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Reviewed, UniProtKB/Swiss-Prot P11586 (C1TC_HUMAN)

Last modified November 25, 2008. Version 107. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (8) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    C-1-tetrahydrofolate synthase, cytoplasmic
      Short name=C1-THF synthase
Including the following 3 domains:
    1- Recommended name:
            Methylenetetrahydrofolate dehydrogenase
              EC=1.5.1.5
    2- Recommended name:
            Methenyltetrahydrofolate cyclohydrolase
              EC=3.5.4.9
    3- Recommended name:
            Formyltetrahydrofolate synthetase
              EC=6.3.4.3
Gene names
Name: MTHFD1
Synonyms: MTHFC, MTHFD
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length935 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

General annotation (Comments)

Catalytic activity

5,10-methylenetetrahydrofolate + NADP(+) = 5,10-methenyltetrahydrofolate + NADPH.

5,10-methenyltetrahydrofolate + H(2)O = 10-formyltetrahydrofolate.

ATP + formate + tetrahydrofolate = ADP + phosphate + 10-formyltetrahydrofolate.

Pathway

One-carbon metabolism; tetrahydrofolate pathway.

Subunit structure

Homodimer.

Subcellular location

Cytoplasm.

Tissue specificity

Ubiquitous.

Domain

This trifunctional enzyme consists of two major domains: an N-terminal part containing the methylene-THF dehydrogenase and cyclohydrolase activities and a larger C-terminal part containing formyl-THF synthetase activity.

Involvement in disease

Defects in MTHFD1 may be a cause of susceptibility to folate-sensitive neural tube defects (folate-sensitive NTD) [MIM:601634]. The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Genetic defects in MTHFD1 may affect the risk of spina bifida via the maternal rather than the embryonic genotype.

Sequence similarities

In the N-terminal section; belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.

In the C-terminal section; belongs to the formate--tetrahydrofolate ligase family.

Ontologies

Keywords

   Biological processAmino-acid biosynthesis
Histidine biosynthesis
Methionine biosynthesis
One-carbon metabolism
Purine biosynthesis
   Cellular componentCytoplasm
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
   LigandATP-binding
NADP
Nucleotide-binding
   Molecular functionHydrolase
Ligase
Oxidoreductase
   PTMPhosphoprotein
   Technical term3D-structure
Direct protein sequencing
Multifunctional enzyme

Gene Ontology (GO)

   Biological processfolic acid and derivative biosynthetic process

Inferred from electronic annotation. Source: InterPro

histidine biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-KW

methionine biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-KW

one-carbon compound metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

oxidation reduction

Inferred from electronic annotation. Source: UniProtKB-KW

purine nucleotide biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular componentmitochondrion

Traceable author statement. Source: ProtInc

   Molecular functionATP binding

Inferred from electronic annotation. Source: InterPro

formate-tetrahydrofolate ligase activity Ref.1

Traceable author statement. Source: ProtInc

methenyltetrahydrofolate cyclohydrolase activity Ref.1

Traceable author statement. Source: ProtInc

methylenetetrahydrofolate dehydrogenase (NADP+) activity

Inferred from electronic annotation. Source: EC

protein binding

Inferred from physical interaction. Source: IntAct

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed
Chain2 – 935934C-1-tetrahydrofolate synthase, cytoplasmic
PRO_0000199321

Regions

Nucleotide binding172 – 1743NADP
Nucleotide binding380 – 3878ATP By similarity
Region2 – 305304Methylenetetrahydrofolate dehydrogenase and cyclohydrolase
Region52 – 565Substrate binding
Region99 – 1013Substrate binding
Region272 – 2765Substrate binding
Region306 – 935630Formyltetrahydrofolate synthetase

Sites

Binding site1971NADP

Amino acid modifications

Modified residue7861Phosphothreonine By similarity

Natural variations

Natural variant1341R → K: dbSNP rs1950902.
VAR_016232
Natural variant2931R → H Associated with susceptibility to folate-sensitive NTD. dbSNP rs34181110.
VAR_010241
Natural variant6531R → Q May be associated with susceptibility to folate-sensitive NTD. dbSNP rs2236225.
VAR_010251
Natural variant7611T → M: dbSNP rs10137921.
VAR_032789
Natural variant7691L → F: dbSNP rs17857382.
VAR_032790

