MTHFD1

Protein identityUniProt · HPA

UniProt accession

P11586

Gene

MTHFD1

Ensembl

ENSG00000100714

Chromosome

14

Canonical length

935 aa

Protein class

Disease related genes, Enzymes, Human disease related genes, Metabolic proteins, Plasma proteins, Potential drug targets, Predicted intracellular proteins

Subcellular location

Cytosol

Quaternary structure

Homodimer

OverviewNCBI Gene

This gene encodes a protein that possesses three distinct enzymatic activities, 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain. [provided by RefSeq, Jul 2008]

Canonical amino-acid sequenceUniProt

935 residues, UniProt reviewed canonical sequence.

>P11586|MTHFD1
     1  MAPAEILNGK EISAQIRARL KNQVTQLKEQ VPGFTPRLAI LQVGNRDDSN LYINVKLKAA
    61  EEIGIKATHI KLPRTTTESE VMKYITSLNE DSTVHGFLVQ LPLDSENSIN TEEVINAIAP
   121  EKDVDGLTSI NAGKLARGDL NDCFIPCTPK GCLELIKETG VPIAGRHAVV VGRSKIVGAP
   181  MHDLLLWNNA TVTTCHSKTA HLDEEVNKGD ILVVATGQPE MVKGEWIKPG AIVIDCGINY
   241  VPDDKKPNGR KVVGDVAYDE AKERASFITP VPGGVGPMTV AMLMQSTVES AKRFLEKFKP
   301  GKWMIQYNNL NLKTPVPSDI DISRSCKPKP IGKLAREIGL LSEEVELYGE TKAKVLLSAL
   361  ERLKHRPDGK YVVVTGITPT PLGEGKSTTT IGLVQALGAH LYQNVFACVR QPSQGPTFGI
   421  KGGAAGGGYS QVIPMEEFNL HLTGDIHAIT AANNLVAAAI DARIFHELTQ TDKALFNRLV
   481  PSVNGVRRFS DIQIRRLKRL GIEKTDPTTL TDEEINRFAR LDIDPETITW QRVLDTNDRF
   541  LRKITIGQAP TEKGHTRTAQ FDISVASEIM AVLALTTSLE DMRERLGKMV VASSKKGEPV
   601  SAEDLGVSGA LTVLMKDAIK PNLMQTLEGT PVFVHAGPFA NIAHGNSSII ADRIALKLVG
   661  PEGFVVTEAG FGADIGMEKF FNIKCRYSGL CPHVVVLVAT VRALKMHGGG PTVTAGLPLP
   721  KAYIQENLEL VEKGFSNLKK QIENARMFGI PVVVAVNAFK TDTESELDLI SRLSREHGAF
   781  DAVKCTHWAE GGKGALALAQ AVQRAAQAPS SFQLLYDLKL PVEDKIRIIA QKIYGADDIE
   841  LLPEAQHKAE VYTKQGFGNL PICMAKTHLS LSHNPEQKGV PTGFILPIRD IRASVGAGFL
   901  YPLVGTMSTM PGLPTRPCFY DIDLDPETEQ VNGLF

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against MTHFD1 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Intracellular

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.22

Highest tissue expression

319 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about MTHFD1.

Disease | AllUniProt

Conditions MTHFD1 is implicated in, by any mechanism.

• Neural tube defects, folate-sensitive (NTDFS) MIM:601634
• Colorectal cancer (CRC) MIM:114500
• Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia (CIMAH) MIM:617780

Disease | GeneticClinVar

40 pathogenic / likely-pathogenic of 663 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia
• Neural tube defects, folate-sensitive
• Severe combined immunodeficiency disease
• MTHFD1-related disorder

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

0.45

gnomAD pLI

0

gnomAD missense Z

1.68

DepMap mean gene effect

-0.33

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 5% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• 10-formyltetrahydrofolate biosynthetic process
• embryonic neurocranium morphogenesis
• embryonic viscerocranium morphogenesis
• folic acid metabolic process
• heart development
• methionine biosynthetic process
• methionine metabolic process
• neural tube closure
• neutrophil homeostasis
• purine nucleotide biosynthetic process
• somite development
• tetrahydrofolate interconversion
• transsulfuration
• purine ribonucleotide biosynthetic process

Molecular functions

• ATP binding
• formate-tetrahydrofolate ligase activity
• methenyltetrahydrofolate cyclohydrolase activity
• methylenetetrahydrofolate dehydrogenase (NADP+) activity

Cellular components

• cytosol
• extracellular exosome
• membrane
• mitochondrion

Protein domainsUniProt · Pfam · InterPro

• Formate-tetrahydrofolate ligase, FTHFS
• Tetrahydrofolate dehydrogenase/cyclohydrolase
• Formate-tetrahydrofolate ligase, FTHFS, conserved site
• Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain
• Tetrahydrofolate dehydrogenase/cyclohydrolase, NAD(P)-binding domain
• Tetrahydrofolate dehydrogenase/cyclohydrolase, conserved site
• P-loop containing nucleoside triphosphate hydrolase
• NAD(P)-binding domain superfamily
• Aminoacid dehydrogenase-like, N-terminal domain superfamily
• Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain
• Formate--tetrahydrofolate ligase
• Tetrahydrofolate dehydrogenase/cyclohydrolase, NAD(P)-binding domain

KeywordsUniProt

• Acetylation
• ATP-binding
• Cytoplasm
• Hydrolase
• Ligase
• Multifunctional enzyme
• NADP
• Nucleotide-binding
• One-carbon metabolism
• Oxidoreductase
• Phosphoprotein