EC Number | Activating Compound | Comment | Organism | Structure |
---|---|---|---|---|
3.5.4.9 | 2',5'-ADP | analog of NADP+ does not stimulate the reverse cyclohydrolase activity | Homo sapiens | |
3.5.4.9 | 2',5'-ADP | the analog of NADP+ stimulates the reverse cyclohydrolase activity by more than 2fold | Homo sapiens | |
3.5.4.9 | 5'-ADP | analog of NADP+ does not stimulate the reverse cyclohydrolase activity | Homo sapiens |
EC Number | Cloned (Comment) | Organism |
---|---|---|
1.5.1.5 | deletion of the MIS1 gene has little effect | Saccharomyces cerevisiae |
1.5.1.5 | null mutation is embryonic lethal at about 12 days gestation, knockout of enzyme establishes the important role of formate production during embryogenesis | Homo sapiens |
3.5.4.9 | deletion of the MIS1 gene has little effect | Saccharomyces cerevisiae |
3.5.4.9 | null mutation is embryonic lethal at about 12 days gestation, knockout of enzyme establishes the important role of formate production during embryogenesis | Homo sapiens |
6.3.4.3 | deletion of the MIS1 gene has little effect | Saccharomyces cerevisiae |
6.3.4.3 | expressed in Escherichia coli | Homo sapiens |
EC Number | Protein Variants | Comment | Organism |
---|---|---|---|
1.5.1.5 | D133E | mutant retains no dehydrogenase activity | Homo sapiens |
1.5.1.5 | D133E | no dehydrogenase activity retained, Mg2+ binding site | Homo sapiens |
1.5.1.5 | K56Q/Q100K | retaines two-third of dehydrogenase activity but no cyclohydrolase activity | Homo sapiens |
1.5.1.5 | K56Q/Q100K | site-directed mutagenesis shows that the double mutant has no cyclohydrolase activity but retains two-thirds of the normal dehydrogenase activity | Homo sapiens |
1.5.1.5 | additional information | asparagine-125 is required for folate-substrate binding, arginine-173 mutation causes 500fold increase in the Km for NADP, serine-197 mutation a 20fold increase | Homo sapiens |
1.5.1.5 | additional information | knockout mutant of MTHFD2 is embryonic lethal in mice at about 12 days gestation, no normal development of hematogenesis in the liver | Homo sapiens |
1.5.1.5 | additional information | mutation of arginine-166 leads to complete loss of dehydrogenase activity, is critically responsible for binding of the inorganic phosphate, with arginine-198 mutation some dehydrogenase activity is retained, it probably only assists in phosphate binding | Homo sapiens |
3.5.4.9 | K56Q/Q100K | site-directed mutagenesis shows that the double mutant has no cyclohydrolase activity but retains two-thirds of the normal dehydrogenase activity | Homo sapiens |
EC Number | Inhibitors | Comment | Organism | Structure |
---|---|---|---|---|
1.5.1.5 | phosphate | competitive inhibitor against NADP+ | Homo sapiens | |
3.5.4.9 | NADP+ | - |
Homo sapiens |
EC Number | KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
---|---|---|---|---|---|---|
1.5.1.5 | additional information | - |
NADP+ | mutation of Arg173 causes a 500fold increase in the Km value for NADP+, while mutation of Ser197 causes a 20fold increase | Homo sapiens | |
3.5.4.9 | additional information | - |
additional information | the overall forward reaction from mythylene- to formyltetrahydrofolate shows a hydride transfer kinetic isotope effect, whereas the the overall reverse reaction does not | Homo sapiens |
EC Number | Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|---|
1.5.1.5 | cytoplasm | - |
Homo sapiens | 5737 | - |
