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Protein

Folylpolyglutamate synthase, mitochondrial

Gene

FPGS

Organism
Homo sapiens (Human)
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. Unsubstituted reduced folates are the preferred substrates. Metabolizes methotrexate (MTX) to polyglutamates.4 Publications

Catalytic activityi

ATP + tetrahydropteroyl-(gamma-Glu)(n) + L-glutamate = ADP + phosphate + tetrahydropteroyl-(gamma-Glu)(n+1).6 Publications

Cofactori

K+1 Publication, NH4(+)1 PublicationNote: A monovalent cation. K+ is most effective, followed by NH4(+) and Rb+. Na+, Li+ and Cs+ are ineffective.1 Publication

Enzyme regulationi

Activated by 10 mM sodium bicarbonate.1 Publication

Kineticsi

  1. KM=201 µM for L-glutamate (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  2. KM=200 µM for MgATP (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  3. KM=59 µM for pteroylglutamic acid (PteGlu) (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  4. KM=16 µM for PteGlu2 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  5. KM=20 µM for PteGlu3 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  6. KM=12 µM for PteGlu4 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  7. KM=64 µM for PteGlu5 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  8. KM=0.81 µM for H2PteGlu (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  9. KM=47 µM for H2PteGlu2 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  10. KM=1.6 µM for (6ambo)-tetrahydropteroylpoly-gamma-glutamate (H4PteGlu) (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  11. KM=4.4 µM for (6S)-H4PteGlu (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  12. KM=3.3 µM for (6S)-H4PteGlu2 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  13. KM=1.4 µM for (6S)-H4PteGlu3 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  14. KM=1.6 µM for (6S)-H4PteGlu4 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  15. KM=1.4 µM for (6S)-H4PteGlu5 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  16. KM=3.7 µM for (6R)-10-formyl-H4PteGlu (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  17. KM=2.7 µM for (6R)-10-formyl-H4PteGlu2 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  18. KM=105 µM for (6S)-5-formyl-H4PteGlu (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  19. KM=13 µM for (6S)-5-formyl-H4PteGlu2 (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  20. KM=48 µM for (6S)-5-methyl-H4PteGlu (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  21. KM=4.4 µM for aminopterin (isoform 2 at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  22. KM=55.5 µM for methotrexate (isoform 2, PubMed:17875718, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)2 Publications
  23. KM=52.6 µM for methotrexate (isoform 1, PubMed:17875718, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)2 Publications
  24. KM=71 µM for methotrexate (Glu-1) (isoform 2, PubMed:8662720, at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  25. KM=50 µM for methotrexate (Glu-2) (isoform 2, PubMed:8662720, at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  26. KM=148 µM for methotrexate (Glu-3) (isoform 2, PubMed:8662720, at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  27. KM=5.3 µM for 5-deazaacyclotetrahydrofolate (isoform 2, at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  28. KM=2.8 µM for 2-methyl-5,8-dideazaisofolate (isoform 2, at 37 degrees Celsius in the presence of 1 mM ATP and 2 mM L-glutamate)2 Publications
  29. KM=1702 µM for glutamic acid (isoform 2, PubMed:17875718, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)2 Publications
  30. KM=2068 µM for glutamic acid (isoform 1, PubMed:17875718, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)2 Publications
  1. Vmax=0.34 µmol/h/mg enzyme with methotrexate as substrate (isoform 2, PubMed:17875718, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)2 Publications
  2. Vmax=0.05 µmol/h/mg enzyme with methotrexate as substrate (isoform 1, PubMed:17875718, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)2 Publications
  3. Vmax=1.26 µmol/h/mg enzyme with glutamic acid as substrate (isoform 2, PubMed:17875718, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)2 Publications
  4. Vmax=0.25 µmol/h/mg enzyme with glutamic acid as substrate (isoform 1, PubMed:17875718, at 37 degrees Celsius in the presence of 10 mM ATP and pH 8.5)2 Publications

pH dependencei

Optimum pH is 9.6 (isoform 2).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

  • animal organ regeneration Source: Ensembl
  • brain development Source: Ensembl
  • cell proliferation Source: BHF-UCL
  • folic acid-containing compound metabolic process Source: BHF-UCL
  • folic acid metabolic process Source: Reactome
  • glutamate metabolic process Source: BHF-UCL
  • liver development Source: Ensembl
  • nucleobase-containing compound metabolic process Source: ProtInc
  • one-carbon metabolic process Source: UniProtKB-KW
  • tetrahydrofolylpolyglutamate biosynthetic process Source: BHF-UCL

Keywordsi

Molecular functionLigase
Biological processOne-carbon metabolism
LigandATP-binding, Magnesium, Metal-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS06237-MONOMER.
ReactomeiR-HSA-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
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 9

Organism-specific databases

EuPathDBiHostDB:ENSG00000136877.14.
HGNCiHGNC:3824. 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

Organism-specific databases

DisGeNETi2356.
MIMi136510. gene+phenotype.
OpenTargetsiENSG00000136877.
PharmGKBiPA167.

