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Literature summary extracted from

  • Shin, M.; Bryant, J.D.; Momb, J.; Appling, D.R.
    Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues (2014), J. Biol. Chem., 289, 15507-15517 .
    View publication on PubMedView publication on EuropePMC

Cloned(Commentary)

EC Number Cloned (Comment) Organism
1.5.1.5 gene MTHFD2L, DNA and amino acid sequence determination and analysis, quantitative real-time PCR enzyme expression analysis, the truncated enzyme mutant rMTHFD2LDELTA1-40 is cloned into vector YEp24-based yeast expression vector containing the Saccharomyces cerevisiae MET6 promoter and expressed in Saccharomyces cerevisiae strain MWY4.4 as N-terminally His6-tagged protein, replacment of the mitochondrial targeting sequence of the rat MTHFD2L with an N-terminal His tag for localization in the yeast cytosol Rattus norvegicus
1.5.1.5 gene Mthfd2l, MTHFD2L is alternatively spliced at exons 2 and 8, quantitative real-time PCR enzyme expression analysis, gene expression profiling of the MTHFD gene family in mouse embryos and adult organs Mus musculus

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.5.1.5 phosphate the NADP+-dependent methylenetetrahydrofolate dehydrogenase activity is inhibited by phosphate, competitive inhibition Mus musculus
1.5.1.5 phosphate the NADP+-dependent methylenetetrahydrofolate dehydrogenase activity is inhibited by phosphate, competitive inhibition Rattus norvegicus

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
1.5.1.5 additional information
-
 additional information Michaelis-Menten kinetics Mus musculus
1.5.1.5 additional information
-
 additional information Michaelis-Menten kinetics Rattus norvegicus
1.5.1.5 0.04
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, monoglutamylated substrate, with NAD+ Mus musculus
1.5.1.5 0.042
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, monoglutamylated substrate, with NADP+ Mus musculus
1.5.1.5 0.13
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, polyglutamylated substrate, with NAD+ Mus musculus
1.5.1.5 0.147
-
 NAD+ pH 8.0, 30°C Mus musculus
1.5.1.5 0.153
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, polyglutamylated substrate, with NADP+ Mus musculus
1.5.1.5 0.537
-
 NADP+ pH 8.0, 30°C Mus musculus

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
1.5.1.5 mitochondrion
-
 Mus musculus 5739
-
1.5.1.5 mitochondrion
-
 Rattus norvegicus 5739
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
1.5.1.5 Mg2+ required for methylenetetrahydrofolate dehydrogenase activity with NADH Mus musculus
1.5.1.5 Mg2+ required for methylenetetrahydrofolate dehydrogenase activity with NADH Rattus norvegicus
1.5.1.5 additional information phosphate appears to counteract the Mg2+ effect with NADP+ Mus musculus
1.5.1.5 additional information phosphate appears to counteract the Mg2+ effect with NADP+ Rattus norvegicus
1.5.1.5 phosphate required for methylenetetrahydrofolate dehydrogenase activity with NADH Mus musculus
1.5.1.5 phosphate required for methylenetetrahydrofolate dehydrogenase activity with NADH Rattus norvegicus

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-methylenetetrahydrofolate + NAD+ Mus musculus
-
 5,10-methenyltetrahydrofolate + NADH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NAD+ Rattus norvegicus
-
 5,10-methenyltetrahydrofolate + NADH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NAD+ Mus musculus C57BL/6
-
 5,10-methenyltetrahydrofolate + NADH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NADP+ Mus musculus
-
 5,10-methenyltetrahydrofolate + NADPH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NADP+ Rattus norvegicus
-
 5,10-methenyltetrahydrofolate + NADPH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NADP+ Mus musculus C57BL/6
-
 5,10-methenyltetrahydrofolate + NADPH + H+
-
 r
1.5.1.5 additional information Mus musculus MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9 ?
-
 ?
1.5.1.5 additional information Rattus norvegicus MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9 ?
-
 ?
1.5.1.5 additional information Mus musculus C57BL/6 MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9 ?
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.5 Mus musculus D3YZG8
-
-
1.5.1.5 Mus musculus C57BL/6 D3YZG8
-
-
1.5.1.5 Rattus norvegicus D3ZUA0
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
1.5.1.5 recombinant His-tagged truncated enzyme mutant rMTHFD2LDELTA1-40 from Saccharomyces cerevisiae strain MWY4.4 by nickel affinity chromatography, sodium carbonate in the extraction buffer is used to release MTHFD2L from membranes Rattus norvegicus

