1.5.1.6: formyltetrahydrofolate dehydrogenase
This is an abbreviated version!
For detailed information about formyltetrahydrofolate dehydrogenase, go to the full flat file.
Word Map on EC 1.5.1.6
Reaction
Synonyms
10-FDH, 10-formyl tetrahydrofolate:NADP oxidoreductase, 10-formyl-H2PtGlu:NADP oxidoreductase, 10-formyl-H4folate dehydrogenase, 10-formyltetrahydrofolate dehydrogenase, 10-fTHF dehydrogenase, 10-FTHFDH, ALDH1L1, ALDH1L2, dehydrogenase, formyltetrahydrofolate, FBP-CI, FBP-CI proteins, FDH, folate-binding proteins, cytosol I, More, mtFDH, N10-formyltetrahydrofolate dehydrogenase, proteins, folate-binding, cytosol I
ECTree
1.5.1.6 formyltetrahydrofolate dehydrogenaseAdvanced search results
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results (Substrates Products
Substrates Products on EC 1.5.1.6 - formyltetrahydrofolate dehydrogenase
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SUBSTRATE 
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
10-formyl-5,8-dideazafolate tetraglutamate + NADP+ + H2O
5,8-dideazafolate tetraglutamate + CO2 + NADPH + H+
-
-
tightly bound product
ir
10-formyltetrahydrofolate + NADP+ + H2O
?
the enzyme is composed of three domains and possesses three catalytic activities but has only two catalytic centers. The amino-terminal domain (residues 1-310) bears 10-formyltetrahydrofolate hydrolase activity, the carboxyl-terminal domain (residues 420-902) bears an aldehyde dehydrogenase activity, and the full-length FDH produces 10-formyltetrahydrofolate dehydrogenase activity
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-
?
10-formyltetrahydropteroylhexaglutamate + NADP+ + H2O
tetrahydropteroylhexaglutamate + CO2 + NADPH
10-formyltetrahydropteroylpentaglutamate + NADP+ + H2O
tetrahydropteroylpentaglutamate + CO2 + NADPH
10-formyltetrahydropteroylpolyglutamate + NADP+ + H2O
tetrahydropteroylpolyglutamate + CO2 + NADPH + H+
ATP + formate + tetrahydrofolate
ADP + phosphate + 10-formyltetrahydrofolate
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-
-
-
?
10-formyl-5,8-dideazafolate + NADP+ + H2O
5,8-dideazafolate + CO2 + NADPH + H+
-
-
-
?
10-formyl-5,8-dideazafolate + NADP+ + H2O
5,8-dideazafolate + CO2 + NADPH + H+
-
good substrate
-
ir
10-formyl-5,8-dideazafolate + NADP+ + H2O
5,8-dideazafolate + CO2 + NADPH + H+
-
-
-
?
10-formyl-5,8-dideazafolate + NADP+ + H2O
5,8-dideazafolate + CO2 + NADPH + H+
-
-
-
?
10-formyl-5,8-dideazafolate + NADP+ + H2O
5,8-dideazafolate + CO2 + NADPH + H+
-
-
-
?
10-formyl-5,8-dideazafolate + NADP+ + H2O
5,8-dideazafolate + CO2 + NADPH + H+
-
good substrate
-
?