Chemistry databases

ChEMBLiCHEMBL3171.
DrugBankiDB00142. L-Glutamic Acid.
DB00563. Methotrexate.
DB06813. Pralatrexate.
DB00293. Raltitrexed.

Polymorphism and mutation databases

BioMutaiFPGS.
DMDMi1706884.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 42MitochondrionCombined sourcesAdd BLAST42
ChainiPRO_000001009743 – 587Folylpolyglutamate synthase, mitochondrialAdd BLAST545

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei43N-acetylmethionineCombined sources1
Modified residuei539PhosphoserineCombined sources1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiQ05932.
MaxQBiQ05932.
PaxDbiQ05932.
PeptideAtlasiQ05932.
PRIDEiQ05932.

PTM databases

iPTMnetiQ05932.
PhosphoSitePlusiQ05932.

Expressioni

Gene expression databases

BgeeiENSG00000136877.
CleanExiHS_FPGS.
ExpressionAtlasiQ05932. baseline and differential.
GenevisibleiQ05932. HS.

Organism-specific databases

HPAiHPA050488.

Interactioni

Subunit structurei

Monomer.

Protein-protein interaction databases

BioGridi108639. 7 interactors.
IntActiQ05932. 1 interactor.
STRINGi9606.ENSP00000362344.

Chemistry databases

BindingDBiQ05932.

Structurei

3D structure databases

ProteinModelPortaliQ05932.
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.
InParanoidiQ05932.
KOiK01930.
OMAiGIYKEGV.
OrthoDBiEOG091G0DO0.
PhylomeDBiQ05932.
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 (4)i

Sequence statusi: Complete.

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

This entry describes 4 isoformsi produced by alternative splicing and alternative initiation. AlignAdd to basket

Isoform 1 (identifier: Q05932-1) [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
MSRARSHLRA ALFLAAASAR GITTQVAARR GLSAWPVPQE PSMEYQDAVR
60 70 80 90 100
MLNTLQTNAG YLEQVKRQRG DPQTQLEAME LYLARSGLQV EDLDRLNIIH
110 120 130 140 150
VTGTKGKGST CAFTECILRS YGLKTGFFSS PHLVQVRERI RINGQPISPE
160 170 180 190 200
LFTKYFWRLY HRLEETKDGS CVSMPPYFRF LTLMAFHVFL QEKVDLAVVE
210 220 230 240 250
VGIGGAYDCT NIIRKPVVCG VSSLGIDHTS LLGDTVEKIA WQKGGIFKQG
260 270 280 290 300
VPAFTVLQPE GPLAVLRDRA QQISCPLYLC PMLEALEEGG PPLTLGLEGE
310 320 330 340 350
HQRSNAALAL QLAHCWLQRQ DRHGAGEPKA SRPGLLWQLP LAPVFQPTSH
360 370 380 390 400
MRLGLRNTEW PGRTQVLRRG PLTWYLDGAH TASSAQACVR WFRQALQGRE
410 420 430 440 450
RPSGGPEVRV LLFNATGDRD PAALLKLLQP CQFDYAVFCP NLTEVSSTGN
460 470 480 490 500
ADQQNFTVTL DQVLLRCLEH QQHWNHLDEE QASPDLWSAP SPEPGGSASL
510 520 530 540 550
LLAPHPPHTC SASSLVFSCI SHALQWISQG RDPIFQPPSP PKGLLTHPVA
560 570 580
HSGASILREA AAIHVLVTGS LHLVGGVLKL LEPALSQ
Length:587
Mass (Da):64,609
Last modified:October 1, 1996 - v3
Checksum:i5AF81409F5F77E5C
GO
Isoform 2 (identifier: Q05932-2) [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):60,167
Checksum:i59650383900A309E
GO
Isoform 3 (identifier: Q05932-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-42: Missing.
     43-50: Missing.

Note: Produced by alternative splicing of isoform 1.
Show »
Length:537
Mass (Da):59,174
Checksum:i4FA022E884342D11
GO
Isoform 4 (identifier: Q05932-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     168-193: Missing.

