mechanisms of reported natural and synthetic aaRS inhibitors are discussed. Using the expanding repository of ligand-bound X-ray crystal structures, we classified these compounds based on their binding sites, focusing on their ability to compete with the association of one, or more of the canonical aaRS substrates. In parallel, we examined the determinants of species-selectivity and discuss potential resistance mechanisms of some of the inhibitor classes. Combined, this structural perspective highlights the opportunities for further exploration of the aaRS enzyme family as antimicrobial targets.

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Carter, Charles W., and Peter R. Wills. "The Roots of Genetic Coding in Aminoacyl-tRNA Synthetase Duality." Annual Review of Biochemistry 90, no. 1 (June 20, 2021): 349–73. http://dx.doi.org/10.1146/annurev-biochem-071620-021218.

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Codon-dependent translation underlies genetics and phylogenetic inferences, but its origins pose two challenges. Prevailing narratives cannot account for the fact that aminoacyl-tRNA synthetases (aaRSs), which translate the genetic code, must collectively enforce the rules used to assemble themselves. Nor can they explain how specific assignments arose from rudimentary differentiation between ancestral aaRSs and corresponding transfer RNAs (tRNAs). Experimental deconstruction of the two aaRS superfamilies created new experimental tools with which to analyze the emergence of the code. Amino acid and tRNA substrate recognition are linked to phase transfer free energies of amino acids and arise largely from aaRS class-specific differences in secondary structure. Sensitivity to protein folding rules endowed ancestral aaRS–tRNA pairs with the feedback necessary to rapidly compare alternative genetic codes and coding sequences. These and other experimental data suggest that the aaRS bidirectional genetic ancestry stabilized the differentiation and interdependence required to initiate and elaborate the genetic coding table.

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Randall, Christopher P., Dace Rasina, Aigars Jirgensons, and Alex J. O'Neill. "Targeting Multiple Aminoacyl-tRNA Synthetases Overcomes the Resistance Liabilities Associated with Antibacterial Inhibitors Acting on a Single Such Enzyme." Antimicrobial Agents and Chemotherapy 60, no. 10 (July 18, 2016): 6359–61. http://dx.doi.org/10.1128/aac.00674-16.

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ABSTRACTBacterial aminoacyl-tRNA synthetases (aaRSs) represent promising antibacterial drug targets. Unfortunately, the aaRS inhibitors that have to date reached clinical trials are subject to rapid resistance development through mutation, a phenomenon that limits their potential clinical utility. Here, we confirm the intuitively correct idea that simultaneous targeting of two different aaRS enzymes prevents the emergence of spontaneous bacterial resistance at high frequency, a finding that supports the development of multitargeted anti-aaRS therapies.

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Nielsen, Søren K., Frederikke Hansen, Henrik Daa Schrøder, Flemming Wibrand, Finn Gustafsson, and Jens Mogensen. "Recessive Inheritance of a Rare Variant in the Nuclear Mitochondrial Gene for AARS2 in Late-Onset Dilated Cardiomyopathy." Circulation: Genomic and Precision Medicine 13, no. 5 (October 2020): 560–62. http://dx.doi.org/10.1161/circgen.120.003086.

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De Michele, Giovanna, Daniele Galatolo, Maria Lieto, Luigi Maione, Sirio Cocozza, Filippo Maria Santorelli, and Alessandro Filla. "New AARS2 Mutations in Two Siblings With Tremor, Downbeat Nystagmus, and Primary Amenorrhea: A Benign Phenotype Without Leukoencephalopathy." Movement Disorders Clinical Practice 7, no. 6 (July 7, 2020): 684–87. http://dx.doi.org/10.1002/mdc3.12991.

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Wolf, Yuri I., L. Aravind, Nick V. Grishin, and Eugene V. Koonin. "Evolution of Aminoacyl-tRNA Synthetases—Analysis of Unique Domain Architectures and Phylogenetic Trees Reveals a Complex History of Horizontal Gene Transfer Events." Genome Research 9, no. 8 (August 1, 1999): 689–710. http://dx.doi.org/10.1101/gr.9.8.689.