10-formyl-5,8-dideazafolate + NADP+ + H2O
5,8-dideazafolate + CO2 + NADPH + H+
-
stable synthetic analogue can substitute for the labile natural substrate, affinity is twice as high as for 10-formyltetrahydrofolate
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
Cys-707 is involved in enzyme activity
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
enzyme is an important factor in regulation of formate oxidation and is related with methanol poisoning
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
folate-dependent metabolism of formate to carbon dioxide
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
regulation of the ratio of 10-formyltetrahydrofolate to tetrahydrofolate and of the purine biosynthesis through control of the level of 10-formyltetrahydrofolate, down-regulation of FDH in tumors is one of the cellular mechanisms that enhance proliferation, FDH possesses tumor specific suppressor effects
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?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
folate-dependent pathway is the exclusive route of formate metabolism in primates, plays major role in disposition of formate generated from one-carbon moieties of environmental chemicals, drugs, and foods, importance in the toxicity of methanol
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
a major liver enzyme, contributing to more than one metabolic pathway, regeneration of the tetrahydrofolate pool, not essential for viability
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
ir
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
structure of enzyme domains and of catalytic centers
high affinity for tetrahydrofolate
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
enzyme requires Cys-707 to form a thiohemiacetal with the formyl group of 10-formyltetrahydrofolate
high affinity for tetrahydrofolate
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
enzyme binds one molecule of tetrahydrofolate and two molecules of NADP+ per tetramer, tetrahydrofolate and NADP+ bind to separate domains, higher affinity for NADP+ at lower enzyme concentrations
high affinity for tetrahydrofolate
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
regulation of the ratio of 10-formyltetrahydrofolate to tetrahydrofolate in the cell in response to yet unknown aldehyde and thiol metabolites
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
very tight binding of product, binds its product rather than its substrate
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
natural substrate
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
Asp-142 is an essential residue in enzyme mechanism, it influences folate binding, model of substrate binding pocket
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
His-106 is involved in enzyme catalysis and in folding of the N-terminal domain, enzyme requires Cys-707 for catalysis, which is located inside the C-terminal domain, mechanism includes hydrolase reaction as essential part
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
structure of enzyme domains and of catalytic centers
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
Cys-707 is a key residue of the dehydrogenase active site and acts as nucleophile in the formation of an enzyme-linked thiohemiacetal intermediate
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
10-formyltetrahydrofolate is associated with enzyme when it is rapidly isolated, after storage for 24 h before separation of the binding proteins there remains none and tetrahydrofolate is the predominant form bound to enzyme because of the hydrolase activity
very tight binding of product, binds its product rather than its substrate
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
specific for NADP+
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
specific for NADP+
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
specific for NADP+
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
specific for NADP+
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
mechanism which proceeds through thiohemiacetal and thioester intermediates, nucleophilic attack by the essential active site Cys-707 on the carbonyl group of 10-formyltetrahydrofolate, folate binding domain requires presence of an intact ring system
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
recycling of excess 10-formyltetrahydrofolate that is not needed for purine biosynthesis and restoration of the tetrahydrofolate pool, important for formate metabolism by clearing it as CO2 and thus protecting cells from formate intoxication
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
regulatory mechanism to control the in vivo folate pool size
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
disposal of excess one-carbon units, oxidation of one-carbon moieties is regulated by the ratio of formyltetrahydrofolate to tetrahydrofolate in liver, regulation of the proportion of folate present in the tetrahydrofolate form, presumably to make it available for other reactions of one-carbon metabolism
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
folate-dependent metabolism of formate to carbon dioxide
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
a major folate-binding protein of liver cytosol, 10-formyltetrahydrofolate polyglutamates are tightly bound in vivo
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
very tight binding of product, binds its product rather than its substrate
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
-
very tight binding of product, binds its product rather than its substrate
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
specific for NADP+
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
specific for NADP+
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
specific for NADP+
-
ir
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
calculated equilibrium constant: 160000000, specific for (-)-10-formyltetrahydrofolate and NADP+
-
ir
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
disposal of excess one-carbon units, oxidation of one-carbon moieties is regulated by the ratio of formyltetrahydrofolate to tetrahydrofolate in liver, regulation of the proportion of folate present in the tetrahydrofolate form, presumably to make it available for other reactions of one-carbon metabolism
-
?
10-formyltetrahydrofolate + NADP+ + H2O
tetrahydrofolate + CO2 + NADPH + H+
-
major disposal route for excess one-carbon units produced in folate-mediated metabolism
-
?
10-formyltetrahydropteroylhexaglutamate + NADP+ + H2O
tetrahydropteroylhexaglutamate + CO2 + NADPH
-
-
-
?
10-formyltetrahydropteroylhexaglutamate + NADP+ + H2O
tetrahydropteroylhexaglutamate + CO2 + NADPH
-
-
-
?
