Cloned (Comment) | Organism |
---|---|
deletion of the MIS1 gene has little effect | Saccharomyces cerevisiae |
null mutation is embryonic lethal at about 12 days gestation, knockout of enzyme establishes the important role of formate production during embryogenesis | Homo sapiens |
Protein Variants | Comment | Organism |
---|---|---|
D133E | mutant retains no dehydrogenase activity | Homo sapiens |
D133E | no dehydrogenase activity retained, Mg2+ binding site | Homo sapiens |
K56Q/Q100K | retaines two-third of dehydrogenase activity but no cyclohydrolase activity | Homo sapiens |
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 |
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 |
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 |
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 |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
phosphate | competitive inhibitor against NADP+ | Homo sapiens |
KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
---|---|---|---|---|---|
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 |
Localization | Comment | Organism | GeneOntology No. | Textmining |
---|---|---|---|---|
cytoplasm | - |
Homo sapiens | 5737 | - |
cytosol | ADE3 | Saccharomyces cerevisiae | 5829 | - |
mitochondrion | - |
Homo sapiens | 5739 | - |
mitochondrion | MIS1 | Saccharomyces cerevisiae | 5739 | - |
Metals/Ions | Comment | Organism | Structure |
---|---|---|---|
inorganic phosphate | required for activity, competitive inhibitor of NADP | Homo sapiens | |
Mg2+ | required for activity | Homo sapiens | |
Mg2+ | absolutely required for activity | Homo sapiens | |
Mn2+ | required for activity when Mg2+ is absent | Homo sapiens |
Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
---|---|---|---|
34000 | - |
MTHFD2 evolves from a trifunctional dehydrogenase-cyclohydrolase-synthetase precursor with the loss of synthetase function | Homo sapiens |
Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
---|---|---|---|---|---|---|
5,10-methylene tetrahydrofolate + NAD+ | Homo sapiens | bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities | 5,10-methenyl tetrahydrofolate + NADH + H+ | - |
r | |
5,10-methylene tetrahydrofolate + NADP+ | Saccharomyces cerevisiae | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | 5,10-methenyl tetrahydrofolate + NADPH | - |
r | |
5,10-methylene tetrahydrofolate + NADP+ | Homo sapiens | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities | 5,10-methenyl tetrahydrofolate + NADPH + H+ | - |
r | |
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 | |
5,10-methylene-tetrahydrofolate + NADP+ | Homo sapiens | - |
5,10-methenyl-tetrahydrofolate + NADPH + H+ | the cyclohydrolase forms formyltetrahydrofolate | r | |
5,10-methylenetetrahydrofolate + NADP+ | Homo sapiens | - |
5,10-methenyltetrahydrofolate + NADPH + H+ | - |
r | |
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 | ? | - |
? |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | - |
- |
- |
Homo sapiens | - |
enzyme is unique in mammals | - |
Saccharomyces cerevisiae | - |
- |
- |
Source Tissue | Comment | Organism | Textmining |
---|---|---|---|
ascites tumor cell | - |
Homo sapiens | - |
additional information | the cytoplasmatic MTHFD1 is ubiquitously expressed in all mammalian cells | Homo sapiens | - |
additional information | the mitochondrial MTHFD2 is detected only in transformed cell lines and embryogenic tissues | Homo sapiens | - |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
5,10-methylene tetrahydrofolate + NAD+ | bifunctional enzyme exhibits dehydrogenase and cyclohydrogenase activities | Homo sapiens | 5,10-methenyl tetrahydrofolate + NADH + H+ | - |
r | |
5,10-methylene tetrahydrofolate + NADP+ | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrolase activities | Saccharomyces cerevisiae | 5,10-methenyl tetrahydrofolate + NADPH | - |
r | |
5,10-methylene tetrahydrofolate + NADP+ | trifunctional enzyme exhibits synthetase, dehydrogenase and cyclohydrogenase activities | Homo sapiens | 5,10-methenyl tetrahydrofolate + NADPH + H+ | - |
r | |
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 | |
5,10-methylene-tetrahydrofolate + NADP+ | - |
Homo sapiens | 5,10-methenyl-tetrahydrofolate + NADPH + H+ | the cyclohydrolase forms formyltetrahydrofolate | r | |
5,10-methylenetetrahydrofolate + NADP+ | - |
Homo sapiens | 5,10-methenyltetrahydrofolate + NADPH + H+ | - |
r | |
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 | ? | - |
? |
Synonyms | Comment | Organism |
---|---|---|
ADE3 | - |
Saccharomyces cerevisiae |
dehydrogenasse-cyclohydrolase-synthetase | - |
Saccharomyces cerevisiae |
methylenetetrahydrofolate dehydrogenase | - |
Homo sapiens |
methylenetetrahydrofolate dehydrogenase | - |
Saccharomyces cerevisiae |
MIS1 | - |
Saccharomyces cerevisiae |
mitochondrial methylenetetrahydrofolate dehydrogenase | - |
Homo sapiens |
MTHFD1 | - |
Homo sapiens |
MTHFD1 protein | trifunctional cytosolic NADP(+)-dependent methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetase | Homo sapiens |
MTHFD2 | - |
Homo sapiens |
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 |
NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase | - |
Homo sapiens |
Cofactor | Comment | Organism | Structure |
---|---|---|---|
NAD+ | instead of NADP as in cytosolic dehydrogenase precursor (higher Km and lower Vmax with NADP) | Homo sapiens | |
NAD+ | mitochondrial dehydrogenase activity | Homo sapiens | |
NADP+ | - |
Homo sapiens | |
NADP+ | - |
Saccharomyces cerevisiae | |
NADP+ | reverse cyclohydrolase activity is stimulated by the NADP analog 2',5'-ADP twofold | Homo sapiens | |
NADP+ | the hydrogenase can also us NADP+ but with a higher Km value and lower Vmax than NAD+ | Homo sapiens |
General Information | Comment | Organism |
---|---|---|
metabolism | cytosolic protein with role in cytosolic purine synthesis, ubiquitously expressed in all mammalian cells | Homo sapiens |
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 |