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Protein

Folylpolyglutamate synthase, mitochondrial

Gene

Fpgs

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Catalyzes conversion of folates to polyglutamate derivatives allowing concentration of folate compounds in the cell and the intracellular retention of these cofactors, which are important substrates for most of the folate-dependent enzymes that are involved in one-carbon transfer reactions involved in purine, pyrimidine and amino acid synthesis. Dihydrofolate, tetrahydrofolate, 5,10-methylenetetrahydrofolate, 10-formyltetrahydrofolate and 5-formyltetrahydrofolate are the best substrates. Folic acid and 5-methyltetrahydrofolate can also act as substrates.2 Publications

Catalytic activityi

ATP + tetrahydropteroyl-(gamma-Glu)(n) + L-glutamate = ADP + phosphate + tetrahydropteroyl-(gamma-Glu)(n+1).3 Publications

Cofactori

a monovalent cationBy similarityNote: A monovalent cation.By similarity

Enzyme regulationi

Inhibited by ammonium sulfate. Inhibited by pentaglutamate derivative of DDATHF, but isoform 2 is inhibited to a greater extent at lower concentrations of the compound that is isoform 5. Isoform 5 is virtually unaffected by H4PteGlu5 and 5,10-CH(2)-H4PteGlu5 at concentrations that substantially inhibits the activity of isoform 2. Isoform 2 and 5 are equally sensitive to polyglutamates of 10-CHO-H(4)-PteGlu.2 Publications

Kineticsi

  1. KM=17.7 µM for aminopterin (isoform 5 at 34 degrees Celsius and pH 8.9)2 Publications
  2. KM=15.4 µM for aminopterin (isoform 2 at 34 degrees Celsius and pH 8.9)2 Publications
  3. KM=7.6 µM for (6R)-DDATHF (isoform 5 at 34 degrees Celsius and pH 8.9)2 Publications
  4. KM=1.2 µM for (6R)-DDATHF (isoform 2 at 34 degrees Celsius and pH 8.9)2 Publications
  5. KM=6.3 µM for (6S)-H4PteGlu (isoform 5 at 34 degrees Celsius and pH 8.9)2 Publications
  6. KM=1.4 µM for (6S)-H4PteGlu (isoform 2 at 34 degrees Celsius and pH 8.9)2 Publications
  7. KM=2.9 µM for (6R)-10-CHO-H4PteGlu (isoform 5 at 34 degrees Celsius and pH 8.9)2 Publications
  8. KM=2.0 µM for (6R)-10-CHO-H4PteGlu (isoform 2 at 34 degrees Celsius and pH 8.9)2 Publications
  9. KM=64 µM for (6S)-5-CH(3)-H4PteGlu (isoform 5 at 34 degrees Celsius and pH 8.9)2 Publications
  10. KM=54 µM for (6S)-5-CH(3)-H4PteGlu (isoform 2 at 34 degrees Celsius and pH 8.9)2 Publications
  11. KM=122 µM for (6S)-5-CHO-H4PteGlu (isoform 5 at 34 degrees Celsius and pH 8.9)2 Publications
  12. KM=75 µM for (6S)-5-CHO-H4PteGlu (isoform 2 at 34 degrees Celsius and pH 8.9)2 Publications

    pH dependencei

    Optimum pH is 8.2-9.5 using 500 µM folic acid (PteGlu) and 25 µM dl-5-formyltetrahydrofolate (dl-5-CHO-H4PteGlu) as substrates.2 Publications

    Temperature dependencei

    Optimum temperature is 37 degrees Celsius. Activity completely lost within a few hours at 4 degrees Celsius in the absence of ATP and glycerol.2 Publications

    Pathwayi: tetrahydrofolylpolyglutamate biosynthesis

    This protein is involved in the pathway tetrahydrofolylpolyglutamate biosynthesis, which is part of Cofactor biosynthesis.
    View all proteins of this organism that are known to be involved in the pathway tetrahydrofolylpolyglutamate biosynthesis and in Cofactor biosynthesis.

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi103 – 1097ATPSequence analysis

    GO - Molecular functioni

    GO - Biological processi

    Complete GO annotation...

    Keywords - Molecular functioni

    Ligase

    Keywords - Biological processi

    One-carbon metabolism

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

    ReactomeiR-MMU-196757. Metabolism of folate and pterines.
    UniPathwayiUPA00850.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Folylpolyglutamate synthase, mitochondrial (EC:6.3.2.17)
    Alternative name(s):
    Folylpoly-gamma-glutamate synthetase
    Short name:
    FPGS
    Tetrahydrofolylpolyglutamate synthase
    Short name:
    Tetrahydrofolate synthase
    Gene namesi
    Name:Fpgs
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    Proteomesi
    • UP000000589 Componenti: Chromosome 2

    Organism-specific databases

    MGIiMGI:95576. Fpgs.