10-formyltetrahydropteroylpentaglutamate + NADP+ + H2O
tetrahydropteroylpentaglutamate + CO2 + NADPH
-
product binds 60fold more tightly than the substrate
-
ir
10-formyltetrahydropteroylpentaglutamate + NADP+ + H2O
tetrahydropteroylpentaglutamate + CO2 + NADPH
-
important site of binding of folylpolyglutamates in liver, regulation of the interconversion of 10-formyltetrahydropteroylpolyglutamate to tetrahydropteroylpolyglutamate and therefore of the high-energy formyl charge of the cell
-
ir
10-formyltetrahydropteroylpentaglutamate + NADP+ + H2O
tetrahydropteroylpentaglutamate + CO2 + NADPH
-
-
-
?
10-formyltetrahydropteroylpentaglutamate + NADP+ + H2O
tetrahydropteroylpentaglutamate + CO2 + NADPH
-
natural substrate
-
?
10-formyltetrahydropteroylpolyglutamate + NADP+ + H2O
tetrahydropteroylpolyglutamate + CO2 + NADPH + H+
-
-
-
ir
10-formyltetrahydropteroylpolyglutamate + NADP+ + H2O
tetrahydropteroylpolyglutamate + CO2 + NADPH + H+
-
-
-
-
?
10-formyltetrahydropteroylpolyglutamate + NADP+ + H2O
tetrahydropteroylpolyglutamate + CO2 + NADPH + H+
-
-
-
?
10-formyltetrahydropteroylpolyglutamate + NADP+ + H2O
tetrahydropteroylpolyglutamate + CO2 + NADPH + H+
-
affinity increases with increasing length of polyglutamyl chain
-
-
?
additional information
?
-
enzyme does not catalyze the oxidation of 10-formyltetrahydrofolate or propanal
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-
?
additional information
?
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-
enzyme does not catalyze the oxidation of 10-formyltetrahydrofolate or propanal
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-
?
additional information
?
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-
FDH-expressing cells show accumulation of cells in G0-G1 phase and a sharp decrease of cells in S phase. Accumulation of the tumor suppressor protein p53 and its downstream target p21. FDH antiproliferative effects on A549 cells include both G1 cell cycle arrest and caspase-dependent apoptosis
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-
?
additional information
?
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activation of p53 tumor suppressor protein-dependent pathways is a general downstream mechanism in response to induction of enzyme expression in p53 functional cancer cells
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?
additional information
?
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enzyme exhibit additional to 10-formyltetrahydrofolate dehydrogenase/hydrolase activities NADP+-dependent aldehyde dehydrogenase activity with propanal as preferred substrate
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-
?
additional information
?
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enzyme exhibit additional to 10-formyltetrahydrofolate dehydrogenase/hydrolase activities NADP+-dependent aldehyde dehydrogenase activity with propanal as preferred substrate
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-
?
additional information
?
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-
enzyme consists of two independent folded domains connected by a linker sequence: a 32 kDa N-terminal domain with 10-formyltetrahydrofolate binding site shows hydrolase activity and a 63 kDa C-terminal domain with NADP+ binding site and Cys-707 shows aldehyde dehydrogenase activity, native structure of enzyme is necessary for 10-formyltetrahydrofolate dehydrogenase activity
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?
additional information
?
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enzyme exhibit additional to 10-formyltetrahydrofolate dehydrogenase/hydrolase activities NADP+-dependent aldehyde dehydrogenase activity with propanal as preferred substrate
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?
additional information
?
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enzyme exhibit additional to 10-formyltetrahydrofolate dehydrogenase/hydrolase activities NADP+-dependent aldehyde dehydrogenase activity with propanal as preferred substrate
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?
additional information
?
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enzyme exhibit additional to 10-formyltetrahydrofolate dehydrogenase/hydrolase activities NADP+-dependent aldehyde dehydrogenase activity with propanal as preferred substrate
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-
?
additional information
?
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enzyme exhibit additional to 10-formyltetrahydrofolate dehydrogenase/hydrolase activities NADP+-dependent aldehyde dehydrogenase activity with propanal as preferred substrate
-
-
?
additional information
?
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-
hydrolysis at 25% of dehydrogenase activity
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-
?
additional information
?
