- 葉酸は二段階の還元でジヒドロ葉酸を経てテトラヒドロ葉酸となる。１段目は7,8位が還元され、２段目で5,6位が還元される。二段階共にジヒドロ葉酸レダクターゼがNADPHを補酵素にして反応する。
- THFは一炭素基の担体である。ビオチンがカルボキシル基、S-アデノシルメチオニンがメチル基専用なのに対して、THFは様々な酸化状態の炭素を転移する。
- 5,10-メテニルTHFと5-ホルミルTHFは異化の反応で相互に変換する。（5,10-methenyl-THF + ADP + phosphate = 5-formyl-THF + ATP ）
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
Catalytic activity
- 5,10-methylenetetrahydrofolate + NADP+ = 5,10-methenyltetrahydrofolate + NADPH. HAMAP-Rule MF_01543
- 5,10-methenyltetrahydrofolate + H2O = 10-formyltetrahydrofolate. HAMAP-Rule MF_01543
- ATP + formate + tetrahydrofolate = ADP + phosphate + 10-formyltetrahydrofolate. HAMAP-Rule MF_01543
- Pathway
- One-carbon metabolism; tetrahydrofolate interconversion. HAMAP-Rule MF_01543
- Subunit structure
- Homodimer. Ref.13
- Subcellular location
- Cytoplasm HAMAP-Rule MF_01543.
- 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. HAMAP-Rule MF_01543
Involvement in disease
- Folate-sensitive neural tube defects (FS-NTD) [MIM:601634]: The most common NTDs are open spina bifida (myelomeningocele) and anencephaly.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.14 Ref.15 Ref.16
- Colorectal cancer (CRC) [MIM:114500]: A 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.
Note: Disease susceptibility may be associated with variations affecting the gene represented in this entry.
- Sequence similarities
- In the N-terminal section; belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
5-formyltetrahydrofolate cyclo-ligase
EC=6.3.3.2
- Alternative name(s)
- 5,10-methenyl-tetrahydrofolate synthetase / Short name=MTHFS / Short name=Methenyl-THF synthetase
- Function
- Contributes to tetrahydrofolate metabolism. Helps regulate carbon flow through the folate-dependent one-carbon metabolic network that supplies carbon for the biosynthesis of purines, thymidine and amino acids.
- Catalytic activity
- ATP + 5-formyltetrahydrofolate = ADP + phosphate + 5,10-methenyltetrahydrofolate.
- Cofactor
- Magnesium.
- Subunit structure
- Monomer.
- Subcellular location
- Cytoplasm.
Sequence similarities :Belongs to the 5-formyltetrahydrofolate cyclo-ligase family.
Monofunctional C1-tetrahydrofolate synthase, mitochondrial
EC=6.3.4.3
Alternative name(s):
Formyltetrahydrofolate synthetase
- Function
- May provide the missing metabolic reaction required to link the mitochondria and the cytoplasm in the mammalian model of one-carbon folate metabolism in embryonic an transformed cells complementing thus the enzymatic activities of MTHFD2 By similarity. Ref.5
- Catalytic activity
- ATP + formate + tetrahydrofolate = ADP + phosphate + 10-formyltetrahydrofolate. HAMAP-Rule MF_01543
- Pathway
- One-carbon metabolism; tetrahydrofolate interconversion. HAMAP-Rule MF_01543
- Subunit structure
- Homodimer. Ref.5
- Subcellular location
- Mitochondrion Ref.1.
- Tissue specificity
- Detected in most tissues, highest expression found in placenta, thymus and brain. Low expression is found in liver and skeletal muscle. Up-regulated in colon adenocarcinoma. Ref.1 Ref.2
Domain:This monofunctional enzyme consists of two major domains: an N-terminal inactive methylene-THF dehydrogenase and cyclohydrolase domain and an active larger formyl-THF synthetase C-terminal domain. HAMAP-Rule MF_01543
- Miscellaneous
- May participate in the progression of colorectal cancer by conferring growth advantage. Could be a new molecular target for cancer therapy.
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.
- Caution
- This enzyme lacks methylenetetrahydrofolate dehydrogenase (EC 1.5.1.5) and ethenyltetrahydrofolate cyclohydrolase (EC 3.5.4.9) activities. An enzyme performing these two complementary activities has not been found in adult mitochondrial tissues; MTHFD2, which performs these two activities, was found in developing tissues only. Was originally (Ref.1) thought to be a trifunctional enzyme but only a formyltetrahydrofolate synthetase activity was detected and not a dehydrogenase/cyclohydrogenase activity.
Biophysicochemical properties
Kinetic parameters:
- KM=500 µM for THF monoglutamate Ref.5
- KM=16 µM for THF triglutamate
- KM=3.6 µM for THF pentaglutamate
Formimidoyltransferase-cyclodeaminase
- Alternative name(s)
- Formiminotransferase-cyclodeaminase
- Short name
- FTCD / LCHC1
Including the following 2 domains:
- Glutamate formimidoyltransferase EC=2.1.2.5
- Alternative name(s):Glutamate formiminotransferase / Glutamate formyltransferase
- Formimidoyltetrahydrofolate cyclodeaminase EC=4.3.1.4
- Alternative name(s):Formiminotetrahydrofolate cyclodeaminase
- Function
- Folate-dependent enzyme, that displays both transferase and deaminase activity. Serves to channel one-carbon units from formiminoglutamate to the folate pool. Binds and promotes bundling of vimentin filaments originating from the Golgi.
Catalytic activity
- 5-formimidoyltetrahydrofolate + L-glutamate = tetrahydrofolate + N-formimidoyl-L-glutamate.
- 5-formyltetrahydrofolate + L-glutamate = tetrahydrofolate + N-formyl-L-glutamate.
- 5-formimidoyltetrahydrofolate = 5,10-methenyltetrahydrofolate + NH3.
- Cofactor
- Pyridoxal phosphate.
- Pathway
- Amino-acid degradation; L-histidine degradation into L-glutamate; L-glutamate from N-formimidoyl-L-glutamate (transferase route): step 1/1.
One-carbon metabolism; tetrahydrofolate interconversion.
- Subunit structure
- Homooctamer, including four polyglutamate binding sites. The subunits are arranged as a tetramer of dimers, and form a planar ring-shaped structure.
- Subcellular location
- Cytoplasm › cytoskeleton › microtubule organizing center › centrosome › centriole. Golgi apparatus By similarity. Note: More abundantly located around the mother centriole. Ref.5
- Involvement in disease
- Glutamate formiminotransferase deficiency (FIGLU-URIA) [MIM:229100]: Autosomal recessive disorder. Features of a severe phenotype, include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and mental retardation. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematological abnormalities.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.6
Sequence similarities
In the C-terminal section; belongs to the cyclodeaminase/cyclohydrolase family.
In the N-terminal section; belongs to the formiminotransferase family.
