FARS2

更新于：2025-05-07

基本信息

别名

dJ236A3.1、FARS1、FARS2

+ [5]

简介

Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation. To a lesser extent, also catalyzes direct attachment of m-Tyr (an oxidized version of Phe) to tRNA(Phe), thereby opening the way for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins.

关联

项与 FARS2 相关的药物

BRD-5018

靶点

FARS2

作用机制

FARS2 inhibitors

在研机构

Eisai, Inc. [+1]

原研机构

The Broad Institute, Inc. [+1]

在研适应症

疟疾

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 FARS2 相关的临床结果

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100 项与 FARS2 相关的转化医学

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0 项与 FARS2 相关的专利（医药）

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625

项与 FARS2 相关的文献（医药）

2025-07-01·Archives of Biochemistry and Biophysics

Impact of pathogenic mutations on the refolding ability and stability of human mitochondrial Phenylalanyl-tRNA synthetase

Article

作者: Chaudhary, Nitin ; Tudu, Surajit ; Dey, Debkanya ; Chakraborty, Shruti ; Banerjee, Rajat ; Verma, Shubhangini Singh ; Roy, Debraj ; Manna, Riya

Human mitochondrial phenylalanyl-tRNA synthetase (hmtPheRS) requires partial unfolding for mitochondrial import and subsequent refolding to maintain proper functionality. Mutations in the FARS2 gene, encoding hmtPheRS, cause disorders such as early-onset epileptic encephalopathy and spastic paraplegia. This study was intended to investigate the impact of mutations on hmtPheRS refolding ability, stability, and solubility. We have selected two mutations associated with early-onset epileptic encephalopathy (G309S, D325Y) with severe phenotype and three mutations associated with spastic paraplegia (P136H, D142Y, P361L) with less severe phenotypes. Some of those mutations were reported to have diminished aminoacylation activity. However, the molecular connection of pathogenicity remained elusive for these mutants. We observed that hmtPheRS showed exceptional structural flexibility and refolding ability even at lower pH. Mutations associated with severe phenotypes (G309S, D325Y) exhibited impaired refolding ability and stability, whereas other mutant versions of hmtPheRS linked to hereditary spastic paraplegia (P136H, D142Y, P361L) retained some stability and refolding capacity. Mutants exhibited expansion in hydrodynamic diameter, indicating significant perturbation in the internal architecture. Molecular simulation studies suggested the presence of structural deformities in hmtPheRS mutants at mildly acidic pH. This analysis reveals how mutations affect protein stability and function, which may play a role in mitochondrial disorders. It may act as a probable model for predicting pathogenicity-related mutants.

2025-05-01·JIMD Reports

Neonatal Cholestasis Progressing to a Multisystem Syndrome With Liver Cirrhosis in Two Siblings With FARSA Deficiency: An Evolving Hepatological Phenotype

Article

作者: Mendes, M. ; Dheedene, A. ; Vande Velde, S. ; Pottie, L. ; Van Biervliet, S. ; Hoorens, A. ; De Bruyne, R. ; Vanlander, A. ; De Bruyne, P. ; Aelvoet, Y. ; Hoste, L. ; Verloo, P.

