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Last update 08 May 2025

FARS2

Last update 08 May 2025

Basic Info

Synonyms

dJ236A3.1, FARS1, FARS2

+ [5]

Introduction

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.

Drugs associated with FARS2

BRD-5018

Target

FARS2

Mechanism

FARS2 inhibitors

Active Org.

Eisai, Inc. [+1]

Originator Org.

The Broad Institute, Inc. [+1]

Active Indication

Malaria

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with FARS2

100 Translational Medicine associated with FARS2

0 Patents (Medical) associated with FARS2

625

Literatures (Medical) associated with FARS2

01 Jul 2025·Archives of Biochemistry and Biophysics

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

Article

Author: 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.

01 May 2025·JIMD Reports

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

Article

Author: 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.

18 Apr 2025·American journal of rhinology & allergy

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

Article

Author: 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.

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