- |||||||||| Journal: Trypanosoma brucei multi-aminoacyl-tRNA synthetase complex formation limits promiscuous tRNA proofreading. (Pubmed Central) - Jul 31, 2024
Kinetic assays showed MCP3 alone has relaxed tRNA specificity and promiscuously hydrolyzes cognate Ala-tRNAAla; this activity is significantly reduced in the presence of Tb alanyl-tRNA synthetase, also housed in the MSC. Taken together, our results provide insight into translational fidelity mechanisms in Tb and lay the foundation for exploring MSC-associated proteins as novel drug targets.
- |||||||||| THE EFFECT OF THERMAL STRESS ON HUMAN AMINOACYL-TRNA SYNTHETASES (Poster Room | Level 0) - Jul 30, 2024 - Abstract #SSIEM2024SSIEM_663;
The thermal sensitivity of aaRS variants should be further studied, particularly in patients with pathogenic variants in AARS1, LARS1, MARS1, YARS1 and VARS1. This could have an important impact on patient treatment, especially during episodes of fever, which are common in early infancy.
- |||||||||| Journal: Eukaryotic AlaX provides multiple checkpoints for quality and quantity of aminoacyl-tRNAs in translation. (Pubmed Central) - Jul 21, 2024
Remarkably, yeast cells with ScAlaX deletion responded differently to translation inhibitor treatment, with a gain in geneticin resistance, but sensitivity to cycloheximide, both of which were rescued by editing-capable ScAlaX, alanyl- or threonyl-tRNA synthetase. Altogether, our results demonstrated the previously undescribed editing peculiarities of eukaryotic AlaXs, which provide multiple checkpoints to maintain the speed and fidelity of genetic decoding.
- |||||||||| Orencia (abatacept) / BMS, Rituxan (rituximab) / Roche
AUTOANTIBODIES AND PRECISION MEDICINE (HALL A) - May 1, 2024 - Abstract #AUTO2024AUTO_507;
However, a more powerful definition of individual phenotypes compatible with the concept of Precision Medicine should combine autoantibodies with a host of other biomarkers, including gene polymorphism, epigenetic markers, microRNA, and microbiome. The availability of multiplex assays and the use of artificial intelligence and machine learning should contribute to the integration of these data into useful information for the management of individual patients.
- |||||||||| Journal: Elucidation of productive alanine recognition mechanism by Escherichia coli alanyl-tRNA synthetase. (Pubmed Central) - Mar 18, 2024
These results suggested that D235 is optimal for AlaRS to specifically recognize alanine. Alanylation activities of an RNA minihelix by the mutants of valine at the 214th position (V214) of another fragment (AlaRS442N), which is the smallest AlaRS with alanine charging activity, suggest the existence of the van der Waals-like interaction between the side chain of V214 and the methyl group of the alanine substrate.
- |||||||||| azithromycin / Generic mfg.
Weak Muscles May Mean a Strong Case for Interstitial Lung Disease (San Diego Convention Center, Area A (Hall A-B2, Ground Level)) - Feb 20, 2024 - Abstract #ATS2024ATS_1530;
She was diagnosed with atypical pneumonia and prescribed a course of azithromycin without improvement...A high clinical suspicion is needed to prompt an extended myositis panel to make a timely diagnosis and prevent irreversible pulmonary fibrosis. This case highlights healthcare disparities for non-English speaking patients who are lost to follow-up in the diagnostic stages due to diagnostic delays and communication barriers.
- |||||||||| Journal: Hypoxia induces mitochondrial protein lactylation to limit oxidative phosphorylation. (Pubmed Central) - Jan 3, 2024
In mouse muscle cells, lactylation is induced by lactate oxidation-induced intracellular hypoxia during exercise to constrain high-intensity endurance running exhaustion time, which can be increased or decreased by decreasing or increasing lactylation levels, respectively. Our results reveal that mitochondrial protein lactylation integrates intracellular hypoxia and lactate signals to regulate OXPHOS.
- |||||||||| Journal: Common evolutionary origins of the bacterial glycyl tRNA synthetase and alanyl tRNA synthetase. (Pubmed Central) - Nov 28, 2023
Further, the catalytic domain of bacGlyRS is more closely related to the catalytic domain of uniAlaRS than to any other aminoacyl tRNA synthetase. The combined data suggest that the ATL and catalytic domains of these two enzymes are ancestral to bacGlyRS and uniAlaRS, which emerged from common protein ancestors by bricolage, stepwise accumulation of protein domains, before the last universal common ancestor of life.
