FARS2

FARS2 is located on the p arm of chromosome 6 in position 25.1 and has 15 exons. This gene encodes a member of the class-II aminoacyl-tRNA synthetase family.{{Cite web|url=https://www.uniprot.org/uniprot/O95363|title=FARS2 - Phenylalanine--tRNA ligase, mitochondrial precursor - Homo sapiens (Human) - FARS2 gene & protein|website=www.uniprot.org|language=en|access-date=2018-09-05}}{{CC-notice|cc=by4}}{{cite journal | title = UniProt: the universal protein knowledgebase | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D158–D169 | date = January 2017 | pmid = 27899622 | pmc = 5210571 | doi = 10.1093/nar/gkw1099 }} FARS2 is a phenylalanine-tRNA synthetase (PheRS) localized to the mitochondrion which consists of a single polypeptide chain, unlike the (alpha-beta)2 structure of the prokaryotic and eukaryotic cytoplasmic forms of PheRS. Structure analysis and catalytic properties indicate mitochondrial PheRSs may constitute a class of PheRS distinct from the enzymes found in prokaryotes and in the eukaryotic cytoplasm.

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. FARS2 charges tRNA(Phe) with phenylalanine and catalyzes direct attachment of m-Tyr (an oxidized version of Phe) to tRNA(Phe). This makes it important for mitochondrial translation and for delivery of the misacylated tRNA to the ribosome and incorporation of ROS-damaged amino acid into proteins.{{cite journal | vauthors = Klipcan L, Moor N, Kessler N, Safro MG | title = Eukaryotic cytosolic and mitochondrial phenylalanyl-tRNA synthetases catalyze the charging of tRNA with the meta-tyrosine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 27 | pages = 11045–8 | date = July 2009 | pmid = 19549855 | pmc = 2700156 | doi = 10.1073/pnas.0905212106 | bibcode = 2009PNAS..10611045K | doi-access = free }}{{cite journal | vauthors = Elo JM, Yadavalli SS, Euro L, Isohanni P, Götz A, Carroll CJ, Valanne L, Alkuraya FS, Uusimaa J, Paetau A, Caruso EM, Pihko H, Ibba M, Tyynismaa H, Suomalainen A | title = Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy | journal = Human Molecular Genetics | volume = 21 | issue = 20 | pages = 4521–9 | date = October 2012 | pmid = 22833457 | doi = 10.1093/hmg/dds294 | doi-access = free }} Alternative splicing results in multiple transcript variants.

ATP + L-phenylalanine + tRNA(Phe) = AMP + diphosphate + L-phenylalanyl-tRNA(Phe)

Mutations in FARS2 have been associated to combined oxidative phosphorylation deficiency 14, spastic paraplegia 77, and infantile-onset epilepsy and cytochrome c oxidase deficiency. Both combined oxidative phosphorylation deficiency 14 and spastic paraplegia 77 are autosomal recessive in nature and have been linked to several pathogenic variants including Y144C,{{cite journal | vauthors = Shamseldin HE, Alshammari M, Al-Sheddi T, Salih MA, Alkhalidi H, Kentab A, Repetto GM, Hashem M, Alkuraya FS | title = Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes | journal = Journal of Medical Genetics | volume = 49 | issue = 4 | pages = 234–41 | date = April 2012 | pmid = 22499341 | doi = 10.1136/jmedgenet-2012-100836 | s2cid = 5856138 }} I329T, D391V, and D142Y.{{cite journal | vauthors = Yang Y, Liu W, Fang Z, Shi J, Che F, He C, Yao L, Wang E, Wu Y | title = A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia | journal = Human Mutation | volume = 37 | issue = 2 | pages = 165–9 | date = February 2016 | pmid = 26553276 | doi = 10.1002/humu.22930 | s2cid = 46241711 | doi-access = free }} Combined oxidative phosphorylation deficiency 14 is characterized by neonatal onset of global developmental delay, refractory seizures, lactic acidosis, and deficiencies of multiple mitochondrial respiratory enzymes. Spastic paraplegia, meanwhile, is a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs, with patients often exhibiting difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. One case of infantile-onset epilepsy and cytochrome c oxidase deficiency resulting from a FARS2 Asp325Tyr missense mutation has also been reported. Early-onset epilepsy, neurological deficits, and complex IV deficiency are the main characteristics of the disease stemming from this mutation.

FARS2 has been shown to have 193 binary protein-protein interactions including 12 co-complex interactions. FARS2 appears to interact with RCBTB2, KRTAP10-9, CALCOCO2, KRT40, MID2, APPL1, IKZF3, KRT13, TADA2A, STX11, TRIM27, KRTAP10-5, KRTAP10-7, TFCP2, MKRN3, KRT31, HMBOX1, AGTRAP, ADAMTSL4, NOTCH2NL, CMTM5, TRIM54, FSD2, CYSRT1, HIGD1C, homez, SPRY1, ZNF500, KRT34, YIF1A, BAG4, TPM2, SYP, KRTAP10-8, KRTAP1-1, AP1B1, TRAF2, GRB10, MESD, TRIP6, CCDC152, BEX5, FHL5, MORN3, DGAT2L6, ZNF438, KCTD17, ZNF655, BANP, SPERT, NFKBID, ZNF526, PCSK5, DVL3, AJUBA, PPP1R16B, MDFI, DPH2, CDCA4, KRTAP3-3, BACH2, KCNF1, MAN1C1, RIMBP3, ZRANB1, ISY1, FKBP7, and E7.{{cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=FARS2 | title = 193 binary interactions found for search term FARS2 | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-09-05 }}

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• [https://www.ncbi.nlm.nih.gov/books/NBK320989/ Nuclear Gene-Encoded Leigh Syndrome Overview]
• [https://www.ncbi.nlm.nih.gov/books/NBK1173/ Mitochondrial DNA-Associated Leigh Syndrome and NARP]
• {{PDBe-KB2|O95363|Phenylalanine--tRNA ligase, mitochondrial}}

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