1.5.1.5 | cytosol | ADE3 | Saccharomyces cerevisiae | 5829 | - |
1.5.1.5 | mitochondrion | - |
Homo sapiens | 5739 | - |
1.5.1.5 | mitochondrion | MIS1 | Saccharomyces cerevisiae | 5739 | - |
3.5.4.9 | cytoplasm | - |
Homo sapiens | 5737 | - |
3.5.4.9 | cytosol | - |
Saccharomyces cerevisiae | 5829 | - |
3.5.4.9 | mitochondrion | - |
Homo sapiens | 5739 | - |
3.5.4.9 | mitochondrion | - |
Saccharomyces cerevisiae | 5739 | - |
6.3.4.3 | cytoplasm | - |
Homo sapiens | 5737 | - |
6.3.4.3 | cytosol | ADE3 | Saccharomyces cerevisiae | 5829 | - |
6.3.4.3 | mitochondrion | - |
Homo sapiens | 5739 | - |
6.3.4.3 | mitochondrion | - |
Saccharomyces cerevisiae | 5739 | - |
EC Number | Metals/Ions | Comment | Organism | Structure |
---|---|---|---|---|
1.5.1.5 | inorganic phosphate | required for activity, competitive inhibitor of NADP | Homo sapiens | |
1.5.1.5 | Mg2+ | required for activity | Homo sapiens | |
1.5.1.5 | Mg2+ | absolutely required for activity | Homo sapiens | |
1.5.1.5 | Mn2+ | required for activity when Mg2+ is absent | Homo sapiens |
EC Number | Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
---|---|---|---|---|
1.5.1.5 | 34000 | - |
MTHFD2 evolves from a trifunctional dehydrogenase-cyclohydrolase-synthetase precursor with the loss of synthetase function | Homo sapiens |
3.5.4.9 | 34000 | - |
MTHFD2 evolves from a trifunctional dehydrogenase-cyclohydrolase-synthetase precursor with the loss of synthetase function | Homo sapiens |
EC Number | Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|---|
1.5.1.5 | 5,10-methylene tetrahydrofolate + NAD+ | Homo sapiens | bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities | 5,10-methenyl tetrahydrofolate + NADH + H+ | - |
r | |
1.5.1.5 | 5,10-methylene tetrahydrofolate + NADP+ | Saccharomyces cerevisiae | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | 5,10-methenyl tetrahydrofolate + NADPH | - |
r | |
1.5.1.5 | 5,10-methylene tetrahydrofolate + NADP+ | Homo sapiens | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities | 5,10-methenyl tetrahydrofolate + NADPH + H+ | - |
r | |
1.5.1.5 | 5,10-methylene-tetrahydrofolate + NAD+ | Homo sapiens | combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase | 5,10-methenyl-tetrahydrofolate + NADH | 50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate | r | |
1.5.1.5 | 5,10-methylene-tetrahydrofolate + NADP+ | Homo sapiens | - |
5,10-methenyl-tetrahydrofolate + NADPH + H+ | the cyclohydrolase forms formyltetrahydrofolate | r | |
1.5.1.5 | 5,10-methylenetetrahydrofolate + NADP+ | Homo sapiens | - |
5,10-methenyltetrahydrofolate + NADPH + H+ | - |
r | |
1.5.1.5 | additional information | Saccharomyces cerevisiae | the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions | ? | - |
? | |
3.5.4.9 | 5,10-methenyl-tetrahydrofolate + H2O | Saccharomyces cerevisiae | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | 10-formyltetrahydrofolate + H+ | - |
r | |
3.5.4.9 | 5,10-methenyltetrahydrofolate + H2O | Homo sapiens | bifunctional enzyme exhibits dihydrogenase and cyclohydrolase activities | 10-formyltetrahydrofolate | - |
r | |
3.5.4.9 | 5,10-methenyltetrahydrofolate + H2O | Homo sapiens | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | 10-formyltetrahydrofolate | - |
r | |
3.5.4.9 | additional information | Homo sapiens | the conversion of formyl- to methylenehydrofolate is rate-limited by the slow conversion by the cyclohydrolase of formyl- to methenyltetrahydrofolate | ? | - |
? | |
