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UniProtKB - P11586 (C1TC_HUMAN)

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Protein

C-1-tetrahydrofolate synthase, cytoplasmic

Gene

MTHFD1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalytic activityi

5,10-methylenetetrahydrofolate + NADP+ = 5,10-methenyltetrahydrofolate + NADPH.
5,10-methenyltetrahydrofolate + H2O = 10-formyltetrahydrofolate.
ATP + formate + tetrahydrofolate = ADP + phosphate + 10-formyltetrahydrofolate.

Pathwayi: tetrahydrofolate interconversion

This protein is involved in the pathway tetrahydrofolate interconversion, which is part of One-carbon metabolism.
View all proteins of this organism that are known to be involved in the pathway tetrahydrofolate interconversion and in One-carbon metabolism.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei197NADP1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi172 – 174NADP1 Publication3
Nucleotide bindingi380 – 387ATPBy similarity8

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionHydrolase, Ligase, Multifunctional enzyme, Oxidoreductase
Biological processAmino-acid biosynthesis, Histidine biosynthesis, Methionine biosynthesis, One-carbon metabolism, Purine biosynthesis
LigandATP-binding, NADP, Nucleotide-binding

Enzyme and pathway databases

BioCyciMetaCyc:HS02138-MONOMER
BRENDAi1.5.1.5 2681
3.5.4.9 2681
6.3.4.3 2681
ReactomeiR-HSA-196757 Metabolism of folate and pterines
UniPathwayiUPA00193

Names & Taxonomyi

Protein namesi
Recommended name:
C-1-tetrahydrofolate synthase, cytoplasmic
Short name:
C1-THF synthase
Cleaved into the following chain:
C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed
Including the following 3 domains:
Methylenetetrahydrofolate dehydrogenase (EC:1.5.1.5)
Methenyltetrahydrofolate cyclohydrolase (EC:3.5.4.9)
Formyltetrahydrofolate synthetase (EC:6.3.4.3)
Gene namesi
Name:MTHFD1
Synonyms:MTHFC, MTHFD
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

EuPathDBiHostDB:ENSG00000100714.15
HGNCiHGNC:7432 MTHFD1
MIMi172460 gene+phenotype
neXtProtiNX_P11586

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

Pathology & Biotechi

Involvement in diseasei

Neural tube defects, folate-sensitive (NTDFS)3 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionThe most common NTDs are open spina bifida (myelomeningocele) and anencephaly.
See also OMIM:601634
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_010241293R → H in NTDFS; associated with disease susceptibility. Corresponds to variant dbSNP:rs34181110EnsemblClinVar.1
Natural variantiVAR_010251653R → Q in NTDFS; associated with disease susceptibility; increases risk for congenital heart defects; decreases enzyme stability. 5 PublicationsCorresponds to variant dbSNP:rs2236225EnsemblClinVar.1
Colorectal cancer (CRC)
Disease susceptibility may be associated with variations affecting the gene represented in this entry.
Disease descriptionA complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history.
See also OMIM:114500
MTHFD1 deficiency, due to mutation in this gene, can cause a metabolic syndrome with variable features including hyperhomocysteinemia, megaloblastic anemia, hemolytic uremic syndrome (HUS), severe combined immunodeficiency, microangiopathy and retinopathy. Symptoms improve after treatment with hydroxocobalamin, betaine and folinic acid.2 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi49S → A: No effect on dehydrogenase and cyclohydrolase activity. Strong increase of Km for NADP. 1 Publication1
Mutagenesisi49S → Q: Reduces dehydrogenase by 75% and cyclohydrolase activity by 99%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate. 1 Publication1
Mutagenesisi52Y → A or S: Reduces dehydrogenase activity by 99%. Reduces cyclohydrolase activity by 70%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate. 1 Publication1
Mutagenesisi52Y → F: Slightly reduces dehydrogenase and cyclohydrolase activity. Increase of Km for NADP and for 5,10-methenyltetrahydrofolate. 1 Publication1
Mutagenesisi56K → A, I, S or T: Decreases dehydrogenase activity over 90%. Loss of cyclohydrolase activity. 1 Publication1
Mutagenesisi56K → 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. 1 Publication1
Mutagenesisi56K → R: Reduces dehydrogenase and cyclohydrolase activity by 99%. No effect on Km for NADP and for 5,10-methenyltetrahydrofolate. 1 Publication1
Mutagenesisi147C → Q: Reduces dehydrogenase activity by 50% and cyclohydrolase activity by 87%. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi4522
MalaCardsiMTHFD1
MIMi114500 phenotype
172460 gene+phenotype
601634 phenotype
Orphaneti268392 Cervical spina bifida aperta
268762 Cervical spina bifida cystica
268397 Cervicothoracic spina bifida aperta
268766 Cervicothoracic spina bifida cystica
268388 Lumbosacral spina bifida aperta
268758 Lumbosacral spina bifida cystica
268384 Thoracolumbosacral spina bifida aperta
268752 Thoracolumbosacral spina bifida cystica
268377 Total spina bifida aperta
268748 Total spina bifida cystica
268740 Upper thoracic spina bifida aperta
268770 Upper thoracic spina bifida cystica
PharmGKBiPA31236

