C-1-tetrahydrofolate synthase, cytoplasmic; C1-THF synthase; includes: methylenetetrahydrofolate dehydrogenase; methenyltetrahydrofolate cyclohydrolase; formyltetrahydrofolate synthetase (MTHFD1, MTHFC, MTHFD)

Function

• one-carbon metabolism; tetrahydrofolate interconversion
• trifunctional enzyme

5,10-methylenetetrahydrofolate + NADP+ = 5,10-methenyltetrahydrofolate + NADPH

5,10-methenyltetrahydrofolate + H2O = 10-formyltetrahydrofolate

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

Structure

• two major domains:
  • an N-terminal part containing the methylene-THF dehydrogenase & cyclohydrolase activities
  • a larger C-terminal part containing formyl-THF synthetase activity
• tetrahydrofolate dehydrogenase/cyclohydrolase family tetrahydrofolate ligase family

Compartment

cytoplasm

Expression

ubiquitous

Pathology

• defects in MTHFD1 may be a cause of susceptibility to folate-sensitive neural tube defects
  • genetic defects in MTHFD1 may affect the risk of spina bifida via the maternal rather than the embryonic genotype
• genetic variation in MTHFD1 could be associated with susceptibility to colorectal carcinoma

More general terms

• oxidoreductase
• N-methyltransferase
• mitochondrial protein
• phosphoprotein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4522
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4522
• OMIM: https://mirror.omim.org/entry/114500
• OMIM: https://mirror.omim.org/entry/172460
• OMIM: https://mirror.omim.org/entry/601634
• UniProt: http://www.uniprot.org/uniprot/P11586.html