3.5.4.9 | additional information | Saccharomyces cerevisiae | the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions | ? | - |
? | |
6.3.4.3 | additional information | Saccharomyces cerevisiae | the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions | ? | - |
? | |
6.3.4.3 | tetrahydrofolate + formate + ATP | Homo sapiens | monofunctional enzyme similar in structure to the cytoplasmatic trifunctional enzyme, dehydrogenase and cyclohydrolase activities are silent due to mutations of critical binding and catalytic residues | 10-formyltetrahydrofolate + ADP + phosphate | mitochondria also use formyltetrahydrofolate to produce formylmethionyl-tRNA to initiate protein synthesis | r | |
6.3.4.3 | tetrahydrofolate + formate + ATP | Homo sapiens | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities | 10-formyltetrahydrofolate + ADP + phosphate | - |
r | |
6.3.4.3 | tetrahydrofolate + formate + ATP | Saccharomyces cerevisiae | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | 10-formyltetrahydrofolate + ADP + phosphate | - |
r |
EC Number | Organism | UniProt | Comment | Textmining |
---|---|---|---|---|
1.5.1.5 | Homo sapiens | - |
- |
- |
1.5.1.5 | Homo sapiens | - |
enzyme is unique in mammals | - |
1.5.1.5 | Saccharomyces cerevisiae | - |
- |
- |
3.5.4.9 | Homo sapiens | - |
- |
- |
3.5.4.9 | Homo sapiens | - |
enzyme is unique in mammals | - |
3.5.4.9 | Saccharomyces cerevisiae | P07245 | - |
- |
3.5.4.9 | Saccharomyces cerevisiae | P09440 | - |
- |
6.3.4.3 | Homo sapiens | - |
- |
- |
6.3.4.3 | Saccharomyces cerevisiae | P07245 | - |
- |
6.3.4.3 | Saccharomyces cerevisiae | P09440 | - |
- |
EC Number | Source Tissue | Comment | Organism | Textmining |
---|---|---|---|---|
1.5.1.5 | ascites tumor cell | - |
Homo sapiens | - |
1.5.1.5 | additional information | the cytoplasmatic MTHFD1 is ubiquitously expressed in all mammalian cells | Homo sapiens | - |
1.5.1.5 | additional information | the mitochondrial MTHFD2 is detected only in transformed cell lines and embryogenic tissues | Homo sapiens | - |
3.5.4.9 | ascites tumor cell | - |
Homo sapiens | - |
3.5.4.9 | additional information | the cytoplasmic MTHFD1 is ubiquitously expressed in all mammalian cells | Homo sapiens | - |
3.5.4.9 | additional information | the mitochondrial MTHFD2 is detected only in transformed cell lines and embryogenic tissues | Homo sapiens | - |
6.3.4.3 | adenocarcinoma cell | - |
Homo sapiens | - |
6.3.4.3 | brain | - |
Homo sapiens | - |
6.3.4.3 | HEK-293 cell | - |
Homo sapiens | - |
6.3.4.3 | leukocyte | low expression | Homo sapiens | - |
6.3.4.3 | lung | - |
Homo sapiens | - |
6.3.4.3 | lymphocyte | low expression | Homo sapiens | - |
6.3.4.3 | additional information | the cytoplasmatic MTHFD1 is ubiquitously expressed in all mammalian cells | Homo sapiens | - |
6.3.4.3 | muscle | low expression | Homo sapiens | - |
6.3.4.3 | ovary | - |
Homo sapiens | - |
6.3.4.3 | placenta | - |
Homo sapiens | - |
6.3.4.3 | spleen | - |
Homo sapiens | - |
6.3.4.3 | thymus | - |
Homo sapiens | - |
EC Number | Specific Activity Minimum [µmol/min/mg] | Specific Activity Maximum [µmol/min/mg] | Comment | Organism |
---|---|---|---|---|
6.3.4.3 | additional information | - |
MTHFD1L is upregulated in colon adeno-carcinomas | Homo sapiens |
6.3.4.3 | additional information | - |
overexpression of MTHFD1L in HEK-292 cells stimulates colony formation indicating that expression of this gene confers a growth advantage | Homo sapiens |