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-
10-formyltetrahydrofolate dehydrogenase/hydrolase activities occur at the same time and are associated with separate active sites
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-
?
additional information
?
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-
10-formyltetrahydrofolate dehydrogenase/hydrolase activities occur at the same time and are associated with separate active sites
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-
?
additional information
?
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enzyme catalyzes also NADP+-independent hydrolytic cleavage of 10-formyltetrahydrofolate to tetrahydrofolate and formate, hydrolysis is very inefficient compared to dehydrogenase reaction and may be an artifact of assay system
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-
?
additional information
?
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bifunctional enzyme: NADP+-dependent dehydrogenase activity and NADP+-independent hydrolase activity of 10-formyltetrahydrofolate with two active sites
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-
?
additional information
?
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10-formyltetrahydrofolate dehydrogenase and hydrolase are closely related and separately compartmentalized enzymes
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?
additional information
?
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2fold higher 10-formyltetrahydrofolate dehydrogenase than hydrolase activity, hydrolase and dehydrogenase catalytic centers are overlapping
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-
?
additional information
?
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-
irreversible covalent linkage of 5-formyltetrahydrofolate to enzyme, 2 mol bound per mol of enzyme monomer, 5-formyltetrahydrofolate is not the natural substrate and arises from 10-formyltetrahydrofolate
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-
?
additional information
?
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-
310 amino acid residue N-terminal domain has 10-formyltetrahydrofolate hydrolase activity and substrate binding site, C-terminal domain has aldehyde dehydrogenase activity and is used as catalytic center in dehydrogenase reaction, full-length enzyme is required for 10-formyltetrahydrofolate dehydrogenase activity, the two domains work in concert
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-
?
additional information
?
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310 amino acid residue N-terminal domain has 10-formyltetrahydrofolate hydrolase activity and substrate binding site, C-terminal domain has aldehyde dehydrogenase activity and is used as catalytic center in dehydrogenase reaction, full-length enzyme is required for 10-formyltetrahydrofolate dehydrogenase activity, the two domains work in concert
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-
?
additional information
?
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310 amino acid residue N-terminal domain has 10-formyltetrahydrofolate hydrolase activity and substrate binding site, C-terminal domain has aldehyde dehydrogenase activity and is used as catalytic center in dehydrogenase reaction, full-length enzyme is required for 10-formyltetrahydrofolate dehydrogenase activity, the two domains work in concert
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?
additional information
?
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bifunctional protein: 10-formyltetrahydrofolate dehydrogenase/hydrolase, hydrolysis at 20-30% of the oxidative rate
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?
additional information
?
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hydrolysis catalyzed by enzyme at 21% of the rate of CO2 formation
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?
additional information
?
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enzyme functions not as an aldehyde dehydrogenase in vivo, 10-formyltetrahydrofolate hydrolase activity is of no physiological significance, disulfiram may inhibit enzyme activity and probably perturb hepatic folate metabolism in vivo
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-
?
additional information
?
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the C-terminal domain (Ct-FDH) of the enzyme is a structural and functional homologue of aldehyde dehydrogenases (ALDHs, EC 1.2.1.4). This domain is capable of catalyzing the NADP+-dependent oxidation of short chain aldehydes to their corresponding acids, and similar to most ALDHs it has two conserved catalytic residues, Cys707 and Glu673. These residues define the conformation of the bound coenzyme and the affinity of its interaction with the protein, proposed mechanism by which Cys707 helps to differentiate between the oxidized and reduced coenzyme during ALDH catalysis, overview
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?
additional information
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not as substrate: (+)-10-formyltetrahydrofolate
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?
additional information
?
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bifunctional enzyme: 10-formyltetrahydrofolate dehydrogenase separated from hydrolase activity, activities are functions of different active sites and take place simultaneously in presence of NADP+
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?
additional information
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enzyme catalyzes hydrolytic cleavage of 10-formyltetrahydrofolate to formate and tetrahydrofolate in absence of NADP+ (15-30% of the rate of oxidative reaction)
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?
additional information
?
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bifunctional protein: 10-formyltetrahydrofolate dehydrogenase/hydrolase, hydrolysis at 20-30% of the oxidative rate
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?
