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Literature summary 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

Activating Compound

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

Cloned(Commentary)

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

Protein Variants

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

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.5 phosphate competitive inhibitor against NADP+ Homo sapiens
3.5.4.9 NADP+
-
Homo sapiens

KM Value [mM]

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

Localization

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
-

Metals/Ions

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

Molecular Weight [Da]

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

Natural Substrates/ Products (Substrates)

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

Organism

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
-
-

Source Tissue

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
-

Specific Activity [micromol/min/mg]

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

Substrates and Products (Substrate)

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

Subunits

EC Number Subunits Comment Organism
6.3.4.3 dimer by gel filtration Homo sapiens

Synonyms

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

Turnover Number [1/s]

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

Cofactor

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

General Information

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