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Literature summary for 1.5.1.5 extracted from

  • Christensen, K.E.; Mackenzie, R.E.
    Mitochondrial methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase, and formyltetrahydrofolate synthetases (2008), Vitam. Horm., 79, 393-410.
    View publication on PubMed

Cloned(Commentary)

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

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

Inhibitors Comment Organism Structure
phosphate competitive inhibitor against NADP+ Homo sapiens

KM Value [mM]

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

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

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 [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/ Products (Substrates)

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

Organism UniProt Comment Textmining
Homo sapiens
-
-
-
Homo sapiens
-
enzyme is unique in mammals
-
Saccharomyces cerevisiae
-
-
-

Source Tissue

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 and Products (Substrate)

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

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

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

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