Source Tissue

EC Number Source Tissue Comment Organism Textmining
1.5.1.5 adipose tissue
-
 Mus musculus
-
1.5.1.5 brain high expression level Mus musculus
-
1.5.1.5 embryo enzyme MTHFD2L is expressed in embryonic tissues during neural tube closure. Expression of the MTHFD2L transcript is low in early mouse embryos but begins to increase at embryonic day 10.5 and remains elevated through birth, in situ hybridization of whole mouse embryos Mus musculus
-
1.5.1.5 heart
-
 Mus musculus
-
1.5.1.5 kidney low expression level Mus musculus
-
1.5.1.5 liver low expression level Mus musculus
-
1.5.1.5 lung
-
 Mus musculus
-
1.5.1.5 additional information in adults, MTHFD2L is expressed in all tissues examined, with the highest levels observed in brain and lung Mus musculus
-
1.5.1.5 small intestine
-
 Mus musculus
-
1.5.1.5 spleen
-
 Mus musculus
-
1.5.1.5 testis low expression level Mus musculus
-

Storage Stability

EC Number Storage Stability Organism
1.5.1.5 -20°C, purified MTHFD2L in 25 mM Tris-Cl, 10 mM 2-mercaptoethanol, 100mM KCl, and 50% v/v glycerol at pH 7.5. The purified enzyme retains about 75% of initial 5,10-CH2THF dehydrogenase activity after 1 week of storage Rattus norvegicus

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.5.1.5 5,10-methylenetetrahydrofolate + NAD+
-
 Mus musculus 5,10-methenyltetrahydrofolate + NADH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NAD+
-
 Rattus norvegicus 5,10-methenyltetrahydrofolate + NADH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NAD+
-
 Mus musculus C57BL/6 5,10-methenyltetrahydrofolate + NADH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NADP+
-
 Mus musculus 5,10-methenyltetrahydrofolate + NADPH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NADP+
-
 Rattus norvegicus 5,10-methenyltetrahydrofolate + NADPH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydrofolate + NADP+
-
 Mus musculus C57BL/6 5,10-methenyltetrahydrofolate + NADPH + H+
-
 r
1.5.1.5 5,10-methylenetetrahydropteroylpoly-L-glutamate + NADP+
-
 Mus musculus 5,10-methenyltetrahydropteroylpoly-L-glutamate + NADPH + H+
-
 ?
1.5.1.5 5,10-methylenetetrahydropteroylpoly-L-glutamate + NADP+
-
 Mus musculus C57BL/6 5,10-methenyltetrahydropteroylpoly-L-glutamate + NADPH + H+
-
 ?
1.5.1.5 additional information MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9 Mus musculus ?
-
 ?
1.5.1.5 additional information MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9 Rattus norvegicus ?
-
 ?
1.5.1.5 additional information enzyme MTHFD2L uses the mono- and polyglutamylated forms of 5,10-methylenetetrahydrofolate with similar catalytic efficiencies Rattus norvegicus ?
-
 ?
1.5.1.5 additional information enzyme MTHFD2Luses the mono- and polyglutamylated forms of 5,10-methylenetetrahydrofolate with similar catalytic efficiencies Mus musculus ?
-
 ?
1.5.1.5 additional information MTHFD2L catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria. Enzyme MTHFD2L is bifunctional, possessing both methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities, cf. EC 3.5.4.9 Mus musculus C57BL/6 ?
-
 ?
1.5.1.5 additional information enzyme MTHFD2Luses the mono- and polyglutamylated forms of 5,10-methylenetetrahydrofolate with similar catalytic efficiencies Mus musculus C57BL/6 ?
-
 ?

Subunits

EC Number Subunits Comment Organism
1.5.1.5 ? x * 33000, recombinant His6-tagged truncated enzyme mutant rMTHFD2LDELTA1-40, SDS-PAGE Rattus norvegicus

Synonyms

EC Number Synonyms Comment Organism
1.5.1.5 CH2-THF dehydrogenase
-
 Mus musculus
1.5.1.5 CH2-THF dehydrogenase
-
 Rattus norvegicus
1.5.1.5 methylenetetrahydrofolate dehydrogenase
-
 Mus musculus
1.5.1.5 methylenetetrahydrofolate dehydrogenase
-
 Rattus norvegicus
1.5.1.5 methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
 Mus musculus
1.5.1.5 methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase
-
 Rattus norvegicus
1.5.1.5 MTHFD2L
-
 Mus musculus
1.5.1.5 MTHFD2L
-
 Rattus norvegicus

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
1.5.1.5 30
-
 assay at Mus musculus
1.5.1.5 30
-
 assay at Rattus norvegicus

Turnover Number [1/s]