EC Number | Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|---|
1.5.1.5 | 5,10-methylene tetrahydrofolate + NAD+ | bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities | Homo sapiens | 5,10-methenyl tetrahydrofolate + NADH + H+ | - |
r | |
1.5.1.5 | 5,10-methylene tetrahydrofolate + NADP+ | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | Saccharomyces cerevisiae | 5,10-methenyl tetrahydrofolate + NADPH | - |
r | |
1.5.1.5 | 5,10-methylene tetrahydrofolate + NADP+ | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities | Homo sapiens | 5,10-methenyl tetrahydrofolate + NADPH + H+ | - |
r | |
1.5.1.5 | 5,10-methylene-tetrahydrofolate + NAD+ | combined cofactors NAD+, Mg2+, and phosphate mimic the binding of NADP+ in NADP(+)-dependent dehydrogenase | Homo sapiens | 5,10-methenyl-tetrahydrofolate + NADH | 50-60% channeled to the cyclohydrolase to form formyltetrahydrofolate | r | |
1.5.1.5 | 5,10-methylene-tetrahydrofolate + NADP+ | - |
Homo sapiens | 5,10-methenyl-tetrahydrofolate + NADPH + H+ | the cyclohydrolase forms formyltetrahydrofolate | r | |
1.5.1.5 | 5,10-methylenetetrahydrofolate + NADP+ | - |
Homo sapiens | 5,10-methenyltetrahydrofolate + NADPH + H+ | - |
r | |
1.5.1.5 | additional information | the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions | Saccharomyces cerevisiae | ? | - |
? | |
3.5.4.9 | 5,10-methenyl-tetrahydrofolate + H2O | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | Saccharomyces cerevisiae | 10-formyltetrahydrofolate + H+ | - |
r | |
3.5.4.9 | 5,10-methenyltetrahydrofolate + H2O | bifunctional enzyme exhibits dihydrogenase and cyclohydrolase activities | Homo sapiens | 10-formyltetrahydrofolate | - |
r | |
3.5.4.9 | 5,10-methenyltetrahydrofolate + H2O | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | Homo sapiens | 10-formyltetrahydrofolate | - |
r | |
3.5.4.9 | additional information | the conversion of formyl- to methylenehydrofolate is rate-limited by the slow conversion by the cyclohydrolase of formyl- to methenyltetrahydrofolate | Homo sapiens | ? | - |
? | |
3.5.4.9 | additional information | the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions | Saccharomyces cerevisiae | ? | - |
? | |
6.3.4.3 | additional information | the presence of cytoplasmic and mitochondrial isoforms of a trifunctional dehydrogenase-cyclohydrolase-synthetase support a model wherin the mitochondria can produce fromate which can be used by the cytoplasmic enzymes for the synthesis of purins and for methylation reactions | Saccharomyces cerevisiae | ? | - |
? | |
6.3.4.3 | tetrahydrofolate + formate + ATP | monofunctional enzyme similar in structure to the cytoplasmatic trifunctional enzyme, dehydrogenase and cyclohydrolase activities are silent due to mutations of critical binding and catalytic residues | Homo sapiens | 10-formyltetrahydrofolate + ADP + phosphate | mitochondria also use formyltetrahydrofolate to produce formylmethionyl-tRNA to initiate protein synthesis | r | |
6.3.4.3 | tetrahydrofolate + formate + ATP | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities | Homo sapiens | 10-formyltetrahydrofolate + ADP + phosphate | - |
r | |
6.3.4.3 | tetrahydrofolate + formate + ATP | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | Saccharomyces cerevisiae | 10-formyltetrahydrofolate + ADP + phosphate | - |
r |
EC Number | Subunits | Comment | Organism |
---|---|---|---|
6.3.4.3 | dimer | by gel filtration | Homo sapiens |
EC Number | Synonyms | Comment | Organism |