    Subcellular locationi

    Isoform 1 :
    • Mitochondrion inner membrane By similarity
    • Mitochondrion matrix By similarity
    Isoform 2 :
    • Cytoplasm By similarity

    GO - Cellular componenti

    • cytosol Source: MGI
    • mitochondrial inner membrane Source: UniProtKB-SubCell
    • mitochondrial matrix Source: GO_Central
    • mitochondrion Source: MGI
    Complete GO annotation...

    Keywords - Cellular componenti

    Cytoplasm, Membrane, Mitochondrion, Mitochondrion inner membrane

    Pathology & Biotechi

    Chemistry

    ChEMBLiCHEMBL2890.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transit peptidei1 – 4242MitochondrionAdd
    BLAST
    Chaini43 – 587545Folylpolyglutamate synthase, mitochondrialPRO_0000010099Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei43 – 431N-acetylmethionineBy similarity
    Modified residuei539 – 5391PhosphoserineBy similarity

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiP48760.
    PaxDbiP48760.
    PeptideAtlasiP48760.
    PRIDEiP48760.

    PTM databases

    iPTMnetiP48760.
    PhosphoSiteiP48760.

    Expressioni

    Tissue specificityi

    With non-specific probe, highest content in kidney and liver and lowest in spleen, lung and small intestine, and readily detectable in all of the tumors except hepatoma. Isoform 1 and isoform 2 expressed in leukemic cells and isoform 4 and isoform 5 in liver cells. Isoform 1 and isoform 2 exclusively expressed in hepatoma and Lewis lung carcinoma. Isoform 1 and isoform 2 also expressed in bone marrow, small intestine and spleen. Kidney expresses isoform 1, isoform 2, isoform 4 and isoform 5.3 Publications

    Gene expression databases

    BgeeiENSMUSG00000009566.
    CleanExiMM_FPGS.
    ExpressionAtlasiP48760. baseline and differential.
    GenevisibleiP48760. MM.

    Interactioni

    Subunit structurei

    Monomer.By similarity

    Protein-protein interaction databases

    STRINGi10090.ENSMUSP00000028148.

    Chemistry

    BindingDBiP48760.

    Structurei

    3D structure databases

    ProteinModelPortaliP48760.
    SMRiP48760. Positions 60-456.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the folylpolyglutamate synthase family.Curated

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG2525. Eukaryota.
    COG0285. LUCA.
    GeneTreeiENSGT00390000016526.
    HOGENOMiHOG000181278.
    HOVERGENiHBG003086.
    InParanoidiP48760.
    KOiK01930.
    OMAiSHIRNNI.
    OrthoDBiEOG091G0DO0.
    TreeFamiTF313956.

    Family and domain databases

    Gene3Di3.40.1190.10. 1 hit.
    3.90.190.20. 1 hit.
    InterProiIPR001645. Folylpolyglutamate_synth.
    IPR018109. Folylpolyglutamate_synth_CS.
    IPR023600. Folylpolyglutamate_synth_euk.
    IPR004101. Mur_ligase_C.
    IPR013221. Mur_ligase_cen.
    [Graphical view]
    PANTHERiPTHR11136. PTHR11136. 2 hits.
    PTHR11136:SF5. PTHR11136:SF5. 2 hits.
    PIRSFiPIRSF038895. FPGS. 1 hit.
    SUPFAMiSSF53244. SSF53244. 1 hit.
    SSF53623. SSF53623. 1 hit.
    TIGRFAMsiTIGR01499. folC. 1 hit.
    PROSITEiPS01011. FOLYLPOLYGLU_SYNT_1. 1 hit.
    PS01012. FOLYLPOLYGLU_SYNT_2. 1 hit.
    [Graphical view]

    Sequences (5)i

    Sequence statusi: Complete.

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

    This entry describes 5 isoformsi produced by alternative promoter usage, alternative splicing and alternative initiation. AlignAdd to basket

    Isoform 1 (identifier: P48760-1) [UniParc]FASTAAdd to basket
    Also known as: Mitochondrial