ABSTRACTBiallelic variants in FARSA or FARSB are associated with reduced cytoplasmic phenylalanyl‐tRNA synthetase (FARS1) activity and underlie a multisystem syndrome characterized by growth limitation, developmental delay, brain calcifications, interstitial lung disease (ILD), and liver involvement. ILD is an early characteristic feature marked by bilateral ground‐glass opacification, subpleural cysts, and cholesterol pneumonitis and seems to be the leading cause of disease burden and death. A 7‐year‐old Iraqi girl was referred with idiopathic liver disease. Her previous medical history revealed neonatal jaundice, failure to thrive (FTT), mild motor development delay, and variceal bleeding at the age of 6 years in Iraq. She was diagnosed with liver cirrhosis, severe splenomegaly, profound thrombocytopenia, and hypoalbuminemia. Her younger brother presented to our hospital at the age of 2 months with neonatal cholestasis progressing to hepatic failure with impaired synthetic function. He suffered from coagulopathy, intractable hypoalbuminemia, FTT with axial hypotonia, multiple infectious episodes, and a prothrombotic state. Whole exome sequencing revealed compound heterozygous missense variants p.(Pro226Leu) and p.(Arg475Trp) in FARSA (OMIM: 602918) in both siblings. Even in the absence of overt clinical symptoms, chest computer tomography following diagnosis showed ILD in both siblings. Decreased FARS1 activity was measured in fibroblasts of both patients. We are the first to report on two siblings with neonatal jaundice evolving to severe liver disease as a cardinal symptom of cytosolic FARS deficiency. We emphasize the importance of performing a pulmonary workup in the diagnostic process of liver failure of unknown origin for detection of ILD as a clue to diagnosis.

2025-04-18·American journal of rhinology & allergy

Lactic Acid Metabolism-Related Gene May Act as a Prognostic Predictor by FARS2 in Nasopharyngeal Carcinoma.

Article

作者: Wang, Zixuan ; Zong, Dan ; Zhu, Huanfeng ; Cao, Xiang ; Zou, Guannan ; Huang, Wenxuan

BackgroundThis study aimed to investigate the clinical value of lactic acid metabolism-related genes (LRGs) in nasopharyngeal carcinoma (NPC).MethodsClinical and genetic information was extracted from the TGCA and Gene Expression Omnibus databases. Consistency clustering was employed to identify NPC subpopulations. Immune infiltration was appraised using TIMER, ESTIMATE, and MCPCounter. Functional analysis was conducted to elucidate potential mechanisms. A prognostic risk model was successfully constructed using the LASSO algorithm and multivariate Cox regression analysis. Phenotypic experiments were conducted to validate the glycolysis and lactic acid metabolism.ResultsAccording to prognostically LRG genes, two clusters were identified and exhibited significant difference in immune landscape, which indicated variations in immune status. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis revealed that the differentially expressed genes were predominantly implicated in immune-related pathways. These findings suggested that the LRG-based risk model could successfully predict the prognosis of NPC patients. Moreover, the risk model retained its predictive potency by stratifying patients with sex and age, with lower risk score patients displaying improved prognosis. In the training cohort, the low-risk group showed significantly lower stromal score, immune score, and ESTIMATE score compared with the high-risk group. To further enhance the precision of prognostic predictions, we developed a nomogram that integrated the risk model with clinical features. In the training cohort, the established nomogram could accurately predict the prognosis of NPC patients. Mechanically, the knockdown of FARS2 in NPC cells resulted in altered glycolysis and lactification. Deregulated FARS2 led to the accumulation of metabolic intensity, which resulted in the disruption of lactic acid metabolism.ConclusionThese results highlighted the potential association between LRGs expression and immune dysfunction, which might contribute to adverse prognosis in NPC patients. This study represented a pioneering effort in exploring the prognostic value of LRGs in NPC.