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Phylogenetic analysis of aminoacyl-tRNA synthetases (aaRSs) of all 20 specificities from completely sequenced bacterial, archaeal, and eukaryotic genomes reveals a complex evolutionary picture. Detailed examination of the domain architecture of aaRSs using sequence profile searches delineated a network of partially conserved domains that is even more elaborate than previously suspected. Several unexpected evolutionary connections were identified, including the apparent origin of the β-subunit of bacterial GlyRS from the HD superfamily of hydrolases, a domain shared by bacterial AspRS and the B subunit of archaeal glutamyl-tRNA amidotransferases, and another previously undetected domain that is conserved in a subset of ThrRS, guanosine polyphosphate hydrolases and synthetases, and a family of GTPases. Comparison of domain architectures and multiple alignments resulted in the delineation of synapomorphies—shared derived characters, such as extra domains or inserts—for most of the aaRSs specificities. These synapomorphies partition sets of aaRSs with the same specificity into two or more distinct and apparently monophyletic groups. In conjunction with cluster analysis and a modification of the midpoint-rooting procedure, this partitioning was used to infer the likely root position in phylogenetic trees. The topologies of the resulting rooted trees for most of the aaRSs specificities are compatible with the evolutionary “standard model” whereby the earliest radiation event separated bacteria from the common ancestor of archaea and eukaryotes as opposed to the two other possible evolutionary scenarios for the three major divisions of life. For almost all aaRSs specificities, however, this simple scheme is confounded by displacement of some of the bacterial aaRSs by their eukaryotic or, less frequently, archaeal counterparts. Displacement of ancestral eukaryotic aaRS genes by bacterial ones, presumably of mitochondrial origin, was observed for three aaRSs. In contrast, there was no convincing evidence of displacement of archaeal aaRSs by bacterial ones. Displacement of aaRS genes by eukaryotic counterparts is most common among parasitic and symbiotic bacteria, particularly the spirochaetes, in which 10 of the 19 aaRSs seem to have been displaced by the respective eukaryotic genes and two by the archaeal counterpart. Unlike the primary radiation events between the three main divisions of life, that were readily traceable through the phylogenetic analysis of aaRSs, no consistent large-scale bacterial phylogeny could be established. In part, this may be due to additional gene displacement events among bacterial lineages. Argument is presented that, although lineage-specific gene loss might have contributed to the evolution of some of the aaRSs, this is not a viable alternative to horizontal gene transfer as the principal evolutionary phenomenon in this gene class.[Complete multiple alignments of all aaRSs from complete genomes as well as the alignments of conserved regions used for phylogenetic tree construction are available at ftp://ncbi.nlm.nih.gov/pub/koonin/aaRS]

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Melnikov, Sergey V., and Dieter Söll. "Aminoacyl-tRNA Synthetases and tRNAs for an Expanded Genetic Code: What Makes them Orthogonal?" International Journal of Molecular Sciences 20, no. 8 (April 19, 2019): 1929. http://dx.doi.org/10.3390/ijms20081929.

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In the past two decades, tRNA molecules and their corresponding aminoacyl-tRNA synthetases (aaRS) have been extensively used in synthetic biology to genetically encode post-translationally modified and unnatural amino acids. In this review, we briefly examine one fundamental requirement for the successful application of tRNA/aaRS pairs for expanding the genetic code. This requirement is known as “orthogonality”—the ability of a tRNA and its corresponding aaRS to interact exclusively with each other and avoid cross-reactions with additional types of tRNAs and aaRSs in a given organism.

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Dong, Qing, Ling Long, Yan-yu Chang, Yan-jun Lin, Mei Liu, and Zheng-qi Lu. "An adolescence-onset male leukoencephalopathy with remarkable cerebellar atrophy and novel compound heterozygous AARS2 gene mutations: a case report." Journal of Human Genetics 63, no. 7 (April 17, 2018): 841–46. http://dx.doi.org/10.1038/s10038-018-0446-7.

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Kiraly-Borri, Catherine, Gareth Jevon, Weizhen Ji, Lauren Jeffries, Jamie-Lee Ricciardi, Monica Konstantino, Kate G. Ackerman, and Saquib A. Lakhani. "Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in the AARS2 gene: further delineation of the phenotypic spectrum." Molecular Case Studies 5, no. 3 (February 28, 2019): a003699. http://dx.doi.org/10.1101/mcs.a003699.

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Feng, Min, and Han Zhang. "Aminoacyl-tRNA Synthetase: A Non-Negligible Molecule in RNA Viral Infection." Viruses 14, no. 3 (March 15, 2022): 613. http://dx.doi.org/10.3390/v14030613.

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Infectious diseases such as the ongoing coronavirus disease 2019 (COVID-19) continue to have a huge impact on global health, and the host-virus interaction remains incompletely understood. To address the global threat, in-depth investigations in pathogenesis are essential for interventions in infectious diseases and vaccine development. Interestingly, aminoacyl-transfer RNA (tRNA) synthetases (aaRSs), an ancient enzyme family that was once considered to play housekeeping roles in protein synthesis, are involved in multiple viral infectious diseases. Many aaRSs in eukaryotes present as the components of a cytoplasmic depot system named the multi-synthetase complex (MSC). Upon viral infections, several components of the MSC are released and exert nonenzymatic activities. Host aaRSs can also be utilized to facilitate viral entry and replication. In addition to their intracellular roles, some aaRSs and aaRS-interacting multi-functional proteins (AIMPs) are secreted as active cytokines or function as “molecule communicators” on the cell surface. The interactions between aaRSs and viruses ultimately affect host innate immune responses or facilitate virus invasion. In this review, we summarized the latest advances of the interactions between aaRSs and RNA viruses, with a particular emphasis on the therapeutic potentials of aaRSs in viral infectious diseases.

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Chen, Meirong, Bernhard Kuhle, Jolene Diedrich, Ze Liu, James J. Moresco, John R. Yates III, Tao Pan, and Xiang-Lei Yang. "Cross-editing by a tRNA synthetase allows vertebrates to abundantly express mischargeable tRNA without causing mistranslation." Nucleic Acids Research 48, no. 12 (June 2, 2020): 6445–57. http://dx.doi.org/10.1093/nar/gkaa469.