Note: Produced by alternative splicing of isoform 1.
Show »
Length:561
Mass (Da):61,562
Checksum:i243138601850E090
GO

Sequence cautioni

Q05932: The sequence AAA35852 differs from that shown. Reason: Erroneous initiation. Translation N-terminally extended.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti101V → A in BAG51826 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_06601613F → L1 PublicationCorresponds to variant dbSNP:rs759336102Ensembl.1
Natural variantiVAR_05930522I → V3 PublicationsCorresponds to variant dbSNP:rs10760502Ensembl.1
Natural variantiVAR_043929437V → D. Corresponds to variant dbSNP:rs12686275Ensembl.1
Natural variantiVAR_066017466R → C Expression is reduced by 1.86-fold; Vmax with methotrexate as substrate is significantly reduced resulting in significantly decreased intrinsic clearance of methotrexate; Km of glutamic acid is increased 3.5-fold and apparent Vmax of it is reduced 3.4-fold; reaction velocity at 100 nmol/L of pemetrexed is significantly reduced and folic acid dose-response curve is shifted to the right which corresponds to 4.32-fold increase in the EC(50) for folic acid; IC(50) of methotrexate is 1.84-fold higher and accumulation of a lower ratio of long-chain methotrexate polyglutamates to short-chain polyglutamates is detected; all results are for isoform 2 variant in comparison to the wild-type of it. 1 PublicationCorresponds to variant dbSNP:rs35789560Ensembl.1
Natural variantiVAR_043930489A → V2 PublicationsCorresponds to variant dbSNP:rs17855900Ensembl.1
Natural variantiVAR_066018499S → F Expression reduced by 2.11-fold; Vmax with methotrexate as substrate is significantly reduced resulting in significantly decreased intrinsic clearance of methotrexate; apparent Vmax for glutamic acid is reduced 5-fold; reaction velocity at 100 nmol/L of pemetrexed is significantly reduced and folic acid dose-response curve is shifted to the right which corresponds to 4.28-fold increase in the EC(50) for folic acid; IC(50) of methotrexate is 1.64-fold higher and accumulation of a lower ratio of long-chain methotrexate polyglutamates to short-chain polyglutamates is detected; all results are for isoform 2 variant in comparison to the wild-type of it. 1 PublicationCorresponds to variant dbSNP:rs200314440Ensembl.1
Natural variantiVAR_043931528S → T. Corresponds to variant dbSNP:rs34354111Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0187331 – 42Missing in isoform 2 and isoform 3. 1 PublicationAdd BLAST42
Alternative sequenceiVSP_04195943 – 50Missing in isoform 3. 1 Publication8
Alternative sequenceiVSP_041960168 – 193Missing in isoform 4. 1 PublicationAdd BLAST26

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK056920 mRNA. Translation: BAG51826.1.
AK295309 mRNA. Translation: BAH12029.1.
AL162586 Genomic DNA. Translation: CAI39770.1.
AL162586 Genomic DNA. Translation: CAI39773.1.
BC064393 mRNA. Translation: AAH64393.1.
AH006037 Genomic DNA. Translation: AAC13871.1.
M98045 mRNA. Translation: AAA35852.1. Different initiation.
U14939 Genomic DNA. Translation: AAA85815.1.
AH003340 Genomic DNA. Translation: AAA87568.1.
CCDSiCCDS35148.1. [Q05932-1]
CCDS35149.1. [Q05932-3]
CCDS75905.1. [Q05932-4]
PIRiA46281.
RefSeqiNP_001018088.1. NM_001018078.2. [Q05932-3]
NP_001275732.1. NM_001288803.1. [Q05932-4]
NP_004948.4. NM_004957.5. [Q05932-1]
UniGeneiHs.335084.

Genome annotation databases

EnsembliENST00000373225; ENSP00000362322; ENSG00000136877. [Q05932-3]
ENST00000373247; ENSP00000362344; ENSG00000136877. [Q05932-1]
ENST00000393706; ENSP00000377309; ENSG00000136877. [Q05932-4]
GeneIDi2356.
KEGGihsa:2356.
UCSCiuc004bsg.3. human. [Q05932-1]

Keywords - Coding sequence diversityi

Alternative initiation, Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiFOLC_HUMAN
AccessioniPrimary (citable) accession number: Q05932
Secondary accession number(s): B3KPW4
, B7Z2Z3, F5H0K6, Q5JU19, Q5JU22, Q6P2P6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: October 1, 1996
Last modified: October 25, 2017
This is version 175 of the entry and version 3 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

Complete proteome, Reference proteome

Documents

  1. Human chromosome 9
    Human chromosome 9: entries, gene names and cross-references to MIM
  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. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. SIMILARITY comments
    Index of protein domains and families