Chemistry databases

ChEMBLiCHEMBL2541
DrugBankiDB03461 2'-Monophosphoadenosine 5'-Diphosphoribose
DB04322 LY249543
DB02358 LY374571
DB00157 NADH
DB00116 Tetrahydrofolic acid

Polymorphism and mutation databases

BioMutaiMTHFD1
DMDMi115206

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00004232801 – 935C-1-tetrahydrofolate synthase, cytoplasmicAdd BLAST935
Initiator methionineiRemoved; alternate3 Publications
ChainiPRO_00001993212 – 935C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processedAdd BLAST934

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei1N-acetylmethionineCombined sources1
Modified residuei318PhosphoserineCombined sources1
Modified residuei413PhosphoserineCombined sources1
Modified residuei490PhosphoserineCombined sources1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP11586
MaxQBiP11586
PaxDbiP11586
PeptideAtlasiP11586
PRIDEiP11586
ProteomicsDBi52794

2D gel databases

REPRODUCTION-2DPAGEiIPI00218342
SWISS-2DPAGEiP11586

PTM databases

iPTMnetiP11586
PhosphoSitePlusiP11586
SwissPalmiP11586

Expressioni

Tissue specificityi

Ubiquitous.

Gene expression databases

BgeeiENSG00000100714
CleanExiHS_MTHFD1
ExpressionAtlasiP11586 baseline and differential
GenevisibleiP11586 HS

Organism-specific databases

HPAiHPA000704
HPA001290
HPA015006
HPA050052

Interactioni

Subunit structurei

Homodimer.1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
Q9WMX23EBI-709638,EBI-710918From Hepatitis C virus genotype 1b (isolate Con1).

Protein-protein interaction databases

BioGridi110622, 84 interactors
DIPiDIP-33682N
IntActiP11586, 29 interactors
MINTiP11586
STRINGi9606.ENSP00000450560

Chemistry databases

BindingDBiP11586

Structurei

Secondary structure

1935
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi9 – 30Combined sources22
Beta strandi37 – 44Combined sources8
Helixi47 – 63Combined sources17
Beta strandi66 – 72Combined sources7
Helixi78 – 90Combined sources13
Beta strandi96 – 99Combined sources4
Helixi111 – 116Combined sources6
Helixi120 – 122Combined sources3
Helixi129 – 136Combined sources8
Helixi147 – 157Combined sources11
Turni158 – 160Combined sources3
Beta strandi167 – 171Combined sources5
Turni175 – 177Combined sources3
Helixi178 – 187Combined sources10
Beta strandi191 – 195Combined sources5
Helixi202 – 206Combined sources5
Beta strandi210 – 214Combined sources5
Helixi224 – 226Combined sources3
Beta strandi232 – 235Combined sources4
Helixi258 – 261Combined sources4
Turni262 – 264Combined sources3
Beta strandi266 – 268Combined sources3
Beta strandi271 – 274Combined sources4
Helixi275 – 295Combined sources21

