FARS2

Last updated
FARS2
Protein FARS2 PDB 3CMQ.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FARS2 , COXPD14, FARS1, HSPC320, PheRS, dJ520B18.2, phenylalanyl-tRNA synthetase 2, mitochondrial, SPG77, mtPheRS
External IDs OMIM: 611592 MGI: 1917205 HomoloGene: 4788 GeneCards: FARS2
Orthologs
SpeciesHumanMouse
Entrez

10667

69955

Ensembl

ENSG00000145982

ENSMUSG00000021420

UniProt

O95363

Q99M01

RefSeq (mRNA)

NM_006567
NM_001318872

NM_001039189
NM_024274

RefSeq (protein)

NP_001034278
NP_077236

Location (UCSC) Chr 6: 5.26 – 5.83 Mb Chr 13: 36.12 – 36.73 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Phenylalanyl-tRNA synthetase, mitochondrial (FARS2) is an enzyme that in humans is encoded by the FARS2 gene. [5] This protein encoded by FARS2 localizes to the mitochondrion and plays a role in mitochondrial protein translation. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 14, also known as Alpers encephalopathy, as well as spastic paraplegia 77 and infantile-onset epilepsy and cytochrome c oxidase deficiency. [6] [7]

Structure

FARS2 is located on the p arm of chromosome 6 in position 25.1 and has 15 exons. [6] This gene encodes a member of the class-II aminoacyl-tRNA synthetase family. [8] [9] 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. [6]

Function

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. [6] 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. [8] [9] [10] [11] Alternative splicing results in multiple transcript variants. [6]

Catalytic activity

ATP + L-phenylalanine + tRNA(Phe) = AMP + diphosphate + L-phenylalanyl-tRNA(Phe) [8] [9] [10] [11]

Clinical significance

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, [12] I329T, D391V, [11] and D142Y. [13] 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. [8] [9] 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. [7]

Interactions

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. [14]

Related Research Articles

Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs. HSP is also known as hereditary spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell disease, or Strumpell-Lorrain disease. The symptoms are a result of dysfunction of long axons in the spinal cord. The affected cells are the primary motor neurons; therefore, the disease is an upper motor neuron disease. HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as spastic diplegia. The origin of HSP is different from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to treat HSP symptoms.

Glucose transporter 1, also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene. GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells. This gene encodes a facilitative glucose transporter that is highly expressed in erythrocytes and endothelial cells, including cells of the blood–brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. GLUT1 accounts for 2 percent of the protein in the plasma membrane of erythrocytes. Mutations in this gene can cause GLUT1 deficiency syndrome 1, GLUT1 deficiency syndrome 2, idiopathic generalized epilepsy 12, dystonia 9, and stomatin-deficient cryohydrocytosis.

<span class="mw-page-title-main">HADHB</span> Protein-coding gene in the species Homo sapiens

Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene.

<span class="mw-page-title-main">MT-RNR1</span> SSU rRNA of the mitochondrial ribosome

Mitochondrially encoded 12S ribosomal RNA is the SSU rRNA of the mitochondrial ribosome. In humans, 12S is encoded by the MT-RNR1 gene and is 959 nucleotides long. MT-RNR1 is one of the 37 genes contained in animal mitochondria genomes. Their 2 rRNA, 22 tRNA and 13 mRNA genes are very useful in phylogenetic studies, in particular the 12S and 16S rRNAs. The 12S rRNA is the mitochondrial homologue of the prokaryotic 16S and eukaryotic nuclear 18S ribosomal RNAs. Mutations in the MT-RNR1 gene may be associated with hearing loss. The rRNA gene also encodes a peptide MOTS-c, also known as Mitochondrial-derived peptide MOTS-c or Mitochondrial open reading frame of the 12S rRNA-c.

<span class="mw-page-title-main">Phenylalanine—tRNA ligase</span>

In enzymology, a phenylalanine—tRNA ligase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">PLA2G6</span> Protein-coding gene in the species Homo sapiens

85 kDa calcium-independent phospholipase A2, also known as 85/88 kDa calcium-independent phospholipase A2, Group VI phospholipase A2, Intracellular membrane-associated calcium-independent phospholipase A2 beta, or Patatin-like phospholipase domain-containing protein 9 is an enzyme that in humans is encoded by the PLA2G6 gene.

<span class="mw-page-title-main">COX4I1</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase subunit 4 isoform 1, mitochondrial (COX4I1) is an enzyme that in humans is encoded by the COX4I1 gene. COX4I1 is a nuclear-encoded isoform of cytochrome c oxidase (COX) subunit 4. Cytochrome c oxidase is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane, acting as the terminal enzyme of the mitochondrial respiratory chain. Antibodies against COX4 can be used to identify the inner membrane of mitochondria in immunofluorescence studies. Mutations in COX4I1 have been associated with COX deficiency and Fanconi anemia.

<span class="mw-page-title-main">Paraplegin</span> Protein-coding gene in the species Homo sapiens

Paraplegin is a protein that in humans is encoded by the SPG7 gene located on chromosome 16.

<span class="mw-page-title-main">FARSB</span> Protein-coding gene in the species Homo sapiens

Phenylalanyl-tRNA synthetase beta chain is an enzyme that in humans is encoded by the FARSB gene.

<span class="mw-page-title-main">FOXRED1</span> Protein-coding gene in the species Homo sapiens

FAD-dependent oxidoreductase domain-containing protein 1 (FOXRED1), also known as H17, or FP634 is an enzyme that in humans is encoded by the FOXRED1 gene. FOXRED1 is an oxidoreductase and complex I-specific molecular chaperone involved in the assembly and stabilization of NADH dehydrogenase (ubiquinone) also known as complex I, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Mutations in FOXRED1 have been associated with Leigh syndrome and infantile-onset mitochondrial encephalopathy.

