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Protein

Phenylalanine--tRNA ligase, mitochondrial

Gene

FARS2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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.2 Publications

Catalytic activityi

ATP + L-phenylalanine + tRNA(Phe) = AMP + diphosphate + L-phenylalanyl-tRNA(Phe).2 Publications

Kineticsi

kcat is 2.8 min(-1), 2.0 min(-1) and 3.1 min(-1) with L-phenylalanine, L-tyrosine and m-tyrosine as substrate, respectively. Thus, the catalytic efficiency of the m-Tyr attachment is only 5-fold lower than that of the correct amino acid, while that of Tyr attachment is 1000-fold lower (PubMed:19549855).1 Publication
  1. KM=2.2 µM for L-phenylalanine2 Publications
  2. KM=1900 µM for L-tyrosine2 Publications
  3. KM=11.7 µM for DL-m-tyrosine2 Publications
  4. KM=7.3 µM for L-phenylalanine2 Publications
  5. KM=2.9 mM for ATP2 Publications
  6. KM=1.2 µM for tRNA(Phe)2 Publications

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei179Substrate2 Publications1
    Binding sitei287Substrate; via carbonyl oxygen2 Publications1
    Binding sitei312Substrate; via carbonyl oxygen2 Publications1

    GO - Molecular functioni

    • ATP binding Source: UniProtKB-KW
    • phenylalanine-tRNA ligase activity Source: UniProtKB
    • tRNA binding Source: UniProtKB

    GO - Biological processi

    Keywordsi

    Molecular functionAminoacyl-tRNA synthetase, Ligase
    Biological processProtein biosynthesis
    LigandATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    BRENDAi6.1.1.20 2681
    ReactomeiR-HSA-379726 Mitochondrial tRNA aminoacylation

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Phenylalanine--tRNA ligase, mitochondrial (EC:6.1.1.202 Publications)
    Alternative name(s):
    Phenylalanyl-tRNA synthetase
    Short name:
    PheRS
    Gene namesi
    Name:FARS2
    Synonyms:FARS1
    ORF Names:HSPC320
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 6

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000145982.11
    HGNCiHGNC:21062 FARS2
    MIMi611592 gene
    neXtProtiNX_O95363

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Mitochondrion

    Pathology & Biotechi

    Involvement in diseasei

    Combined oxidative phosphorylation deficiency 14 (COXPD14)2 Publications
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA severe multisystemic autosomal recessive disorder characterized by neonatal onset of global developmental delay, refractory seizures, and lactic acidosis. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes.
    See also OMIM:614946
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_069487144Y → C in COXPD14; results in decreased affinity for tRNA causing a decrease in the catalytic efficiency for tRNA charging; does not affect ATP or Phe binding. 2 PublicationsCorresponds to variant dbSNP:rs397514610EnsemblClinVar.1
    Natural variantiVAR_069488329I → T in COXPD14; results in a 4-fold decrease in the catalytic efficiency of amino acid activation mainly due to a decreased affinity for ATP; does not affect Phe binding; affects the stability of the enzyme, leading to a significant decrease in overall charging capacity. 1 PublicationCorresponds to variant dbSNP:rs397514611EnsemblClinVar.1
    Natural variantiVAR_069489391D → V in COXPD14; results in a decrease in affinity for Phe causing a decrease in aminoacylation activity; affects the stability of the enzyme, leading to a significant decrease in overall charging capacity. 1 PublicationCorresponds to variant dbSNP:rs397514612EnsemblClinVar.1
    Spastic paraplegia 77, autosomal recessive (SPG77)1 Publication
    The disease is caused by mutations affecting the gene represented in this entry.
    Disease descriptionA form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body.
    See also OMIM:617046
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_077044142D → Y in SPG77; resulted in severely impaired phenylalanine-tRNA ligase activity. 1 PublicationCorresponds to variant dbSNP:rs145555213EnsemblClinVar.1

    Keywords - Diseasei

    Disease mutation, Hereditary spastic paraplegia, Neurodegeneration, Primary mitochondrial disease

    Organism-specific databases

    DisGeNETi10667
    MalaCardsiFARS2
    MIMi614946 phenotype
    617046 phenotype
    OpenTargetsiENSG00000145982
    Orphaneti466722 Autosomal recessive spastic paraplegia type 77
    319519 Combined oxidative phosphorylation defect type 14
    PharmGKBiPA134954893