---|---|---|---|
1.5.1.5 | ADE3 | - |
Saccharomyces cerevisiae |
1.5.1.5 | dehydrogenasse-cyclohydrolase-synthetase | - |
Saccharomyces cerevisiae |
1.5.1.5 | methylenetetrahydrofolate dehydrogenase | - |
Homo sapiens |
1.5.1.5 | methylenetetrahydrofolate dehydrogenase | - |
Saccharomyces cerevisiae |
1.5.1.5 | MIS1 | - |
Saccharomyces cerevisiae |
1.5.1.5 | mitochondrial methylenetetrahydrofolate dehydrogenase | - |
Homo sapiens |
1.5.1.5 | MTHFD1 | - |
Homo sapiens |
1.5.1.5 | MTHFD1 protein | trifunctional cytosolic NADP(+)-dependent methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetase | Homo sapiens |
1.5.1.5 | MTHFD2 | - |
Homo sapiens |
1.5.1.5 | MTHFD2 protein | bifunctional mitochondrial NAD(+)-dependent methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase, derived from trifunctional precursor by loss of the formyltetrahydrofolate synthetase domain, unique in mammals | Homo sapiens |
1.5.1.5 | NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase | - |
Homo sapiens |
3.5.4.9 | ADE3 | - |
Saccharomyces cerevisiae |
3.5.4.9 | dehydrogenasse-cyclohydrolase-synthetase | - |
Saccharomyces cerevisiae |
3.5.4.9 | methenyltetrahydrofolate cyclohydrolase | - |
Homo sapiens |
3.5.4.9 | methenyltetrahydrofolate cyclohydrolase | - |
Saccharomyces cerevisiae |
3.5.4.9 | MIS1 | - |
Saccharomyces cerevisiae |
3.5.4.9 | MTHFD1 | - |
Homo sapiens |
3.5.4.9 | MTHFD2 | - |
Homo sapiens |
3.5.4.9 | NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase | - |
Homo sapiens |
6.3.4.3 | 10-Formyltetrahydrofolate synthetase | - |
Homo sapiens |
6.3.4.3 | ADE3 | - |
Saccharomyces cerevisiae |
6.3.4.3 | dehydrogenasse-cyclohydrolase-synthetase | - |
Saccharomyces cerevisiae |
6.3.4.3 | Formyltetrahydrofolate synthetase | - |
Homo sapiens |
6.3.4.3 | Formyltetrahydrofolate synthetase | - |
Saccharomyces cerevisiae |
6.3.4.3 | MIS1 | - |
Saccharomyces cerevisiae |
6.3.4.3 | MTHFD1 | - |
Homo sapiens |
6.3.4.3 | MTHFD1L | - |
Homo sapiens |
EC Number | Turnover Number Minimum [1/s] | Turnover Number Maximum [1/s] | Substrate | Comment | Organism | Structure |
---|---|---|---|---|---|---|
6.3.4.3 | additional information | - |
additional information | the Kcat/Km tetrahydrofolate values are 0.03 s/M for the monoglutamate and 0.71 s/M for the pentaglutatmate substrates | Homo sapiens |
EC Number | Cofactor | Comment | Organism | Structure |
---|---|---|---|---|
1.5.1.5 | NAD+ | instead of NADP as in cytosolic dehydrogenase precursor (higher Km and lower Vmax with NADP) | Homo sapiens | |
1.5.1.5 | NAD+ | mitochondrial dehydrogenase activity | Homo sapiens | |
1.5.1.5 | NADP+ | - |
Homo sapiens | |
1.5.1.5 | NADP+ | - |
Saccharomyces cerevisiae | |
1.5.1.5 | NADP+ | reverse cyclohydrolase activity is stimulated by the NADP analog 2',5'-ADP twofold | Homo sapiens | |
1.5.1.5 | NADP+ | the hydrogenase can also us NADP+ but with a higher Km value and lower Vmax than NAD+ | Homo sapiens | |
6.3.4.3 | ATP | - |
Homo sapiens |
EC Number | General Information | Comment | Organism |
---|---|---|---|
1.5.1.5 | metabolism | cytosolic protein with role in cytosolic purine synthesis, ubiquitously expressed in all mammalian cells | Homo sapiens |
1.5.1.5 | metabolism | mitochondrial protein with role in cytosolic purine synthesis (main switch for format production in mitochondria) during embryonic development and in cells undergoing rapid growth, not expressed in differentiated cells | Homo sapiens |