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MSWARSRLCS TLSLAAVSAR GATTEGAARR GMSAWPAPQE PGMEYQDAVR
    60 70 80 90 100
    TLNTLQTNAS YLEQVKRQRS DPQAQLEAME MYLARSGLQV EDLNRLNIIH
    110 120 130 140 150
    VTGTKGKGST CAFTERILRN YGLKTGFFSS PHMVQVRERI RINGKPISPE
    160 170 180 190 200
    LFTKHFWCLY NQLEEFKDDS HVSMPSYFRF LTLMAFHVFL QEKVDLAVVE
    210 220 230 240 250
    VGIGGAFDCT NIIRKPVVCG VSSLGIDHTS LLGDTVEKIA WQKGGIFKPG
    260 270 280 290 300
    VPAFTVVQPE GPLAVLRDRA QQIGCPLYLC PPLEALEEVG LPLSLGLEGA
    310 320 330 340 350
    HQRSNAALAL QLAHCWLERQ DHQDIQELKV SRPSIRWQLP LAPVFRPTPH
    360 370 380 390 400
    MRRGLRDTVW PGRTQILQRG PLTWYLDGAH TTSSVQACVH WYRQSLERSK
    410 420 430 440 450
    RTDGGSEVHI LLFNSTGDRD SAALLKLLQP CQFDYAVFCP NVTEVSSIGN
    460 470 480 490 500
    ADQQNFTVTL DQVLLRCLQH QQHWNGLAEK QASSNLWSSC GPDPAGPGSL
    510 520 530 540 550
    LLAPHPPQPT RTSSLVFSCI SHALLWISQG RDPIFQPQSL PRNLLNHPTA
    560 570 580
    NSGASILREA AAIHVLVTGS LHLVGGVLKL LDPSMSQ
    Length:587
    Mass (Da):64,955
    Last modified:July 27, 2011 - v3
    Checksum:iB93261CBA110CA41
    GO
    Isoform 2 (identifier: P48760-2) [UniParc]FASTAAdd to basket
    Also known as: Cytoplasmic

    The sequence of this isoform differs from the canonical sequence as follows:
         1-42: Missing.

    Note: Produced by alternative initiation at Met-43 of isoform 1.
    Show »
    Length:545
    Mass (Da):60,626
    Checksum:i0FEC36DFD5CF1699
    GO
    Isoform 3 (identifier: P48760-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-15: MSWARSRLCSTLSLA → MAVIRRCFSLVRENLETRI

    Note: Produced by alternative splicing of isoform 1.
    Show »
    Length:591
    Mass (Da):65,580
    Checksum:i039C9531A030B4BC
    GO
    Isoform 4 (identifier: P48760-4) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-46: MSWARSRLCS...APQEPGMEYQ → MMKSTRSLPM...AYEAKTASFQ

    Note: Produced by alternative promoter usage.
    Show »
    Length:583
    Mass (Da):65,028
    Checksum:i94AE134B2F999277
    GO
    Isoform 5 (identifier: P48760-5) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-46: MSWARSRLCSTLSLAAVSARGATTEGAARRGMSAWPAPQEPGMEYQ → MEWKDPSGSAYEAKTASFQ

    Note: Produced by alternative initiation at Met-24 of isoform 4.
    Show »
    Length:560
    Mass (Da):62,190
    Checksum:i7F1479FA24A0D878
    GO

    Sequence cautioni

    The sequence AAH05484 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti27 – 271A → P in AAC52812 (PubMed:7592937).Curated
    Sequence conflicti27 – 271A → P no nucleotide entry (PubMed:8798611).Curated
    Sequence conflicti27 – 271A → P no nucleotide entry (PubMed:9038166).Curated
    Sequence conflicti35 – 351W → G in AAC52812 (PubMed:7592937).Curated
    Sequence conflicti35 – 351W → G no nucleotide entry (PubMed:8798611).Curated
    Sequence conflicti35 – 351W → G no nucleotide entry (PubMed:9038166).Curated
    Sequence conflicti75 – 762QL → HV in AAC52426 (PubMed:8605241).Curated
    Sequence conflicti129 – 1291S → R in AAC52812 (PubMed:7592937).Curated
    Sequence conflicti129 – 1291S → R no nucleotide entry (PubMed:8798611).Curated
    Sequence conflicti138 – 1381E → D in AAC52812 (PubMed:7592937).Curated
    Sequence conflicti138 – 1381E → D no nucleotide entry (PubMed:8798611).Curated
    Sequence conflicti464 – 4641L → M in BAE33941 (PubMed:16141072).Curated
    Sequence conflicti491 – 4911G → S in AAC52426 (PubMed:8605241).Curated