    Chemistry databases

    ChEMBLiCHEMBL2511
    DrugBankiDB00120 L-Phenylalanine

    Polymorphism and mutation databases

    BioMutaiFARS2

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_0000035813? – 451Phenylalanine--tRNA ligase, mitochondrial
    Transit peptidei1 – ?MitochondrionSequence analysis

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei202N6-acetyllysineCombined sources1

    Keywords - PTMi

    Acetylation

    Proteomic databases

    EPDiO95363
    MaxQBiO95363
    PaxDbiO95363
    PeptideAtlasiO95363
    PRIDEiO95363
    ProteomicsDBi50824

    PTM databases

    iPTMnetiO95363
    PhosphoSitePlusiO95363

    Expressioni

    Gene expression databases

    BgeeiENSG00000145982 Expressed in 206 organ(s), highest expression level in epithelium of bronchus
    CleanExiHS_FARS2
    ExpressionAtlasiO95363 baseline and differential
    GenevisibleiO95363 HS

    Organism-specific databases

    HPAiHPA018148
    HPA028836

    Interactioni

    Subunit structurei

    Monomer.3 Publications

    Binary interactionsi

    Protein-protein interaction databases

    BioGridi115909, 52 interactors
    IntActiO95363, 78 interactors
    MINTiO95363
    STRINGi9606.ENSP00000274680

    Chemistry databases

    BindingDBiO95363

    Structurei

    Secondary structure

    1451
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliO95363
    SMRiO95363
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiO95363

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini358 – 450FDX-ACBPROSITE-ProRule annotationAdd BLAST93

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni157 – 160Substrate binding4
    Regioni186 – 188Substrate binding3
    Regioni193 – 195Substrate binding3

    Sequence similaritiesi

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG2783 Eukaryota
    COG0016 LUCA
    COG0072 LUCA
    GeneTreeiENSGT00530000063467
    HOGENOMiHOG000165163
    HOVERGENiHBG082540
    InParanoidiO95363
    KOiK01889
    OMAiTYFPFTQ
    OrthoDBiEOG091G07OD
    PhylomeDBiO95363
    TreeFamiTF105798

    Family and domain databases

    Gene3Di3.30.70.380, 1 hit
    InterProiView protein in InterPro
    IPR006195 aa-tRNA-synth_II
    IPR005121 Fdx_antiC-bd
    IPR036690 Fdx_antiC-bd_sf
    IPR004530 Phe-tRNA-synth_IIc_mito
    IPR002319 Phenylalanyl-tRNA_Synthase
    PANTHERiPTHR11538:SF41 PTHR11538:SF41, 1 hit
    PfamiView protein in Pfam
    PF03147 FDX-ACB, 1 hit
    PF01409 tRNA-synt_2d, 2 hits
    SMARTiView protein in SMART
    SM00896 FDX-ACB, 1 hit
    SUPFAMiSSF54991 SSF54991, 1 hit
    TIGRFAMsiTIGR00469 pheS_mito, 1 hit
    PROSITEiView protein in PROSITE
    PS50862 AA_TRNA_LIGASE_II, 1 hit
    PS51447 FDX_ACB, 1 hit

    Sequence (1+)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

    O95363-1 [UniParc]FASTAAdd to basket
    « Hide
            10         20         30         40         50
    MVGSALRRGA HAYVYLVSKA SHISRGHQHQ AWGSRPPAAE CATQRAPGSV
    60 70 80 90 100
    VELLGKSYPQ DDHSNLTRKV LTRVGRNLHN QQHHPLWLIK ERVKEHFYKQ
    110 120 130 140 150
    YVGRFGTPLF SVYDNLSPVV TTWQNFDSLL IPADHPSRKK GDNYYLNRTH
    160 170 180 190 200
    MLRAHTSAHQ WDLLHAGLDA FLVVGDVYRR DQIDSQHYPI FHQLEAVRLF
    210 220 230 240 250
    SKHELFAGIK DGESLQLFEQ SSRSAHKQET HTMEAVKLVE FDLKQTLTRL
    260 270 280 290 300
    MAHLFGDELE IRWVDCYFPF THPSFEMEIN FHGEWLEVLG CGVMEQQLVN
    310 320 330 340 350
    SAGAQDRIGW AFGLGLERLA MILYDIPDIR LFWCEDERFL KQFCVSNINQ
    360 370 380 390 400
    KVKFQPLSKY PAVINDISFW LPSENYAEND FYDLVRTIGG DLVEKVDLID
    410 420 430 440 450
    KFVHPKTHKT SHCYRITYRH MERTLSQREV RHIHQALQEA AVQLLGVEGR