3D structure databases

ProteinModelPortaliP11586
SMRiP11586
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP11586

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni2 – 305Methylenetetrahydrofolate dehydrogenase and cyclohydrolaseAdd BLAST304
Regioni52 – 56Substrate binding5
Regioni99 – 101Substrate binding3
Regioni272 – 276Substrate binding5
Regioni306 – 935Formyltetrahydrofolate synthetaseAdd BLAST630

Domaini

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.

Sequence similaritiesi

In the N-terminal section; belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.Curated
In the C-terminal section; belongs to the formate--tetrahydrofolate ligase family.Curated

Phylogenomic databases

eggNOGiKOG4230 Eukaryota
COG0190 LUCA
COG2759 LUCA
HOVERGENiHBG004916
InParanoidiP11586
KOiK00288
PhylomeDBiP11586
TreeFamiTF300623

Family and domain databases

CDDicd00477 FTHFS, 1 hit
HAMAPiMF_01543 FTHFS, 1 hit
MF_01576 THF_DHG_CYH, 1 hit
InterProiView protein in InterPro
IPR000559 Formate_THF_ligase
IPR020628 Formate_THF_ligase_CS
IPR036291 NAD(P)-bd_dom_sf
IPR027417 P-loop_NTPase
IPR000672 THF_DH/CycHdrlase
IPR020630 THF_DH/CycHdrlase_cat_dom
IPR020867 THF_DH/CycHdrlase_CS
IPR020631 THF_DH/CycHdrlase_NAD-bd_dom
PfamiView protein in Pfam
PF01268 FTHFS, 1 hit
PF00763 THF_DHG_CYH, 1 hit
PF02882 THF_DHG_CYH_C, 1 hit
PRINTSiPR00085 THFDHDRGNASE
SUPFAMiSSF51735 SSF51735, 1 hit
SSF52540 SSF52540, 2 hits
PROSITEiView protein in PROSITE
PS00721 FTHFS_1, 1 hit
PS00722 FTHFS_2, 1 hit
PS00766 THF_DHG_CYH_1, 1 hit
PS00767 THF_DHG_CYH_2, 1 hit

Sequencei

Sequence statusi: Complete.

