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Protein

Folylpolyglutamate synthase, mitochondrial

Gene

Fpgs

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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-CH2-H4PteGlu5 at concentrations that substantially inhibits the activity of isoform 2. Isoform 2 and 5 are equally sensitive to polyglutamates of 10-CHO-H4-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-CH3-H4PteGlu (isoform 5 at 34 degrees Celsius and pH 8.9)2 Publications
  10. KM=54 µM for (6S)-5-CH3-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.

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi130Magnesium 1By similarity1
    Metal bindingi200Magnesium 1By similarity1
    Metal bindingi228Magnesium 2By similarity1
    Binding sitei363ATPBy similarity1
    Binding sitei377ATPBy similarity1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi106 – 109ATPBy similarity4

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionLigase
    Biological processOne-carbon metabolism
    LigandATP-binding, Magnesium, Metal-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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
    Proteomesi
    • UP000000589 Componenti: Chromosome 2

    Organism-specific databases

    MGIiMGI:95576 Fpgs

    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

    Cytoplasm, Membrane, Mitochondrion, Mitochondrion inner membrane

    Pathology & Biotechi

    Chemistry databases

    ChEMBLiCHEMBL2890

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 42MitochondrionAdd BLAST42
    ChainiPRO_000001009943 – 587Folylpolyglutamate synthase, mitochondrialAdd BLAST545

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei539PhosphoserineBy similarity1

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    MaxQBiP48760
    PaxDbiP48760
    PeptideAtlasiP48760
    PRIDEiP48760

    PTM databases

    iPTMnetiP48760
    PhosphoSitePlusiP48760

    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 databases

    BindingDBiP48760

    Structurei

    3D structure databases

    ProteinModelPortaliP48760
    SMRiP48760
    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
    OMAiHTFMLGN
    OrthoDBiEOG091G0DO0
    TreeFamiTF313956

    Family and domain databases

    Gene3Di3.40.1190.10, 1 hit
    3.90.190.20, 1 hit
    InterProiView protein in InterPro
    IPR001645 Folylpolyglutamate_synth
    IPR018109 Folylpolyglutamate_synth_CS
    IPR023600 Folylpolyglutamate_synth_euk
    IPR036565 Mur-like_cat_sf
    IPR036615 Mur_ligase_C_dom_sf
    PANTHERiPTHR11136 PTHR11136, 1 hit
    PTHR11136:SF5 PTHR11136:SF5, 1 hit
    PIRSFiPIRSF038895 FPGS, 1 hit
    SUPFAMiSSF53244 SSF53244, 1 hit
    SSF53623 SSF53623, 1 hit
    TIGRFAMsiTIGR01499 folC, 1 hit
    PROSITEiView protein in PROSITE
    PS01011 FOLYLPOLYGLU_SYNT_1, 1 hit
    PS01012 FOLYLPOLYGLU_SYNT_2, 1 hit

    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)DescriptionActionsGraphical viewLength
    Sequence conflicti27A → P in AAC52812 (PubMed:7592937).Curated1
    Sequence conflicti27A → P no nucleotide entry (PubMed:8798611).Curated1
    Sequence conflicti27A → P no nucleotide entry (PubMed:9038166).Curated1
    Sequence conflicti35W → G in AAC52812 (PubMed:7592937).Curated1
    Sequence conflicti35W → G no nucleotide entry (PubMed:8798611).Curated1
    Sequence conflicti35W → G no nucleotide entry (PubMed:9038166).Curated1
    Sequence conflicti75 – 76QL → HV in AAC52426 (PubMed:8605241).Curated2
    Sequence conflicti129S → R in AAC52812 (PubMed:7592937).Curated1
    Sequence conflicti129S → R no nucleotide entry (PubMed:8798611).Curated1
    Sequence conflicti138E → D in AAC52812 (PubMed:7592937).Curated1
    Sequence conflicti138E → D no nucleotide entry (PubMed:8798611).Curated1
    Sequence conflicti464L → M in BAE33941 (PubMed:16141072).Curated1
    Sequence conflicti491G → S in AAC52426 (PubMed:8605241).Curated1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0419621 – 46MSWAR…GMEYQ → MMKSTRSLPMSWPVREKFWW EAAMEWKDPSGSAYEAKTAS FQ in isoform 4. CuratedAdd BLAST46
    Alternative sequenceiVSP_0419671 – 46MSWAR…GMEYQ → MEWKDPSGSAYEAKTASFQ in isoform 5. CuratedAdd BLAST46
    Alternative sequenceiVSP_0187341 – 42Missing in isoform 2. CuratedAdd BLAST42
    Alternative sequenceiVSP_0419611 – 15MSWAR…TLSLA → MAVIRRCFSLVRENLETRI in isoform 3. CuratedAdd BLAST15

    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

    Similar proteinsi

    Entry informationi

    Entry nameiFOLC_MOUSE
    AccessioniPrimary (citable) accession number: P48760
    Secondary accession number(s): A2AK69, Q3U0B4, Q99K38
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1996
    Last sequence update: July 27, 2011
    Last modified: May 23, 2018
    This is version 161 of the entry and version 3 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

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