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Abstract The accuracy in pairing tRNAs with correct amino acids by aminoacyl-tRNA synthetases (aaRSs) dictates the fidelity of translation. To ensure fidelity, multiple aaRSs developed editing functions that remove a wrong amino acid from tRNA before it reaches the ribosome. However, no specific mechanism within an aaRS is known to handle the scenario where a cognate amino acid is mischarged onto a wrong tRNA, as exemplified by AlaRS mischarging alanine to G4:U69-containing tRNAThr. Here, we report that the mischargeable G4:U69-containing tRNAThr are strictly conserved in vertebrates and are ubiquitously and abundantly expressed in mammalian cells and tissues. Although these tRNAs are efficiently mischarged, no corresponding Thr-to-Ala mistranslation is detectable. Mistranslation is prevented by a robust proofreading activity of ThrRS towards Ala-tRNAThr. Therefore, while wrong amino acids are corrected within an aaRS, a wrong tRNA is handled in trans by an aaRS cognate to the mischarged tRNA species. Interestingly, although Ala-tRNAThr mischarging is not known to occur in bacteria, Escherichia coli ThrRS also possesses robust cross-editing ability. We propose that the cross-editing activity of ThrRS is evolutionarily conserved and that this intrinsic activity allows G4:U69-containing tRNAThr to emerge and be preserved in vertebrates to have alternative functions without compromising translational fidelity.

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Baumann, Tobias, Matthias Hauf, Florian Richter, Suki Albers, Andreas Möglich, Zoya Ignatova, and Nediljko Budisa. "Computational Aminoacyl-tRNA Synthetase Library Design for Photocaged Tyrosine." International Journal of Molecular Sciences 20, no. 9 (May 11, 2019): 2343. http://dx.doi.org/10.3390/ijms20092343.

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Engineering aminoacyl-tRNA synthetases (aaRSs) provides access to the ribosomal incorporation of noncanonical amino acids via genetic code expansion. Conventional targeted mutagenesis libraries with 5–7 positions randomized cover only marginal fractions of the vast sequence space formed by up to 30 active site residues. This frequently results in selection of weakly active enzymes. To overcome this limitation, we use computational enzyme design to generate a focused library of aaRS variants. For aaRS enzyme redesign, photocaged ortho-nitrobenzyl tyrosine (ONBY) was chosen as substrate due to commercial availability and its diverse applications. Diversifying 17 first- and second-shell sites and performing conventional aaRS positive and negative selection resulted in a high-activity aaRS. This MjTyrRS variant carries ten mutations and outperforms previously reported ONBY-specific aaRS variants isolated from traditional libraries. In response to a single in-frame amber stop codon, it mediates the in vivo incorporation of ONBY with an efficiency matching that of the wild type MjTyrRS enzyme acylating cognate tyrosine. These results exemplify an improved general strategy for aaRS library design and engineering.

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Lynch, David S., Charles Wade, Anderson Rodrigues Brandão de Paiva, Nevin John, Justin A. Kinsella, Áine Merwick, Rebekah M. Ahmed, et al. "Practical approach to the diagnosis of adult-onset leukodystrophies: an updated guide in the genomic era." Journal of Neurology, Neurosurgery & Psychiatry 90, no. 5 (November 22, 2018): 543–54. http://dx.doi.org/10.1136/jnnp-2018-319481.

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Adult-onset leukodystrophies and genetic leukoencephalopathies comprise a diverse group of neurodegenerative disorders of white matter with a wide age of onset and phenotypic spectrum. Patients with white matter abnormalities detected on MRI often present a diagnostic challenge to both general and specialist neurologists. Patients typically present with a progressive syndrome including various combinations of cognitive impairment, movement disorders, ataxia and upper motor neuron signs. There are a number of important and treatable acquired causes for this imaging and clinical presentation. There are also a very large number of genetic causes which due to their relative rarity and sometimes variable and overlapping presentations can be difficult to diagnose. In this review, we provide a structured approach to the diagnosis of inherited disorders of white matter in adults. We describe clinical and radiological clues to aid diagnosis, and we present an overview of both common and rare genetic white matter disorders. We provide advice on testing for acquired causes, on excluding small vessel disease mimics, and detailed advice on metabolic and genetic testing available to the practising neurologist. Common genetic leukoencephalopathies discussed in detail include CSF1R, AARS2, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and mitochondrial and metabolic disorders.

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Xie, Stanley C., Riley D. Metcalfe, Elyse Dunn, Craig J. Morton, Shih-Chung Huang, Tanya Puhalovich, Yawei Du, et al. "Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy." Science 376, no. 6597 (June 3, 2022): 1074–79. http://dx.doi.org/10.1126/science.abn0611.

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Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5′-monophosphate–mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid–sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5′-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum , namely tyrosine RS ( Pf YRS). ML901 exerts whole-life-cycle–killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.

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Lynch, David S., Wei Jia Zhang, Rahul Lakshmanan, Justin A. Kinsella, Günes Altiokka Uzun, Merih Karbay, Zeynep Tüfekçioglu, et al. "Analysis of Mutations in AARS2 in a Series of CSF1R-Negative Patients With Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia." JAMA Neurology 73, no. 12 (December 1, 2016): 1433. http://dx.doi.org/10.1001/jamaneurol.2016.2229.