EC Number Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
1.5.1.5 1.1
-
 NADP+ pH 8.0, 30°C Mus musculus
1.5.1.5 1.3
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, monoglutamylated substrate, with NADP+ Mus musculus
1.5.1.5 2.7
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, monoglutamylated substrate, with NAD+ Mus musculus
1.5.1.5 3.6
-
 NAD+ pH 8.0, 30°C Mus musculus
1.5.1.5 7.2
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, polyglutamylated substrate, with NADP+ Mus musculus
1.5.1.5 8.8
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, polyglutamylated substrate, with NAD+ Mus musculus

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.5.1.5 8
-
 assay at Mus musculus
1.5.1.5 8
-
 assay at Rattus norvegicus

Cofactor

EC Number Cofactor Comment Organism Structure
1.5.1.5 additional information enzyme MTHFD2L uses both NAD+ and NADP+ for methylenetetrahydrofolate dehydrogenase activity but requires both phosphate and Mg2+ when using NAD+ Rattus norvegicus
1.5.1.5 additional information the enzyme MTHFD2L uses both NAD+ and NADP+ for methylenetetrahydrofolate dehydrogenase activity but requires both phosphate and Mg2+ when using NAD+ Mus musculus
1.5.1.5 NAD+
-
 Mus musculus
1.5.1.5 NAD+
-
 Rattus norvegicus
1.5.1.5 NADH
-
 Mus musculus
1.5.1.5 NADH
-
 Rattus norvegicus
1.5.1.5 NADP+
-
 Mus musculus
1.5.1.5 NADP+
-
 Rattus norvegicus
1.5.1.5 NADPH
-
 Mus musculus
1.5.1.5 NADPH
-
 Rattus norvegicus

General Information

EC Number General Information Comment Organism
1.5.1.5 evolution the redox cofactor requirements of the isozymes from Mus musculus and Rattus norvegicus are quite similar, both exhibit lower Km values for NAD+ than for NADP+, their NAD+-dependent activities require phosphate and Mg2+, and their NADP+-dependent activities are inhibited by phosphate Mus musculus
1.5.1.5 evolution the redox cofactor requirements of the isozymes from Mus musculus and Rattus norvegicus are quite similar, both exhibit lower Km values for NAD+ than for NADP+, their NAD+-dependent activities require phosphate and Mg2+, and their NADP+-dependent activities are inhibited by phosphate Rattus norvegicus
1.5.1.5 additional information MTFHD2 isozyme has been named NAD+-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase but in fact exhibits dehydrogenase activity with NADP+, albeit with a much higher Km and lower Vmax Mus musculus
1.5.1.5 additional information MTFHD2 isozyme has been named NAD+-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase but in fact exhibits dehydrogenase activity with NADP+, albeit with a much higher Km and lower Vmax Rattus norvegicus
1.5.1.5 physiological function MTHFD2L uses both NAD+ and NADP+ and is expressed in embryonic tissues during neural tube closure. The cofactor specificity allows for rapid response to changing metabolic conditions. MTHFD2 uses Mg2+ and phosphate to convert an NADP+ binding site into an NAD+ binding site. Phosphate binds in close proximity to the 2'-hydroxyl of NAD+ and competes with NADP+ binding. Mg2 plays a role in positioning phosphatei and NAD+ Mus musculus
1.5.1.5 physiological function MTHFD2L uses both NAD+ and NADP+ and is expressed in embryonic tissues during neural tube closure. The cofactor specificity allows for rapid response to changing metabolic conditions. MTHFD2 uses Mg2+ and phosphate to convert an NADP+ binding site into an NAD+ binding site. Phosphate binds in close proximity to the 2'-hydroxyl of NAD+ and competes with NADP+ binding. Mg2 plays a role in positioning phosphatei and NAD+ Rattus norvegicus

kcat/KM [mM/s]

EC Number kcat/KM Value [1/mMs-1] kcat/KM Value Maximum [1/mMs-1] Substrate Comment Organism Structure
1.5.1.5 2.05
-
 NADP+ pH 8.0, 30°C Mus musculus
1.5.1.5 24.49
-
 NAD+ pH 8.0, 30°C Mus musculus
1.5.1.5 30.95
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, monoglutamylated substrate, with NADP+ Mus musculus
1.5.1.5 47.06
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, polyglutamylated substrate, with NADP+ Mus musculus
1.5.1.5 67.5
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, monoglutamylated substrate, with NAD+ Mus musculus
1.5.1.5 67.69
-
 5,10-methylenetetrahydropteroylpoly-L-glutamate pH 8.0, 30°C, polyglutamylated substrate, with NAD+ Mus musculus