- |||||||||| Biomarker, Journal, IO biomarker, Pan tumor: AARS2 as a novel biomarker for prognosis and its molecular characterization in pan-cancer. (Pubmed Central) - Nov 22, 2023
The AARS2 could serve as a new oncogenic gene that promotes cell proliferation and migration in HCC. The comprehensive investigations increased the understanding of AARS2 across human cancers and generated beginning insights of AARS2 in genomic landscape, molecular biological function, prognosis, and clinical treatment.
- |||||||||| Journal: Anticodon sequence determines the impact of mistranslating tRNA variants. (Pubmed Central) - Sep 30, 2023
Differences in decoding specificity, even between synonymous anticodons, resulted in each tRNA variant mistranslating unique sets of peptides and proteins. We suggest that these differences in decoding specificity are also important in determining the impact of tRNA anticodon variants.
- |||||||||| propranolol / Generic mfg.
Parkinson () - Aug 30, 2023 - Abstract #MDSCongress2023MDS_Congress_909;
This is the first reported case of CMT2N, and PD associated with AARS mutation. Tremor in association with peripheral neuropathy should be investigated for underlying PD before accepting it as a neuropathic tremor.
- |||||||||| Journal: Sequence-specific targeting of C. elegans C-Ala to the D-loop of tRNA. (Pubmed Central) - Aug 12, 2023
Despite bearing little resemblance to other C-Ala domains, C. elegans mitochondrial C-Ala (Ce-C-Ala) robustly bound both tRNA and DNA and maintained targeting specificity for the D-loop of its cognate tRNA. This study uncovers the underlying mechanism of how C. elegans C-Ala specifically targets the D-loop of tRNA.
- |||||||||| Journal, Tumor mutational burden, PARP Biomarker: Comprehensive proteogenomic characterization of early duodenal cancer reveals the carcinogenesis tracks of different subtypes. (Pubmed Central) - Mar 30, 2023
The drug-targetable alanyl-tRNA synthetase (AARS1) in the high tumor mutation burden/immune infiltration is significantly enhanced in DC progression, and catalyzes the lysine-alanylation of poly-ADP-ribose polymerases (PARP1), which decreases the apoptosis of cancer cells, eventually promoting cell proliferation and tumorigenesis. We assess the proteogenomic landscape of early DC, and provide insights into the molecular features corresponding therapeutic targets.
- |||||||||| Rituxan (rituximab) / Biogen, Zenyaku Kogyo, Roche
A Case of Anti-synthetase Syndrome Presenting as Fever of Unknown Origin (Walter E. Washington Convention Center, Area G, Hall C (Lower Level)) - Mar 25, 2023 - Abstract #ATS2023ATS_4694;
The patient was diagnosed with seronegative rheumatoid arthritis and was started on oral methotrexate which helped with her arthritis, however she continued to have fevers...Patient was started on glucocorticosteroids and rituximab...The clinical manifestations may develop over the course of weeks to years and vary in frequency and order of presentation which makes early recognition and diagnosis often challenging especially in cases of unexplained fever, inflammatory arthritis, and RP. This case highlights that fever is a common clinical manifestation of ASSD (reported in 26-61% of cases) and might be the presenting symptom in few cases.
- |||||||||| Journal: Tyrosine-targeted covalent inhibition of a tRNA synthetase aided by zinc ion. (Pubmed Central) - Jan 29, 2023
In addition, when this tyrosine was replaced by a lysine or even a weakly nucleophilic arginine, similar bonds could also be formed. Our report of the mechanism of a class of AARS covalent inhibitor targeting multiple amino acid residues could facilitate approaches to drug discovery for cancer and infectious diseases.
- |||||||||| Journal: Alanyl-tRNA Synthetase 1 Gene Variants in Hereditary Neuropathy: Genotype and Phenotype Overview. (Pubmed Central) - Sep 14, 2022
Most experienced motor weakness and sensory loss in the lower limbs. In total, 11 AARS1 variants can currently be classified as pathogenic or likely pathogenic and are associated with sensorimotor axonal or intermediate, slowly progressive polyneuropathy with common asymmetry and variable age of symptom onset with no apparent involvement of other organ systems.
- |||||||||| Journal: Streptococcus mutans gene expression and functional profile in root caries: an RNA-seq study. (Pubmed Central) - Jun 24, 2022
Some functional patterns related to sugar (starch, sucrose, fructose, mannose and lactose) and heterofermentative metabolisms, to cell-wall biosynthesis and to acid tolerance stress seem to be enriched on carious root surfaces conferring ecological advantages to S. mutans. Altogether, the present data suggest that a functional signature may be associated with carious root lesions.