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Zhang, Baole, Luping Pang, Manesh Nautiyal, Steff De Graef, Bharat Gadakh, Eveline Lescrinier, Jef Rozenski, Sergei V. Strelkov, Stephen D. Weeks, and Arthur Van Aerschot. "Synthesis and Biological Evaluation of 1,3-Dideazapurine-Like 7-Amino-5-Hydroxymethyl-Benzimidazole Ribonucleoside Analogues as Aminoacyl-tRNA Synthetase Inhibitors." Molecules 25, no. 20 (October 16, 2020): 4751. http://dx.doi.org/10.3390/molecules25204751.

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Aminoacyl-tRNA synthetases (aaRSs) have become viable targets for the development of antimicrobial agents due to their crucial role in protein translation. A series of six amino acids were coupled to the purine-like 7-amino-5-hydroxymethylbenzimidazole nucleoside analogue following an optimized synthetic pathway. These compounds were designed as aaRS inhibitors and can be considered as 1,3-dideazaadenine analogues carrying a 2-hydroxymethyl substituent. Despite our intentions to obtain N1-glycosylated 4-aminobenzimidazole congeners, resembling the natural purine nucleosides glycosylated at the N9-position, we obtained the N3-glycosylated benzimidazole derivatives as the major products, resembling the respective purine N7-glycosylated nucleosides. A series of X-ray crystal structures of class I and II aaRSs in complex with newly synthesized compounds revealed interesting interactions of these “base-flipped” analogues with their targets. While the exocyclic amine of the flipped base mimics the reciprocal interaction of the N3-purine atom of aminoacyl-sulfamoyl adenosine (aaSA) congeners, the hydroxymethyl substituent of the flipped base apparently loses part of the standard interactions of the adenine N1 and the N6-amine as seen with aaSA analogues. Upon the evaluation of the inhibitory potency of the newly obtained analogues, nanomolar inhibitory activities were noted for the leucine and isoleucine analogues targeting class I aaRS enzymes, while rather weak inhibitory activity against the corresponding class II aaRSs was observed. This class bias could be further explained by detailed structural analysis.

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Bhowal, Pratyasha, Priyanka Biswas Karmakar, Debkanya Dey, Riya Manna, Debraj Roy, and Rajat Banerjee. "Aminoacyl-tRNA Synthetases, Indispensable Players in Lung Tumorigenesis." Protein & Peptide Letters 29, no. 3 (March 2022): 208–17. http://dx.doi.org/10.2174/0929866529666220110143520.

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Abstract: Being an essential enzyme in protein synthesis, the aminoacyl-tRNA synthetases (aaRSs) have a conserved function throughout evolution. However, research has uncovered altered expressions as well as interactions of aaRSs, in league with aaRS-interacting multi-functional proteins (AIMPs), forming a multi-tRNA synthetase complex (MSC) and divulging into their roles outside the range of protein synthesis. In this review, we have directed our focus into the rudimentary structure of this compact association and also how these aaRSs and AIMPs are involved in the maintenance and progression of lung cancer, the principal cause of most cancer-related deaths. There is substantial validation that suggests the crucial role of these prime housekeeping proteins in lung cancer regulation. Here, we have addressed the biological role that the three AIMPs and the aaRSs play in tumorigenesis, along with an outline of the different molecular mechanisms involved in the same. In conclusion, we have introduced the potentiality of these components as possible therapeutics for the evolution of new-age treatments of lung tumorigenesis.

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Ferrer, Isidro. "The Primary Microglial Leukodystrophies: A Review." International Journal of Molecular Sciences 23, no. 11 (June 6, 2022): 6341. http://dx.doi.org/10.3390/ijms23116341.

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Primary microglial leukodystrophy or leukoencephalopathy are disorders in which a genetic defect linked to microglia causes cerebral white matter damage. Pigmented orthochromatic leukodystrophy, adult-onset orthochromatic leukodystrophy associated with pigmented macrophages, hereditary diffuse leukoencephalopathy with (axonal) spheroids, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) are different terms apparently used to designate the same disease. However, ALSP linked to dominantly inherited mutations in CSF1R (colony stimulating factor receptor 1) cause CSF-1R-related leukoencephalopathy (CRP). Yet, recessive ALSP with ovarian failure linked to AARS2 (alanyl-transfer (t)RNA synthase 2) mutations (LKENP) is a mitochondrial disease and not a primary microglial leukoencephalopathy. Polycystic membranous lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; Nasu–Hakola disease: NHD) is a systemic disease affecting bones, cerebral white matter, selected grey nuclei, and adipose tissue The disease is caused by mutations of one of the two genes TYROBP or TREM2, identified as PLOSL1 and PLOSL2, respectively. TYROBP associates with receptors expressed in NK cells, B and T lymphocytes, dendritic cells, monocytes, macrophages, and microglia. TREM2 encodes the protein TREM2 (triggering receptor expressed on myeloid cells 2), which forms a receptor signalling complex with TYROBP in macrophages and dendritic cells. Rather than pure microglial leukoencephalopathy, NHD can be considered a multisystemic “immunological” disease.

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Ferrer, Isidro. "The Primary Microglial Leukodystrophies: A Review." International Journal of Molecular Sciences 23, no. 11 (June 6, 2022): 6341. http://dx.doi.org/10.3390/ijms23116341.