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

P11586-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAPAEILNGK EISAQIRARL KNQVTQLKEQ VPGFTPRLAI LQVGNRDDSN 
        60         70         80         90        100
LYINVKLKAA EEIGIKATHI KLPRTTTESE VMKYITSLNE DSTVHGFLVQ 
       110        120        130        140        150
LPLDSENSIN TEEVINAIAP EKDVDGLTSI NAGRLARGDL NDCFIPCTPK 
       160        170        180        190        200
GCLELIKETG VPIAGRHAVV VGRSKIVGAP MHDLLLWNNA TVTTCHSKTA 
       210        220        230        240        250
HLDEEVNKGD ILVVATGQPE MVKGEWIKPG AIVIDCGINY VPDDKKPNGR 
       260        270        280        290        300
KVVGDVAYDE AKERASFITP VPGGVGPMTV AMLMQSTVES AKRFLEKFKP 
       310        320        330        340        350
GKWMIQYNNL NLKTPVPSDI DISRSCKPKP IGKLAREIGL LSEEVELYGE 
       360        370        380        390        400
TKAKVLLSAL ERLKHRPDGK YVVVTGITPT PLGEGKSTTT IGLVQALGAH 
       410        420        430        440        450
LYQNVFACVR QPSQGPTFGI KGGAAGGGYS QVIPMEEFNL HLTGDIHAIT 
       460        470        480        490        500
AANNLVAAAI DARIFHELTQ TDKALFNRLV PSVNGVRRFS DIQIRRLKRL 
       510        520        530        540        550
GIEKTDPTTL TDEEINRFAR LDIDPETITW QRVLDTNDRF LRKITIGQAP 
       560        570        580        590        600
TEKGHTRTAQ FDISVASEIM AVLALTTSLE DMRERLGKMV VASSKKGEPV 
       610        620        630        640        650
SAEDLGVSGA LTVLMKDAIK PNLMQTLEGT PVFVHAGPFA NIAHGNSSII 
       660        670        680        690        700
ADRIALKLVG PEGFVVTEAG FGADIGMEKF FNIKCRYSGL CPHVVVLVAT 
       710        720        730        740        750
VRALKMHGGG PTVTAGLPLP KAYIQENLEL VEKGFSNLKK QIENARMFGI 
       760        770        780        790        800
PVVVAVNAFK TDTESELDLI SRLSREHGAF DAVKCTHWAE GGKGALALAQ 
       810        820        830        840        850
AVQRAAQAPS SFQLLYDLKL PVEDKIRIIA QKIYGADDIE LLPEAQHKAE 
       860        870        880        890        900
VYTKQGFGNL PICMAKTHLS LSHNPEQKGV PTGFILPIRD IRASVGAGFL 
       910        920        930 
YPLVGTMSTM PGLPTRPCFY DIDLDPETEQ VNGLF
Length:935
Mass (Da):101,559
Last modified:January 23, 2007 - v3
Checksum:i29AE1C04B4922885
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_07407549S → F Found in patients with MTFDH1 deficiency; unknown pathological significance. 1 Publication1
Natural variantiVAR_016232134R → K Associated with increased risk of colorectal cancer. Combined sources3 PublicationsCorresponds to variant dbSNP:rs1950902Ensembl.1
Natural variantiVAR_055458162P → L. Corresponds to variant dbSNP:rs4902283Ensembl.1
Natural variantiVAR_074076173R → C Found in patients with MTFDH1 deficiency; unknown pathological significance. 1 Publication1
Natural variantiVAR_074077269T → I Found in patients with MTFDH1 deficiency. 1 Publication1
Natural variantiVAR_010241293R → H in NTDFS; associated with disease susceptibility. Corresponds to variant dbSNP:rs34181110EnsemblClinVar.1
Natural variantiVAR_010251653R → Q in NTDFS; associated with disease susceptibility; increases risk for congenital heart defects; decreases enzyme stability. 5 PublicationsCorresponds to variant dbSNP:rs2236225EnsemblClinVar.1
Natural variantiVAR_032789761T → M. Corresponds to variant dbSNP:rs10813Ensembl.1
Natural variantiVAR_032790769L → F1 PublicationCorresponds to variant dbSNP:rs17857382Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
J04031 mRNA Translation: AAA59574.1
AK312361 mRNA Translation: BAG35279.1
AL122035 Genomic DNA No translation available.
CH471061 Genomic DNA Translation: EAW80857.1
BC001014 mRNA Translation: AAH01014.2
BC009806 mRNA Translation: AAH09806.1
BC050420 mRNA Translation: AAH50420.1
CCDSiCCDS9763.1
PIRiA31903
RefSeqiNP_005947.3, NM_005956.3
UniGeneiHs.652308

Genome annotation databases

EnsembliENST00000216605; ENSP00000216605; ENSG00000100714
ENST00000555709; ENSP00000450560; ENSG00000100714
GeneIDi4522
KEGGihsa:4522
UCSCiuc001xhb.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Entry informationi

Entry nameiC1TC_HUMAN
AccessioniPrimary (citable) accession number: P11586
Secondary accession number(s): B2R5Y2
, G3V2B8, Q86VC9, Q9BVP5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1989
Last sequence update: January 23, 2007
Last modified: July 18, 2018
This is version 210 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

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 14
    Human chromosome 14: 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. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families

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