<span class="mw-page-title-main">COX15</span> Protein-coding gene in the species Homo sapiens

Cytochrome c oxidase assembly protein COX15 homolog (COX15), also known as heme A synthase, is a protein that in humans is encoded by the COX15 gene. This protein localizes to the inner mitochondrial membrane and involved in heme A biosynthesis. COX15 is also part of a three-component mono-oxygenase that catalyses the hydroxylation of the methyl group at position eight of the protoheme molecule. Mutations in this gene has been reported in patients with hypertrophic cardiomyopathy as well as Leigh syndrome, and characterized by delayed onset of symptoms, hypotonia, feeding difficulties, failure to thrive, motor regression, and brain stem signs.

Mitochondrially encoded tRNA glutamic acid also known as MT-TE is a transfer RNA which in humans is encoded by the mitochondrial MT-TE gene. MT-TE is a small 69 nucleotide RNA that transfers the amino acid glutamic acid to a growing polypeptide chain at the ribosome site of protein synthesis during translation.

Mitochondrially encoded tRNA phenylalanine also known as MT-TF is a transfer RNA which in humans is encoded by the mitochondrial MT-TF gene.

Mitochondrially encoded tRNA glycine also known as MT-TG is a transfer RNA which in humans is encoded by the mitochondrial MT-TG gene.

Mitochondrially encoded tRNA isoleucine also known as MT-TI is a transfer RNA which in humans is encoded by the mitochondrial MT-TI gene.

Mitochondrially encoded tRNA lysine also known as MT-TK is a transfer RNA which in humans is encoded by the mitochondrial MT-TK gene.

Mitochondrially encoded tRNA proline also known as MT-TP is a transfer RNA that in humans is encoded by the mitochondrial MT-TP gene.

Mitochondrially encoded tRNA arginine also known as MT-TR is a transfer RNA which in humans is encoded by the mitochondrial MT-TR gene.

Mitochondrially encoded tRNA threonine also known as MT-TT is a transfer RNA which in humans is encoded by the mitochondrial MT-TT gene.

<span class="mw-page-title-main">Michaela Jaksch-Angerer</span>

Michaela Jaksch-Angerer is a German medical doctor, consultant in laboratory medicine, and Associate Professor for Clinical Chemistry. She has held the position of "Managing and Medical Director" since 2004 at the Freiburg Medical Laboratory Middle East LLC, Dubai, UAE, a member of Synlab since 2013. FML was founded in 2002 as a joint venture of the University of Freiburg Germany and the Al Abbas Group, Dubai, UAE.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000145982 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021420 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Bullard JM, Cai YC, Demeler B, Spremulli LL (May 1999). "Expression and characterization of a human mitochondrial phenylalanyl-tRNA synthetase". Journal of Molecular Biology. 288 (4): 567–77. doi:10.1006/jmbi.1999.2708. PMID   10329163.
  6. 1 2 3 4 5 "Entrez Gene: FARS2 phenylalanyl-tRNA synthetase 2, mitochondrial".PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. 1 2 Almalki A, Alston CL, Parker A, Simonic I, Mehta SG, He L, Reza M, Oliveira JM, Lightowlers RN, McFarland R, Taylor RW, Chrzanowska-Lightowlers ZM (January 2014). "Mutation of the human mitochondrial phenylalanine-tRNA synthetase causes infantile-onset epilepsy and cytochrome c oxidase deficiency". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842 (1): 56–64. doi:10.1016/j.bbadis.2013.10.008. PMC   3898479 . PMID   24161539.
  8. 1 2 3 4 "FARS2 - Phenylalanine--tRNA ligase, mitochondrial precursor - Homo sapiens (Human) - FARS2 gene & protein". www.uniprot.org. Retrieved 2018-09-05. CC BY icon-80x15.png  This article incorporates text available under the CC BY 4.0 license.
  9. 1 2 3 4 "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC   5210571 . PMID   27899622.
  10. 1 2 Klipcan L, Moor N, Kessler N, Safro MG (July 2009). "Eukaryotic cytosolic and mitochondrial phenylalanyl-tRNA synthetases catalyze the charging of tRNA with the meta-tyrosine". Proceedings of the National Academy of Sciences of the United States of America. 106 (27): 11045–8. Bibcode:2009PNAS..10611045K. doi: 10.1073/pnas.0905212106 . PMC   2700156 . PMID   19549855.
  11. 1 2 3 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 (October 2012). "Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy". Human Molecular Genetics. 21 (20): 4521–9. doi: 10.1093/hmg/dds294 . PMID   22833457.
  12. ↑ Shamseldin HE, Alshammari M, Al-Sheddi T, Salih MA, Alkhalidi H, Kentab A, Repetto GM, Hashem M, Alkuraya FS (April 2012). "Genomic analysis of mitochondrial diseases in a consanguineous population reveals novel candidate disease genes". Journal of Medical Genetics. 49 (4): 234–41. doi:10.1136/jmedgenet-2012-100836. PMID   22499341. S2CID   5856138.
  13. ↑ Yang Y, Liu W, Fang Z, Shi J, Che F, He C, Yao L, Wang E, Wu Y (February 2016). "A Newly Identified Missense Mutation in FARS2 Causes Autosomal-Recessive Spastic Paraplegia". Human Mutation. 37 (2): 165–9. doi: 10.1002/humu.22930 . PMID   26553276. S2CID   46241711.
  14. ↑ "193 binary interactions found for search term FARS2". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-09-05.


Further reading

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