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Primary microglial leukodystrophy or leukoencephalopathy are disorders in which a genetic defect linked to microglia causes cerebral white matter damage. Pigmented orthochromatic leukodystrophy, adult-onset orthochromatic leukodystrophy associated with pigmented macrophages, hereditary diffuse leukoencephalopathy with (axonal) spheroids, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) are different terms apparently used to designate the same disease. However, ALSP linked to dominantly inherited mutations in CSF1R (colony stimulating factor receptor 1) cause CSF-1R-related leukoencephalopathy (CRP). Yet, recessive ALSP with ovarian failure linked to AARS2 (alanyl-transfer (t)RNA synthase 2) mutations (LKENP) is a mitochondrial disease and not a primary microglial leukoencephalopathy. Polycystic membranous lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; Nasu–Hakola disease: NHD) is a systemic disease affecting bones, cerebral white matter, selected grey nuclei, and adipose tissue The disease is caused by mutations of one of the two genes TYROBP or TREM2, identified as PLOSL1 and PLOSL2, respectively. TYROBP associates with receptors expressed in NK cells, B and T lymphocytes, dendritic cells, monocytes, macrophages, and microglia. TREM2 encodes the protein TREM2 (triggering receptor expressed on myeloid cells 2), which forms a receptor signalling complex with TYROBP in macrophages and dendritic cells. Rather than pure microglial leukoencephalopathy, NHD can be considered a multisystemic “immunological” disease.

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Zheng, Wen-Qiang, Yuying Zhang, Qin Yao, Yuzhe Chen, Xinhua Qiao, En-Duo Wang, Chang Chen, and Xiao-Long Zhou. "Nitrosative stress inhibits aminoacylation and editing activities of mitochondrial threonyl-tRNA synthetase by S-nitrosation." Nucleic Acids Research 48, no. 12 (June 2, 2020): 6799–810. http://dx.doi.org/10.1093/nar/gkaa471.

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Abstract Structure and/or function of proteins are frequently affected by oxidative/nitrosative stress via posttranslational modifications. Aminoacyl-tRNA synthetases (aaRSs) constitute a class of ubiquitously expressed enzymes that control cellular protein homeostasis. Here, we found the activity of human mitochondrial (mt) threonyl-tRNA synthetase (hmtThrRS) is resistant to oxidative stress (H2O2) but profoundly sensitive to nitrosative stress (S-nitrosoglutathione, GSNO). Further study showed four Cys residues in hmtThrRS were modified by S-nitrosation upon GSNO treatment, and one residue was one of synthetic active sites. We analyzed the effect of modification at individual Cys residue on aminoacylation and editing activities of hmtThrRS in vitro and found that both activities were decreased. We further confirmed that S-nitrosation of mtThrRS could be readily detected in vivo in both human cells and various mouse tissues, and we systematically identified dozens of S-nitrosation-modified sites in most aaRSs, thus establishing both mitochondrial and cytoplasmic aaRS species with S-nitrosation ex vivo and in vivo, respectively. Interestingly, a decrease in the S-nitrosation modification level of mtThrRS was observed in a Huntington disease mouse model. Overall, our results establish, for the first time, a comprehensive S-nitrosation-modified aaRS network and a previously unknown mechanism on the basis of the inhibitory effect of S-nitrosation on hmtThrRS.

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Ruan, Liang-Liang, Xiao-Long Zhou, Min Tan, and En-Duo Wang. "Human cytoplasmic ProX edits mischarged tRNAPro with amino acid but not tRNA specificity." Biochemical Journal 450, no. 1 (January 24, 2013): 243–52. http://dx.doi.org/10.1042/bj20121493.

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aaRSs (aminoacyl-tRNA synthetases) are responsible for ensuring the fidelity of the genetic code translation by accurately linking a particular amino acid to its cognate tRNA isoacceptor. To ensure accuracy of protein biosynthesis, some aaRSs have evolved an editing process to remove mischarged tRNA. The hydrolysis of the mischarged tRNA usually occurs in an editing domain, which is inserted into or appended to the main body of the aaRS. In addition, autonomous, editing domain-homologous proteins can also trans-edit mischarged tRNA in concert or in compensating for the editing function of its corresponding aaRS. The freestanding ProX is a homologue of the editing domain of bacterial ProRS (prolyl-tRNA synthetase). In the present study, we cloned for the first time a gene encoding HsProX (human cytoplasmic ProX) and purified the expressed recombinant protein. The catalytic specificity of HsProX for non-cognate amino acids and identity elements on tRNAPro for editing were also investigated. We found that HsProX could deacylate mischarged Ala-tRNAPro, but not Cys-HstRNAUGGPro, and specifically targeted the alanine moiety of Ala-tRNAPro. The importance of the CCA76 end of the tRNA for deacylation activity and key amino acid residues in HsProX for its editing function were also identified.

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Chen, Zilu, Kun Mei, Yao Xiao, Yan Xiong, Wei Long, Qin Wang, Jiang Zhong, et al. "Prognostic Assessment of Oxidative Stress-Related Genes in Colorectal Cancer and New Insights into Tumor Immunity." Oxidative Medicine and Cellular Longevity 2022 (October 15, 2022): 1–19. http://dx.doi.org/10.1155/2022/2518340.