项与 FARS2 相关的新闻（医药）

2024-02-22

·生物探索

Circulation | 空军军医大学吴元明/刘丽文等合作发现心肌病的致病新机制

引言肥厚性心肌病是一种常见的遗传性心肌病。尽管HCM已被报道与许多参与肌体蛋白生物力学的基因变异相关，但在部分HCM患者中尚未发现致病基因。FARS2 (线粒体phenylalanyl-tRNA合成酶)是线粒体氨基酰基-tRNA合成酶的一种，在线粒体翻译机制中起作用。FARS2的几种变体已被认为可引起神经系统疾病；然而，涉及其他器官的FARS2相关疾病尚未报道。2024年2月16日，空军军医大学吴元明、刘丽文、Chen Kun共同通讯在Circulation（IF 38）在线发表题为“FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System”的研究论文，该研究表明FARS2缺乏通过破坏线粒体稳态和线粒体质量控制系统引起心肌病。该研究在HCM患者中发现了7个未报道的FARS2变异。心脏特异性Fars2缺陷小鼠表现为心脏肥厚、左心室扩张、进行性心力衰竭伴心肌和线粒体功能障碍、寿命短。杂合子心脏特异性Fars2R415L小鼠在4周龄时表现出心肌肥厚的倾向，并伴有心肌功能障碍。此外，Fars2敲低的斑马鱼出现心包水肿和心力衰竭。FARS2缺陷通过直接阻断mt-tRNAPhe的氨基酰化和抑制线粒体蛋白的合成来破坏线粒体稳态，最终通过加速线粒体超片段化和破坏线粒体相关的自噬，导致线粒体质量控制系统失衡。使用腺相关病毒9或特异性抑制剂干扰线粒体质量控制系统，通过恢复线粒体稳态，减轻由FARS2缺陷引发的心脏和线粒体功能障碍。该研究揭示了先前未被认识到的FARS2在心脏和线粒体稳态中的作用，为遗传性心肌病的分子诊断和预防以及FARS2相关心肌病的治疗选择提供新的见解。肥厚性心肌病(HCM)是最常见的遗传性心肌病，发病率约为1/500。HCM以左心室不对称增厚和舒张功能受损为特征，是心力衰竭(HF)和心源性猝死的主要原因在过去的20年里，分子遗传学的进展已经揭示了超过1000个与HCM相关的遗传变异，其中大多数与肌体基因有关，如MYH7和MYBPC3。然而，相当比例的HCM患者没有表现出任何已知遗传变异的证据。因此，其他新的致病变异可能负责或促成这些患者的HCM表型。线粒体独立于细胞质，具有由线粒体DNA (mtDNA)编码的tRNA、核糖体RNA和核DNA编码的线粒体氨基酰基tRNA合成酶(mtARS)调节的翻译机制。超过1500个线粒体蛋白中只有13个是在线粒体中合成的。这13种蛋白构成了OXPHOS复合物的关键亚基，mtARS负责线粒体蛋白的合成，其中涉及到tRNA与其同源氨基酸的共价配对。全基因组测序的广泛应用揭示了与疾病相关的mtARS编码基因的多种变异，这些变异主要在需要高能量的器官中观察到。尽管酶具有共同的生化作用，但mtARS变异患者的广泛临床表现涉及不同的生理系统然而，mtARS编码基因的变异在很大程度上与中枢神经系统有关。只有一些变异，包括AARS2、VARS2、PARS2和YARS2，被确定为人类心肌病的病因，但病理机制尚不清楚。所有已知的FARS2变异仅与中枢神经系统相关疾病有关，如遗传性痉挛性截瘫FARS2变异与其他全身性疾病的相关性尚未报道。FARS2缺乏通过破坏线粒体稳态和线粒体质量控制系统引起心肌病（Credit: Circulation）线粒体功能、形态和质量的维持，也称为线粒体稳态，对心脏功能和衰老至关重要线粒体质量控制(MQC)系统是一个强大的协调器，在基础条件和各种应激条件下(如心脏重构)维持线粒体稳态。复杂的信号通路构成了MQC系统，包括线粒体裂变、融合和线粒体相关的自噬。已有研究揭示了MQC系统的关键功能分子在心脏功能和应激诱导重构中的作用。然而，mtARS相关HCM的分子机制尚不清楚，线粒体稳态变化和MQC系统的作用也不清楚。该研究发现FARS2是遗传性心肌病的潜在致病基因。FARS2缺乏通过损害线粒体稳态和破坏MQC系统导致心脏肥厚。该研究不仅强化了FARS2在心脏病中的生物学功能，而且为线粒体翻译缺陷相关HCM的潜在预防和FARS2相关心肌病的治疗靶点提供了新的见解。原文链接https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.064489责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 癌症与神经系统的致命舞蹈

信使RNA临床1期抗体药物偶联物