    F
    Length:451
    Mass (Da):52,357
    Last modified:May 1, 1999 - v1
    Checksum:i1E5CC647A4A7193B
    GO

    Computationally mapped potential isoform sequencesi

    There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    Q5JRF7Q5JRF7_HUMAN
    Phenylalanine--tRNA ligase, mitocho...
    FARS2
    101Annotation score:
    R4GMX6R4GMX6_HUMAN
    Phenylalanine--tRNA ligase, mitocho...
    FARS2
    47Annotation score:

    Sequence cautioni

    The sequence AAF28998 differs from that shown. Reason: Frameshift at position 414.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti158A → T in BAD97143 (Ref. 4) Curated1
    Sequence conflicti361P → T in AAF28998 (Ref. 7) Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_05264257S → C. Corresponds to variant dbSNP:rs34382405EnsemblClinVar.1
    Natural variantiVAR_077044142D → Y in SPG77; resulted in severely impaired phenylalanine-tRNA ligase activity. 1 PublicationCorresponds to variant dbSNP:rs145555213EnsemblClinVar.1
    Natural variantiVAR_069487144Y → C in COXPD14; results in decreased affinity for tRNA causing a decrease in the catalytic efficiency for tRNA charging; does not affect ATP or Phe binding. 2 PublicationsCorresponds to variant dbSNP:rs397514610EnsemblClinVar.1
    Natural variantiVAR_052643280N → S3 PublicationsCorresponds to variant dbSNP:rs11243011EnsemblClinVar.1
    Natural variantiVAR_069488329I → T in COXPD14; results in a 4-fold decrease in the catalytic efficiency of amino acid activation mainly due to a decreased affinity for ATP; does not affect Phe binding; affects the stability of the enzyme, leading to a significant decrease in overall charging capacity. 1 PublicationCorresponds to variant dbSNP:rs397514611EnsemblClinVar.1
    Natural variantiVAR_069489391D → V in COXPD14; results in a decrease in affinity for Phe causing a decrease in aminoacylation activity; affects the stability of the enzyme, leading to a significant decrease in overall charging capacity. 1 PublicationCorresponds to variant dbSNP:rs397514612EnsemblClinVar.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF097441 mRNA Translation: AAC83802.1
    AK312454 mRNA Translation: BAG35361.1
    CR542279 mRNA Translation: CAG47075.1
    AK223423 mRNA Translation: BAD97143.1
    AL133473 Genomic DNA No translation available.
    AL022097 Genomic DNA No translation available.
    AL392184 Genomic DNA No translation available.
    AL121978 Genomic DNA No translation available.
    AL590868 Genomic DNA No translation available.
    BC020239 mRNA Translation: AAH20239.1
    BC021112 mRNA Translation: AAH21112.1
    AF161438 mRNA Translation: AAF28998.1 Frameshift.
    CCDSiCCDS4494.1
    RefSeqiNP_001305801.1, NM_001318872.1
    NP_006558.1, NM_006567.4
    XP_005248869.1, XM_005248812.3
    XP_016865675.1, XM_017010186.1
    XP_016865676.1, XM_017010187.1
    UniGeneiHs.484547

    Genome annotation databases

    EnsembliENST00000274680; ENSP00000274680; ENSG00000145982
    ENST00000324331; ENSP00000316335; ENSG00000145982
    GeneIDi10667
    KEGGihsa:10667
    UCSCiuc003mwr.3 human

    Keywords - Coding sequence diversityi

    Polymorphism

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF097441 mRNA Translation: AAC83802.1
    AK312454 mRNA Translation: BAG35361.1
    CR542279 mRNA Translation: CAG47075.1
    AK223423 mRNA Translation: BAD97143.1
    AL133473 Genomic DNA No translation available.
    AL022097 Genomic DNA No translation available.
    AL392184 Genomic DNA No translation available.
    AL121978 Genomic DNA No translation available.
    AL590868 Genomic DNA No translation available.
    BC020239 mRNA Translation: AAH20239.1
    BC021112 mRNA Translation: AAH21112.1
    AF161438 mRNA Translation: AAF28998.1 Frameshift.
    CCDSiCCDS4494.1
    RefSeqiNP_001305801.1, NM_001318872.1
    NP_006558.1, NM_006567.4
    XP_005248869.1, XM_005248812.3
    XP_016865675.1, XM_017010186.1
    XP_016865676.1, XM_017010187.1
    UniGeneiHs.484547

