C-1-tetrahydrofolate synthase, cytoplasmic

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Reviewed, UniProtKB/Swiss-Prot P11586 (C1TC_HUMAN)

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

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	935 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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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.

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Ontologies

Keywords
Biological process	Amino-acid biosynthesis Histidine biosynthesis Methionine biosynthesis One-carbon metabolism Purine biosynthesis
Cellular component	Cytoplasm
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Ligand	ATP-binding NADP Nucleotide-binding
Molecular function	Hydrolase Ligase Oxidoreductase
PTM	Phosphoprotein
Technical term	3D-structure Direct protein sequencing Multifunctional enzyme
Gene Ontology (GO)
Biological process	folic 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 component	mitochondrion Traceable author statement. Source: ProtInc
Molecular function	ATP 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...

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Binary interactions

With	Entry	#Exp.	IntAct
MCC	P23508	1	EBI-709638,EBI-307531
TRAF6	Q9Y4K3	1	EBI-709638,EBI-359276
WDR8	Q9P2S5	1	EBI-709638,EBI-1054904

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

Removed

Chain

2 – 935

934

C-1-tetrahydrofolate synthase, cytoplasmic

PRO_0000199321

Regions

Nucleotide binding

172 – 174

NADP

Nucleotide binding

380 – 387

ATP By similarity

Region

2 – 305

304

Methylenetetrahydrofolate dehydrogenase and cyclohydrolase

Region

52 – 56

Substrate binding

Region

99 – 101

Substrate binding

Region

272 – 276

Substrate binding

Region

306 – 935

630

Formyltetrahydrofolate synthetase

Sites

Binding site

197

NADP

Amino acid modifications

Modified residue

786

Phosphothreonine By similarity

Natural variations

Natural variant

134

R → K: dbSNP rs1950902.

VAR_016232

Natural variant

293

R → H Associated with susceptibility to folate-sensitive NTD. dbSNP rs34181110.

VAR_010241

Natural variant

653

R → Q May be associated with susceptibility to folate-sensitive NTD. dbSNP rs2236225.

VAR_010251

Natural variant

761

T → M: dbSNP rs10137921.

VAR_032789

Natural variant

769

L → F: dbSNP rs17857382.

VAR_032790

Experimental info

Mutagenesis

S → A: No effect on dehydrogenase and cyclohydrolase activity. Strong increase of Km for NADP

Mutagenesis

S → Q: Reduces dehydrogenase by 75% and cyclohydrolase activity by 99%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate

Mutagenesis

Y → A or S: Reduces dehydrogenase activity by 99%. Reduces cyclohydrolase activity by 70%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate

Mutagenesis

Y → F: Slightly reduces dehydrogenase and cyclohydrolase activity. Increase of Km for NADP and for 5,10-methenyltetrahydrofolate

Mutagenesis

K → A, I, S or T: Decreases dehydrogenase activity over 90%. Loss of cyclohydrolase activity

Mutagenesis

K → 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

Mutagenesis

K → R: Reduces dehydrogenase and cyclohydrolase activity by 99%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate

Mutagenesis

147

C → Q: Reduces dehydrogenase activity by 50% and cyclohydrolase activity by 87%

Secondary structure

935

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P11586-1 [UniParc].

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

935

101,559

        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

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References

	« Hide 'large scale' referencesShow '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.