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Literature summary extracted from

  • Christensen, K.E.; Rohlicek, C.V.; Andelfinger, G.U.; Michaud, J.; Bigras, J.L.; Richter, A.; Mackenzie, R.E.; Rozen, R.
    The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects (2009), Hum. Mutat., 30, 212-220.
    View publication on PubMed

Cloned(Commentary)

EC Number Cloned (Comment) Organism
1.5.1.5 the wild type and R653Q mutant pBKeDCS constructs are transformed into Escherichia coli BL21 DE3 to express the full-length protein Homo sapiens
3.5.4.9 the wild type and R653Q mutant pBKeDCS constructs are transformed into Escherichia coli BL21 DE3 to express the full-length protein Homo sapiens
6.3.4.3 the wild type and R653Q mutant pBKeDCS constructs are transformed into Escherichia coli BL21 DE3 to express the full-length protein Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
1.5.1.5 R653Q mutant enzyme has normal substrate affinity but a 36% reduction in half-life at 42°C Homo sapiens
3.5.4.9 R653Q mutant enzyme only affects the synthetase activity Homo sapiens
6.3.4.3 R653Q mutant enzyme has normal substrate affinity but a 36% reduction in half-life at 42°C, the mutation reduces the metabolic activity of MTHFD1 within cells: formate incorporation into DNA in murine Mthfd1 knockout cells transfected with Arg653Gln is reduced by 26%, compared to cells transfected with wild-type protein, the mutant may increase the risk for neural tube defects, under ideal storage and standard assay conditions, the synthetase activity of MTHFD1 is unaffected by the R653Q mutation Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
6.3.4.3 ADP
-
Homo sapiens
6.3.4.3 pteroylpentaglutamate
-
Homo sapiens

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
6.3.4.3 0.0286
-
ATP mutant R653Q Homo sapiens
6.3.4.3 0.0302
-
ATP wild type Homo sapiens
6.3.4.3 0.0367
-
formate wild type Homo sapiens
6.3.4.3 0.0371
-
formate mutant R653Q Homo sapiens
6.3.4.3 0.333
-
tetrahydrofolate mutant R653Q Homo sapiens
6.3.4.3 0.364
-
tetrahydrofolate wild type 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 + NADP+ Homo sapiens dehydrogenase activity of MTHFD1 5,10-methenyltetrahydrofolate + NADPH
-
r
1.5.1.5 additional information Homo sapiens (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis ?
-
?
3.5.4.9 5,10-methenyltetrahydrofolate + H2O Homo sapiens cyclodehydrolase activity of MTHFD1 10-formyltetrahydrofolate + ?
-
r
3.5.4.9 additional information Homo sapiens MTHFD1 is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis ?
-
?
6.3.4.3 formate + ATP + tetrahydrofolate Homo sapiens synthetase activity of MTHFD1 10-formyltetrahydrofolate + ADP + phosphate
-
?
6.3.4.3 additional information Homo sapiens (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis ?
-
?

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.5 Homo sapiens P11586
-
-
3.5.4.9 Homo sapiens P11586
-
-
6.3.4.3 Homo sapiens P11586
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
1.5.1.5 by anion-exchange chromatography Homo sapiens
3.5.4.9 by anion-exchange chromatography Homo sapiens
6.3.4.3 by anion-exchange chromatography Homo sapiens

Specific Activity [micromol/min/mg]