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 4646MSWAR…GMEYQ → MMKSTRSLPMSWPVREKFWW EAAMEWKDPSGSAYEAKTAS FQ in isoform 4. CuratedVSP_041962Add
    BLAST
    Alternative sequencei1 – 4646MSWAR…GMEYQ → MEWKDPSGSAYEAKTASFQ in isoform 5. CuratedVSP_041967Add
    BLAST
    Alternative sequencei1 – 4242Missing in isoform 2. CuratedVSP_018734Add
    BLAST
    Alternative sequencei1 – 1515MSWAR…TLSLA → MAVIRRCFSLVRENLETRI in isoform 3. CuratedVSP_041961Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    U33557 mRNA. Translation: AAC52812.1.
    U32197 mRNA. Translation: AAC52426.1.
    AK157040 mRNA. Translation: BAE33941.1.
    AL772271 Genomic DNA. Translation: CAM16618.1.
    CH466542 Genomic DNA. Translation: EDL08563.1.
    BC005484 mRNA. Translation: AAH05484.1. Different initiation.
    CCDSiCCDS15926.1. [P48760-1]
    PIRiI49357.
    S65755.
    RefSeqiNP_034366.2. NM_010236.2. [P48760-1]
    UniGeneiMm.3830.

    Genome annotation databases

    EnsembliENSMUST00000028148; ENSMUSP00000028148; ENSMUSG00000009566. [P48760-1]
    GeneIDi14287.
    KEGGimmu:14287.
    UCSCiuc008jgm.2. mouse. [P48760-1]

    Keywords - Coding sequence diversityi

    Alternative initiation, Alternative promoter usage, Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    U33557 mRNA. Translation: AAC52812.1.
    U32197 mRNA. Translation: AAC52426.1.
    AK157040 mRNA. Translation: BAE33941.1.
    AL772271 Genomic DNA. Translation: CAM16618.1.
    CH466542 Genomic DNA. Translation: EDL08563.1.
    BC005484 mRNA. Translation: AAH05484.1. Different initiation.
    CCDSiCCDS15926.1. [P48760-1]
    PIRiI49357.
    S65755.
    RefSeqiNP_034366.2. NM_010236.2. [P48760-1]
    UniGeneiMm.3830.

    3D structure databases

    ProteinModelPortaliP48760.
    SMRiP48760. Positions 60-456.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    STRINGi10090.ENSMUSP00000028148.

    Chemistry

    BindingDBiP48760.
    ChEMBLiCHEMBL2890.

    PTM databases

    iPTMnetiP48760.
    PhosphoSiteiP48760.

    Proteomic databases

    MaxQBiP48760.
    PaxDbiP48760.
    PeptideAtlasiP48760.
    PRIDEiP48760.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENSMUST00000028148; ENSMUSP00000028148; ENSMUSG00000009566. [P48760-1]
    GeneIDi14287.
    KEGGimmu:14287.
    UCSCiuc008jgm.2. mouse. [P48760-1]

    Organism-specific databases

    CTDi2356.
    MGIiMGI:95576. Fpgs.

    Phylogenomic databases

    eggNOGiKOG2525. Eukaryota.
    COG0285. LUCA.
    GeneTreeiENSGT00390000016526.
    HOGENOMiHOG000181278.
    HOVERGENiHBG003086.
    InParanoidiP48760.
    KOiK01930.
    OMAiSHIRNNI.
    OrthoDBiEOG091G0DO0.
    TreeFamiTF313956.

    Enzyme and pathway databases

    UniPathwayiUPA00850.
    ReactomeiR-MMU-196757. Metabolism of folate and pterines.

    Miscellaneous databases

    PROiP48760.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSMUSG00000009566.
    CleanExiMM_FPGS.
    ExpressionAtlasiP48760. baseline and differential.
    GenevisibleiP48760. MM.

    Family and domain databases

    Gene3Di3.40.1190.10. 1 hit.
    3.90.190.20. 1 hit.
    InterProiIPR001645. Folylpolyglutamate_synth.
    IPR018109. Folylpolyglutamate_synth_CS.
    IPR023600. Folylpolyglutamate_synth_euk.
    IPR004101. Mur_ligase_C.
    IPR013221. Mur_ligase_cen.
    [Graphical view]
    PANTHERiPTHR11136. PTHR11136. 2 hits.
    PTHR11136:SF5. PTHR11136:SF5. 2 hits.
    PIRSFiPIRSF038895. FPGS. 1 hit.
    SUPFAMiSSF53244. SSF53244. 1 hit.
    SSF53623. SSF53623. 1 hit.
    TIGRFAMsiTIGR01499. folC. 1 hit.
    PROSITEiPS01011. FOLYLPOLYGLU_SYNT_1. 1 hit.
    PS01012. FOLYLPOLYGLU_SYNT_2. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiFOLC_MOUSE
    AccessioniPrimary (citable) accession number: P48760
    Secondary accession number(s): A2AK69, Q3U0B4, Q99K38
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: February 1, 1996
    Last sequence update: July 27, 2011
    Last modified: September 7, 2016
    This is version 149 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    3. SIMILARITY comments
      Index of protein domains and families

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.