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Oxidative stress is crucial to the biology of tumors. Oxidative stress’ potential predictive significance in colorectal cancer (CRC) has not been studied; nevertheless here, we developed a forecasting model based on oxidative stress to forecast the result of CRC survival and enhance clinical judgment. The training set was chosen from the transcriptomes of 177 CRC patients in GSE17536. For validation, 65 samples of colon cancer from GSE29621 were utilized. For the purpose of choosing prognostic genes, the expression of oxidative stress-related genes (OXEGs) was found. Prognostic risk models were built using multivariate Cox regression analysis, univariate Cox regression analysis, and LASSO regression analysis. The outcomes of the western blot and transcriptome sequencing tests were finally confirmed. ATF4, CARS2, CRP, GPX1, IL1B, MAPK8, MRPL44, MTFMT, NOS1, OSGIN2, SOD2, AARS2, and FOXO3 were among the 14 OXEGs used to build prognostic characteristics. Patients with CRC were categorized into low-risk and high-risk groups according on their median risk scores. Cox regression analysis using single and multiple variables revealed that OXEG-related signals were independent risk factors for CRC. Additionally, the validation outcomes from western blotting and transcriptome sequencing demonstrated that OXEGs were differently expressed. Using 14 OXEGs, our work creates a predictive signature that may be applied to the creation of new prognostic models and the identification of possible medication candidates for the treatment of CRC.

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Tiosano, Dov, Jason A. Mears, and David A. Buchner. "Mitochondrial Dysfunction in Primary Ovarian Insufficiency." Endocrinology 160, no. 10 (August 8, 2019): 2353–66. http://dx.doi.org/10.1210/en.2019-00441.

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Abstract Primary ovarian insufficiency (POI) is defined by the loss or dysfunction of ovarian follicles associated with amenorrhea before the age of 40. Symptoms include hot flashes, sleep disturbances, and depression, as well as reduced fertility and increased long-term risk of cardiovascular disease. POI occurs in ∼1% to 2% of women, although the etiology of most cases remains unexplained. Approximately 10% to 20% of POI cases are due to mutations in a single gene or a chromosomal abnormality, which has provided considerable molecular insight into the biological underpinnings of POI. Many of the genes for which mutations have been associated with POI, either isolated or syndromic cases, function within mitochondria, including MRPS22, POLG, TWNK, LARS2, HARS2, AARS2, CLPP, and LRPPRC. Collectively, these genes play roles in mitochondrial DNA replication, gene expression, and protein synthesis and degradation. Although mutations in these genes clearly implicate mitochondrial dysfunction in rare cases of POI, data are scant as to whether these genes in particular, and mitochondrial dysfunction in general, contribute to most POI cases that lack a known etiology. Further studies are needed to better elucidate the contribution of mitochondria to POI and determine whether there is a common molecular defect in mitochondrial function that distinguishes mitochondria-related genes that when mutated cause POI vs those that do not. Nonetheless, the clear implication of mitochondrial dysfunction in POI suggests that manipulation of mitochondrial function represents an important therapeutic target for the treatment or prevention of POI.

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Zirin, Jonathan, Xiaochun Ni, Laura M. Sack, Donghui Yang-Zhou, Yanhui Hu, Roderick Brathwaite, Martha L. Bulyk, Stephen J. Elledge, and Norbert Perrimon. "Interspecies analysis of MYC targets identifies tRNA synthetases as mediators of growth and survival in MYC-overexpressing cells." Proceedings of the National Academy of Sciences 116, no. 29 (July 1, 2019): 14614–19. http://dx.doi.org/10.1073/pnas.1821863116.

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Aberrant MYC oncogene activation is one of the most prevalent characteristics of cancer. By overlapping datasets of Drosophila genes that are insulin-responsive and also regulate nucleolus size, we enriched for Myc target genes required for cellular biosynthesis. Among these, we identified the aminoacyl tRNA synthetases (aaRSs) as essential mediators of Myc growth control in Drosophila and found that their pharmacologic inhibition is sufficient to kill MYC-overexpressing human cells, indicating that aaRS inhibitors might be used to selectively target MYC-driven cancers. We suggest a general principle in which oncogenic increases in cellular biosynthesis sensitize cells to disruption of protein homeostasis.

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Morant, Laura, Maria-Luise Erfurth, and Albena Jordanova. "Drosophila Models for Charcot–Marie–Tooth Neuropathy Related to Aminoacyl-tRNA Synthetases." Genes 12, no. 10 (September 27, 2021): 1519. http://dx.doi.org/10.3390/genes12101519.

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Aminoacyl-tRNA synthetases (aaRS) represent the largest cluster of proteins implicated in Charcot–Marie–Tooth neuropathy (CMT), the most common neuromuscular disorder. Dominant mutations in six aaRS cause different axonal CMT subtypes with common clinical characteristics, including progressive distal muscle weakness and wasting, impaired sensory modalities, gait problems and skeletal deformities. These clinical manifestations are caused by “dying back” axonal degeneration of the longest peripheral sensory and motor neurons. Surprisingly, loss of aminoacylation activity is not a prerequisite for CMT to occur, suggesting a gain-of-function disease mechanism. Here, we present the Drosophila melanogaster disease models that have been developed to understand the molecular pathway(s) underlying GARS1- and YARS1-associated CMT etiology. Expression of dominant CMT mutations in these aaRSs induced comparable neurodegenerative phenotypes, both in larvae and adult animals. Interestingly, recent data suggests that shared molecular pathways, such as dysregulation of global protein synthesis, might play a role in disease pathology. In addition, it has been demonstrated that the important function of nuclear YARS1 in transcriptional regulation and the binding properties of mutant GARS1 are also conserved and can be studied in D. melanogaster in the context of CMT. Taken together, the fly has emerged as a faithful companion model for cellular and molecular studies of aaRS-CMT that also enables in vivo investigation of candidate CMT drugs.