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    3CMQX-ray2.20A38-451[»]
    3HFVX-ray2.60A38-451[»]
    3TEGX-ray2.20A38-451[»]
    3TUPX-ray3.05A38-451[»]
    5MGHX-ray1.87A47-451[»]
    5MGUX-ray1.89A46-451[»]
    5MGVX-ray2.05A47-451[»]
    5MGWX-ray1.46A46-451[»]
    ProteinModelPortaliO95363
    SMRiO95363
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi115909, 52 interactors
    IntActiO95363, 78 interactors
    MINTiO95363
    STRINGi9606.ENSP00000274680

    Chemistry databases

    BindingDBiO95363
    ChEMBLiCHEMBL2511
    DrugBankiDB00120 L-Phenylalanine

    PTM databases

    iPTMnetiO95363
    PhosphoSitePlusiO95363

    Polymorphism and mutation databases

    BioMutaiFARS2

    Proteomic databases

    EPDiO95363
    MaxQBiO95363
    PaxDbiO95363
    PeptideAtlasiO95363
    PRIDEiO95363
    ProteomicsDBi50824

    Protocols and materials databases

    DNASUi10667
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000274680; ENSP00000274680; ENSG00000145982
    ENST00000324331; ENSP00000316335; ENSG00000145982
    GeneIDi10667
    KEGGihsa:10667
    UCSCiuc003mwr.3 human

    Organism-specific databases

    CTDi10667
    DisGeNETi10667
    EuPathDBiHostDB:ENSG00000145982.11
    GeneCardsiFARS2
    HGNCiHGNC:21062 FARS2
    HPAiHPA018148
    HPA028836
    MalaCardsiFARS2
    MIMi611592 gene
    614946 phenotype
    617046 phenotype
    neXtProtiNX_O95363
    OpenTargetsiENSG00000145982
    Orphaneti466722 Autosomal recessive spastic paraplegia type 77
    319519 Combined oxidative phosphorylation defect type 14
    PharmGKBiPA134954893
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2783 Eukaryota
    COG0016 LUCA
    COG0072 LUCA
    GeneTreeiENSGT00530000063467
    HOGENOMiHOG000165163
    HOVERGENiHBG082540
    InParanoidiO95363
    KOiK01889
    OMAiTYFPFTQ
    OrthoDBiEOG091G07OD
    PhylomeDBiO95363
    TreeFamiTF105798

    Enzyme and pathway databases

    BRENDAi6.1.1.20 2681
    ReactomeiR-HSA-379726 Mitochondrial tRNA aminoacylation

    Miscellaneous databases

    ChiTaRSiFARS2 human
    EvolutionaryTraceiO95363
    GeneWikiiFARS2
    GenomeRNAii10667
    PROiPR:O95363
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000145982 Expressed in 206 organ(s), highest expression level in epithelium of bronchus
    CleanExiHS_FARS2
    ExpressionAtlasiO95363 baseline and differential
    GenevisibleiO95363 HS

    Family and domain databases

    Gene3Di3.30.70.380, 1 hit
    InterProiView protein in InterPro
    IPR006195 aa-tRNA-synth_II
    IPR005121 Fdx_antiC-bd
    IPR036690 Fdx_antiC-bd_sf
    IPR004530 Phe-tRNA-synth_IIc_mito
    IPR002319 Phenylalanyl-tRNA_Synthase
    PANTHERiPTHR11538:SF41 PTHR11538:SF41, 1 hit
    PfamiView protein in Pfam
    PF03147 FDX-ACB, 1 hit
    PF01409 tRNA-synt_2d, 2 hits
    SMARTiView protein in SMART
    SM00896 FDX-ACB, 1 hit
    SUPFAMiSSF54991 SSF54991, 1 hit
    TIGRFAMsiTIGR00469 pheS_mito, 1 hit
    PROSITEiView protein in PROSITE
    PS50862 AA_TRNA_LIGASE_II, 1 hit
    PS51447 FDX_ACB, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiSYFM_HUMAN
    AccessioniPrimary (citable) accession number: O95363
    Secondary accession number(s): B2R664
    , Q53F66, Q5TCS3, Q6FG29, Q9NPY7, Q9P062
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 23, 2004
    Last sequence update: May 1, 1999
    Last modified: November 7, 2018
    This is version 171 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Human chromosome 6
      Human chromosome 6: entries, gene names and cross-references to MIM
    7. Aminoacyl-tRNA synthetases
      List of aminoacyl-tRNA synthetase entries
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