- |||||||||| Review, Journal: Aminoacyl-tRNA Synthetases: On Anti-Synthetase Syndrome and Beyond. (Pubmed Central) - Jun 4, 2022
This review will address what is known about the function of the aaRSs with a focus on their autoantigenic properties. We will also describe the anti-aaRSs autoantibodies and their association to specific clinical manifestations, and discuss their potential contribution to the pathogenesis of ASSD.
- |||||||||| Journal: E. coli Alanyl-tRNA Synthetase Maintains Proofreading Activity and Translational Accuracy under Oxidative Stress. (Pubmed Central) - Apr 19, 2022
Alanine scanning mutagenesis showed that none of the identified residues were solely responsible for the change in cognate tRNA aminoacylation observed under oxidative stress, suggesting that these residues may act as ROS "sinks" to protect catalytically-critical sites from oxidative damage. Combined, our results indicate E. coli AlaRS proofreading is resistant to oxidative damage, providing an important mechanism of stress resistance that helps to maintain proteome integrity and cellular viability.
- |||||||||| Journal: Gain of C-Ala enables AlaRS to target the L-shaped tRNAAla. (Pubmed Central) - Apr 19, 2022
Phylogenetic analysis showed that CeAlaRSm once possessed the C-Ala domain but later lost most of it during evolution, perhaps in response to the deletion of the T-arm (part of the elbow) from its cognate tRNA. This study underscores the evolutionary gain of C-Ala for docking AlaRS to the L-shaped tRNAAla.
- |||||||||| Journal: Design, Synthesis, and Proof-of-Concept of Triple-Site Inhibitors against Aminoacyl-tRNA Synthetases. (Pubmed Central) - Apr 19, 2022
Compounds 36b, 36k, and 36l exhibited antibacterial activities with minimum inhibitory concentration values of 2-8 μg/mL against the tested bacteria, which are superior to those of the reported dual-site ThrRS inhibitors. Our study provides the first proof-of-concept for developing triple-site inhibitors against aaRSs, inspiring future aaRS-based drug discoveries.
- |||||||||| ABUNDANT AUTOANTIBODY ISOTYPES IN IDIOPATHIC INFLAMMATORY MYOPATHIES (Poster Tour Auditorium 5) - Apr 4, 2022 - Abstract #EULAR2022EULAR_1094;
Our results suggest that for anti-aaRS autoantibodies it could be important to investigate additional autoantibody isotypes, as some patients only harbor autoantibodies of IgM or IgA isotypes but not IgG. The clinical relevance of the different antibody isotypes still needs to be determined.
- |||||||||| Journal: Protein instability associated with AARS1 and MARS1 mutations causes Trichothiodystrophy. (Pubmed Central) - Mar 31, 2022
Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging, the first step in protein translation. The extension of reduced abundance of TTD factors to translation as well as transcription, redefines TTD as a syndrome in which proteins involved in gene expression are unstable.
- |||||||||| Journal: Expanded phenotype of AARS1-related white matter disease. (Pubmed Central) - Mar 23, 2022
However, a subgroup of affected individuals manifests with late-onset disease and similarly rapid progressive clinical decline. Longitudinal imaging and clinical follow-up will be valuable in understanding factors affecting disease progression and outcome.
- |||||||||| Journal: The uniqueness of AlaRS and its human disease connections. (Pubmed Central) - Feb 26, 2022
Given both essential canonical and diverse non-canonical roles of AlaRS, dysfunction of AlaRS leads to neurodegenerative disorders in human and various pathological phenotypes in mouse models. In this review, the uniqueness of AlaRS in both physiological and pathological events are systematically discussed, with a particular focus on its novel functions gained in evolution.
- |||||||||| Preclinical, Journal: NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice. (Pubmed Central) - Feb 12, 2022
Although we cannot fully explain its origin, it may reflect increased stress response or metabolic disturbances in CMT. Further large and longitudinal patient studies should be performed to establish the value of these proteins as diagnostic and prognostic molecular biomarkers for CMT.
- |||||||||| Journal: Defects in aminoacyl-tRNA synthetase cause partial B and T cell immunodeficiency. (Pubmed Central) - Feb 2, 2022
Misacylation of ARS and the consequent translational infidelity induce disturbances in signaling pathways critical for immune cell survival and responses. Our findings provide a novel mechanism by which translational fidelity might play a critical role in cellular and humoral immune responses.
- |||||||||| Journal: CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS. (Pubmed Central) - Jan 1, 2022
Moreover, we revealed a distinct structural loosening effect induced by a mutation in the editing domain and a lack of conformational impact with C-Ala domain mutations, indicating mutations in the same protein may cause neuropathy through different mechanisms. Our results show that, as with other CMT-associated tRNA synthetases, aminoacylation per se is not relevant to the pathology.
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