Experimental info

Mutagenesis491S → A: No effect on dehydrogenase and cyclohydrolase activity. Strong increase of Km for NADP
Mutagenesis491S → Q: Reduces dehydrogenase by 75% and cyclohydrolase activity by 99%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate
Mutagenesis521Y → A or S: Reduces dehydrogenase activity by 99%. Reduces cyclohydrolase activity by 70%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate
Mutagenesis521Y → F: Slightly reduces dehydrogenase and cyclohydrolase activity. Increase of Km for NADP and for 5,10-methenyltetrahydrofolate
Mutagenesis561K → A, I, S or T: Decreases dehydrogenase activity over 90%. Loss of cyclohydrolase activity
Mutagenesis561K → E, M or Q: Moderate decrease of dehydrogenase activity. Loss of cyclohydrolase activity. Strong increase of Km for NADP. Decrease of Km for 5,10-methenyltetrahydrofolate
Mutagenesis561K → R: Reduces dehydrogenase and cyclohydrolase activity by 99%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate
Mutagenesis1471C → Q: Reduces dehydrogenase activity by 50% and cyclohydrolase activity by 87%

Secondary structure

............................................. 935
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P11586-1 [UniParc].

Last modified January 23, 2007. Version 3.
Checksum: 29AE1C04B4922885

FASTA935101,559
        10         20         30         40         50         60 
MAPAEILNGK EISAQIRARL KNQVTQLKEQ VPGFTPRLAI LQVGNRDDSN LYINVKLKAA 

        70         80         90        100        110        120 
EEIGIKATHI KLPRTTTESE VMKYITSLNE DSTVHGFLVQ LPLDSENSIN TEEVINAIAP 

       130        140        150        160        170        180 
EKDVDGLTSI NAGRLARGDL NDCFIPCTPK GCLELIKETG VPIAGRHAVV VGRSKIVGAP 

       190        200        210        220        230        240 
MHDLLLWNNA TVTTCHSKTA HLDEEVNKGD ILVVATGQPE MVKGEWIKPG AIVIDCGINY 

       250        260        270        280        290        300 
VPDDKKPNGR KVVGDVAYDE AKERASFITP VPGGVGPMTV AMLMQSTVES AKRFLEKFKP 

       310        320        330        340        350        360 
GKWMIQYNNL NLKTPVPSDI DISRSCKPKP IGKLAREIGL LSEEVELYGE TKAKVLLSAL 

       370        380        390        400        410        420 
ERLKHRPDGK YVVVTGITPT PLGEGKSTTT IGLVQALGAH LYQNVFACVR QPSQGPTFGI 

       430        440        450        460        470        480 
KGGAAGGGYS QVIPMEEFNL HLTGDIHAIT AANNLVAAAI DARIFHELTQ TDKALFNRLV 

       490        500        510        520        530        540 
PSVNGVRRFS DIQIRRLKRL GIEKTDPTTL TDEEINRFAR LDIDPETITW QRVLDTNDRF 

       550        560        570        580        590        600 
LRKITIGQAP TEKGHTRTAQ FDISVASEIM AVLALTTSLE DMRERLGKMV VASSKKGEPV 

       610        620        630        640        650        660 
SAEDLGVSGA LTVLMKDAIK PNLMQTLEGT PVFVHAGPFA NIAHGNSSII ADRIALKLVG 

       670        680        690        700        710        720 
PEGFVVTEAG FGADIGMEKF FNIKCRYSGL CPHVVVLVAT VRALKMHGGG PTVTAGLPLP 

       730        740        750        760        770        780 
KAYIQENLEL VEKGFSNLKK QIENARMFGI PVVVAVNAFK TDTESELDLI SRLSREHGAF 

       790        800        810        820        830        840 
DAVKCTHWAE GGKGALALAQ AVQRAAQAPS SFQLLYDLKL PVEDKIRIIA QKIYGADDIE 

       850        860        870        880        890        900 
LLPEAQHKAE VYTKQGFGNL PICMAKTHLS LSHNPEQKGV PTGFILPIRD IRASVGAGFL 