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Kalidas, Savitha, Igor Cestari, Severine Monnerat, Qiong Li, Sandesh Regmi, Nicholas Hasle, Mehdi Labaied, Marilyn Parsons, Kenneth Stuart, and Margaret A. Phillips. "Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei." Eukaryotic Cell 13, no. 4 (February 21, 2014): 504–16. http://dx.doi.org/10.1128/ec.00017-14.

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ABSTRACT Human African trypanosomiasis (HAT) is an important public health threat in sub-Saharan Africa. Current drugs are unsatisfactory, and new drugs are being sought. Few validated enzyme targets are available to support drug discovery efforts, so our goal was to obtain essentiality data on genes with proven utility as drug targets. Aminoacyl-tRNA synthetases (aaRSs) are known drug targets for bacterial and fungal pathogens and are required for protein synthesis. Here we survey the essentiality of eight Trypanosoma brucei aaRSs by RNA interference (RNAi) gene expression knockdown, covering an enzyme from each major aaRS class: valyl-tRNA synthetase (ValRS) (class Ia), tryptophanyl-tRNA synthetase (TrpRS-1) (class Ib), arginyl-tRNA synthetase (ArgRS) (class Ic), glutamyl-tRNA synthetase (GluRS) (class 1c), threonyl-tRNA synthetase (ThrRS) (class IIa), asparaginyl-tRNA synthetase (AsnRS) (class IIb), and phenylalanyl-tRNA synthetase (α and β) (PheRS) (class IIc). Knockdown of mRNA encoding these enzymes in T. brucei mammalian stage parasites showed that all were essential for parasite growth and survival in vitro . The reduced expression resulted in growth, morphological, cell cycle, and DNA content abnormalities. ThrRS was characterized in greater detail, showing that the purified recombinant enzyme displayed ThrRS activity and that the protein localized to both the cytosol and mitochondrion. Borrelidin, a known inhibitor of ThrRS, was an inhibitor of T. brucei ThrRS and showed antitrypanosomal activity. The data show that aaRSs are essential for T. brucei survival and are likely to be excellent targets for drug discovery efforts.

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Hartman, Hyman, and Temple F. Smith. "Origin of the Genetic Code Is Found at the Transition between a Thioester World of Peptides and the Phosphoester World of Polynucleotides." Life 9, no. 3 (August 22, 2019): 69. http://dx.doi.org/10.3390/life9030069.

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The early metabolism arising in a Thioester world gave rise to amino acids and their simple peptides. The catalytic activity of these early simple peptides became instrumental in the transition from Thioester World to a Phosphate World. This transition involved the appearances of sugar phosphates, nucleotides, and polynucleotides. The coupling of the amino acids and peptides to nucleotides and polynucleotides is the origin for the genetic code. Many of the key steps in this transition are seen in in the catalytic cores of the nucleotidyltransferases, the class II tRNA synthetases (aaRSs) and the CCA adding enzyme. These catalytic cores are dominated by simple beta hairpin structures formed in the Thioester World. The code evolved from a proto-tRNA a tetramer XCCA interacting with a proto-aminoacyl-tRNA synthetase (aaRS) activating Glycine and Proline, the initial expanded code is found in the acceptor arm of the tRNA, the operational code. It is the coevolution of the tRNA with the aaRSs that is at the heart of the origin and evolution of the genetic code. There is also a close relationship between the accretion models of the evolving tRNA and that of the ribosome.

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Mazurova, Stella, Martin Magner, Vendula Kucerova-Vidrova, Alzbeta Vondrackova, Viktor Stranecky, Anna Pristoupilova, Josef Zamecnik, et al. "Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature." Cardiology in the Young 27, no. 5 (November 14, 2016): 936–44. http://dx.doi.org/10.1017/s1047951116001876.

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AbstractCardiomyopathy is a common manifestation in neonates and infants with mitochondrial disorders. In this study, we report two cases manifesting with fatal mitochondrial hypertrophic cardiomyopathy, which include the third known patient with thymidine kinase 2 deficiency and the ninth patient with alanyl-tRNA synthetase 2 deficiency. The girl with thymidine kinase 2 deficiency had hypertrophic cardiomyopathy together with regression of gross motor development at the age of 13 months. Neurological symptoms and cardiac involvement progressed into severe myopathy, psychomotor arrest, and cardiorespiratory failure at the age of 22 months. The imaging methods and autoptic studies proved that she suffered from unique findings of leucoencephalopathy, severe, mainly cerebellar neuronal degeneration, and hepatic steatosis. The girl with alanyl-tRNA synthetase 2 deficiency presented with cardiac failure and underlying hypertrophic cardiomyopathy within 12 hours of life and subsequently died at 9 weeks of age. Muscle biopsy analyses demonstrated respiratory chain complex I and IV deficiencies, and histological evaluation revealed massive mitochondrial accumulation and cytochrome c oxidase-negative fibres in both cases. Exome sequencing in the first case revealed compound heterozygozity for one novel c.209T>C and one previously published c.416C>T mutation in the TK2 gene, whereas in the second case homozygozity for the previously described mutation c.1774C>T in the AARS2 gene was determined. The thymidine kinase 2 mutations resulted in severe mitochondrial DNA depletion (to 12% of controls) in the muscle. We present, for the first time, severe leucoencephalopathy and hepatic steatosis in a patient with thymidine kinase 2 deficiency and the finding of a ragged red fibre-like image in the muscle biopsy in a patient with alanyl-tRNA synthetase 2 deficiency.