EC Number Specific Activity Minimum [µmol/min/mg] Specific Activity Maximum [µmol/min/mg] Comment Organism
1.5.1.5 13.2
-
dehydrogenase activity of the wild type enzyme Homo sapiens
1.5.1.5 13.9
-
dehydrogenase activity of the mutant R653Q Homo sapiens
6.3.4.3 additional information
-
100.2% activity of mutant R653Q after heating at 42°C for 90 min, in 7.5% glycerol and 0.35 mM folate pentaglutamate Homo sapiens
6.3.4.3 additional information
-
102% activity of wild type enzyme after heating at 42°C for 90 min, in 7.5% glycerol and 0.35 mM folate pentaglutamate Homo sapiens
6.3.4.3 additional information
-
57.4% activity of mutant R653Q, without adding of any cofactor, after heating at 42°C for 90 min, in 7.5% glycerol Homo sapiens
6.3.4.3 additional information
-
72.3% activity of wild type enzyme, without adding of any cofactor, after heating at 42°C for 90 min, in 7.5% glycerol Homo sapiens
6.3.4.3 additional information
-
80.5% activity of mutant R653Q after heating at 42°C for 90 min, in 7.5% glycerol, 1.2 mM MgCl, 0.6 mM ATP Homo sapiens
6.3.4.3 additional information
-
88.2% activity of wild type enzyme after heating at 42°C for 90 min, in 7.5% glycerol, 1.2 mM MgCl, 0.6 mM ATP Homo sapiens
6.3.4.3 additional information
-
enzyme knock-out cells are transfected with either wild type or R653Q mutant and their ability to synthesize purines is assessed by a 14C-formate incorporation assay, the cells expressing the R653Q variant incorporate only 74% of wild-type levels of formate into DNA, the R653Q protein appears to have a significant impact on cellular nucleotide metabolism Homo sapiens
6.3.4.3 23
-
synthetase activity of the wild type enzyme Homo sapiens
6.3.4.3 23.8
-
synthetase activity of the mutant R653Q 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 + NADP+ dehydrogenase activity of MTHFD1 Homo sapiens 5,10-methenyltetrahydrofolate + NADPH
-
r
1.5.1.5 additional information (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis Homo sapiens ?
-
?
3.5.4.9 5,10-methenyltetrahydrofolate + H2O cyclodehydrolase activity of MTHFD1 Homo sapiens 10-formyltetrahydrofolate + ?
-
r
3.5.4.9 additional information MTHFD1 is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis Homo sapiens ?
-
?
6.3.4.3 (R,S)-tetrahydrofolate + ATP + formate
-
Homo sapiens ?
-
r
6.3.4.3 formate + ATP + tetrahydrofolate synthetase activity of MTHFD1 Homo sapiens 10-formyltetrahydrofolate + ADP + phosphate
-
?
6.3.4.3 additional information (MTHFD1) is a trifunctional enzyme that interconverts tetrahydrofolate derivatives for nucleotide synthesis Homo sapiens ?
-
?

Synonyms

EC Number Synonyms Comment Organism
1.5.1.5 methylenetetrahydrofolate dehydrogenase
-
Homo sapiens
1.5.1.5 methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase
-
Homo sapiens
1.5.1.5 MTHFD1
-
Homo sapiens
3.5.4.9 methenyltetrahydrofolate cyclohydrolase
-
Homo sapiens
3.5.4.9 methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase
-
Homo sapiens
3.5.4.9 MTHFD1
-
Homo sapiens
6.3.4.3 Formyltetrahydrofolate synthetase
-
Homo sapiens
6.3.4.3 methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase
-
Homo sapiens
6.3.4.3 MTHFD1
-
Homo sapiens

Temperature Stability [°C]

EC Number Temperature Stability Minimum [°C] Temperature Stability Maximum [°C] Comment Organism
6.3.4.3 additional information
-
thermolability is reduced by magnesium adenosine triphosphate and eliminated by the substrate analog folate pentaglutamate, suggesting that folate status may modulate impact of the variant R653Q Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
1.5.1.5 NADP+
-
Homo sapiens
6.3.4.3 ATP
-
Homo sapiens

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
6.3.4.3 0.0296
-
pteroylpentaglutamate wild type enzyme Homo sapiens
6.3.4.3 0.0328
-
pteroylpentaglutamate mutant R653Q Homo sapiens
6.3.4.3 0.0338
-
ADP mutant R653Q Homo sapiens
6.3.4.3 0.0364
-
ADP wild type enzyme Homo sapiens