       910        920        930 
YPLVGTMSTM PGLPTRPCFY DIDLDPETEQ VNGLF 

« Hide

References

« Hide 'large scale' references
[1]"Primary structure of a human trifunctional enzyme. Isolation of a cDNA encoding methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase."
Hum D.W., Bell A.W., Rozen R., Mackenzie R.E.
J. Biol. Chem. 263:15946-15950(1988) [PubMed: 3053686] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 2-31.
Tissue: Liver.
[2]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANTS GLN-653 AND PHE-769.
Tissue: Brain, Eye and Lymph.
[3]"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides."
Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J.
Nat. Biotechnol. 21:566-569(2003) [PubMed: 12665801] [Abstract]
Cited for: PROTEIN SEQUENCE OF 2-17.
Tissue: Platelet.
[4]"The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5-A resolution."
Allaire M., Li Y., Mackenzie R.E., Cygler M.
Structure 6:173-182(1998) [PubMed: 9519408] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 1-302.
[5]"Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase."
Schmidt A., Wu H., MacKenzie R.E., Chen V.J., Bewly J.R., Ray J.E., Toth J.E., Cygler M.
Biochemistry 39:6325-6335(2000) [PubMed: 10828945] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1-306 IN COMPLEX WITH NADP AND SUBSTRATE ANALOGS, SUBUNIT, MUTAGENESIS OF SER-49; TYR-52; LYS-56 AND CYS-147.
[6]"Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects."
Hol F.A., van der Put N.M.J., Geurds M.P.A., Heil S.G., Trijbels F.J.M., Hamel B.C.J., Mariman E.C.M., Blom H.J.
Clin. Genet. 53:119-125(1998) [PubMed: 9611072] [Abstract]
Cited for: ASSOCIATION OF VARIANT HIS-293 WITH SUSCEPTIBILITY TO FOLATE-SENSITIVE NTD, VARIANT GLN-653.
[7]"A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group."
Brody L.C., Conley M., Cox C., Kirke P.N., McKeever M.P., Mills J.L., Molloy A.M., O'Leary V.B., Parle-McDermott A., Scott J.M., Swanson D.A.
Am. J. Hum. Genet. 71:1207-1215(2002) [PubMed: 12384833] [Abstract]
Cited for: ASSOCIATION OF VARIANT GLN-653 WITH SUSCEPTIBILITY TO FOLATE-SENSITIVE NTD, VARIANT LYS-134.
[8]"Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population."
Parle-McDermott A., Kirke P.N., Mills J.L., Molloy A.M., Cox C., O'Leary V.B., Pangilinan F., Conley M., Cleary L., Brody L.C., Scott J.M.
Eur. J. Hum. Genet. 14:768-772(2006) [PubMed: 16552426] [Abstract]
Cited for: ASSOCIATION OF VARIANT GLN-653 WITH SUSCEPTIBILITY TO FOLATE-SENSITIVE NTD, VARIANT LYS-134.
+Additional computationally mapped references.

Cross-references

Sequence databases

J04031 mRNA. Translation: AAA59574.1.
BC001014 mRNA. Translation: AAH01014.2.
BC009806 mRNA. Translation: AAH09806.1.
BC050420 mRNA. Translation: AAH50420.1.
PIRA31903.
RefSeqNP_005947.2.
UniGeneHs.652308

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
1A4IX-ray1.50A/B1-301[»]
1DIAX-ray2.20A/B1-306[»]
1DIBX-ray2.70A/B1-306[»]
1DIGX-ray2.20A/B1-306[»]
ModBaseSearch...

Protein-protein interaction databases

IntActP11586.

PTM databases

PhosphoSiteP11586.

2-D gel databases

SWISS-2DPAGEP11586.
REPRODUCTION-2DPAGEIPI00218342.

Genome annotation databases

EnsemblENSG00000100714. Homo sapiens. [Contig view]
GeneID4522.
KEGGhsa:4522.

Organism-specific databases

H-InvDBHIX0011731.
HGNCHGNC:7432. MTHFD1.
HPAHPA000704.
HPA001290.
HPA015006.
MIM172460. gene+phenotype.
601634. phenotype.
Orphanet3388. Neural tube defects.
PharmGKBPA31236.
GenAtlasSearch...
GeneCardsSearch...

Phylogenomic databases

HOGENOMP11586.
HOVERGENP11586.

Enzyme and pathway databases

BioCycMetaCyc:MON-11654.
ReactomeREACT_11127. Metabolism of vitamins and cofactors.

Gene expression databases

ArrayExpressP11586.
CleanExHS_MTHFD1.
GermOnlineENSG00000100714. Homo sapiens.

Family and domain databases

InterProIPR000559. Fmtethyd_synth.
IPR016040. NAD(P)-bd.
IPR000672. THF_DHase/CycOHase.
[Graphical view]
Gene3DG3DSA:3.40.50.720. NAD(P)-bd. 1 hit.
PfamPF01268. FTHFS. 1 hit.
PF00763. THF_DHG_CYH. 1 hit.
PF02882. THF_DHG_CYH_C. 1 hit.
[Graphical view]