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Nautiyal, Manesh, Bharat Gadakh, Steff De Graef, Luping Pang, Masroor Khan, Yi Xun, Jef Rozenski, and Arthur Van Aerschot. "Synthesis and Biological Evaluation of Lipophilic Nucleoside Analogues as Inhibitors of Aminoacyl-tRNA Synthetases." Antibiotics 8, no. 4 (October 9, 2019): 180. http://dx.doi.org/10.3390/antibiotics8040180.

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Emerging antibiotic resistance in pathogenic bacteria and reduction of compounds in the existing antibiotics discovery pipeline is the most critical concern for healthcare professionals. A potential solution aims to explore new or existing targets/compounds. Inhibition of bacterial aminoacyl-tRNA synthetase (aaRSs) could be one such target for the development of antibiotics. The aaRSs are a group of enzymes that catalyze the transfer of an amino acid to their cognate tRNA and therefore play a pivotal role in translation. Thus, selective inhibition of these enzymes could be detrimental to microbes. The 5′-O-(N-(L-aminoacyl)) sulfamoyladenosines (aaSAs) are potent inhibitors of the respective aaRSs, however due to their polarity and charged nature they cannot cross the bacterial membranes. In this work, we increased the lipophilicity of these existing aaSAs in an effort to promote their penetration through the bacterial membrane. Two strategies were followed, either attaching a (permanent) alkyl moiety at the adenine ring via alkylation of the N6-position or introducing a lipophilic biodegradable prodrug moiety at the alpha-terminal amine, totaling eight new aaSA analogues. All synthesized compounds were evaluated in vitro using either a purified Escherichia coli aaRS enzyme or in presence of total cellular extract obtained from E. coli. The prodrugs showed comparable inhibitory activity to the parent aaSA analogues, indicating metabolic activation in cellular extracts, but had little effect on bacteria. During evaluation of the N6-alkylated compounds against different microbes, the N6-octyl containing congener 6b showed minimum inhibitory concentration (MIC) of 12.5 µM against Sarcina lutea while the dodecyl analogue 6c displayed MIC of 6.25 µM against Candida albicans.

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Suzuki, Tateki, Keitaro Yamashita, Yoshikazu Tanaka, Isao Tanaka, and Min Yao. "Crystallization and preliminary X-ray crystallographic analysis of a bacterial Asn-transamidosome." Acta Crystallographica Section F Structural Biology Communications 70, no. 6 (May 24, 2014): 790–93. http://dx.doi.org/10.1107/s2053230x14007274.

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Most canonical aminoacyl-tRNAs are synthesized directly by their cognate aminoacyl-tRNA synthetases (aaRSs), but glutaminyl-tRNAGlnand asparaginyl-tRNAAsnare synthesized indirectly by two-step processes. These processes are catalyzed by the transamidosome, a large ribonucleoprotein particle composed of GatA, GatB, GatC, aaRS and tRNA. In this study, the Asn-transamidosome fromPseudomonas aeruginosawas reconstructed and crystallized by mixing purified GatCAB complex, AspRS and tRNAAsn. The crystal of the Asn-transamidosome belonged to space groupP21, with unit-cell parametersa= 93.3,b= 186.0,c= 287.8 Å, β = 93.3°, and diffracted to 3.73 Å resolution. Preliminary X-ray crystallographic analysis showed that the asymmetric unit contained two Asn-transamidosomes, each composed of two GatCABs, one AspRS dimer and two tRNAAsns, indicating that the construction of the current Asn-transamidosome differs from that ofThermus thermophilus.

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Bui, Thi Buu Hue, Cuong Quoc Nguyen, and Quang De Tran. "Docking-Based Virtual Screening for the Discovery of 1,3,4-Oxadiazoles as Aminoacyl-tRNA Synthetase Inhibitors." Can Tho University Journal of Science 14, no. 2 (June 27, 2022): 83–92. http://dx.doi.org/10.22144/ctu.jen.2022.021.

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Aminoacyl-tRNA synthetases (aaRSs) are one of the leading targets for the development of antibiotic agents. In this paper, we reported the discovery of aaRS inhibitors using a structure-based virtual screening method. The interactions of 52 designed structures with the methionyl-tRNA synthetase (MetRS) target were performed by docking the ligands into the active zone of the MetRS using Autodock Vina. The data revealed 14 compounds displaying interactions with key amino acids (Asp287, Tyr250, Val473, Trp474, Phe522, Ile519, Ala477, Leu478, and His523) at the binding pocket of the enzyme, indicating their potential as MetRS inhibitors. These results could be served as the references for further synthetic work and bioassays experiments for discovering MetRS inhibitors and other pharmaceutical agents that may assist in the generation of new antibiotics.

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Journal articles on the topic 'AARS2'

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