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Information on EC 3.5.4.9 - methenyltetrahydrofolate cyclohydrolase and Organism(s) Leishmania major and UniProt Accession Q4Q9F9

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IUBMB Comments
In eukaryotes, the enzyme occurs as a trifunctional enzyme that also has methylenetetrahydrofolate dehydrogenase (NADP+) (EC 1.5.1.5) and formate---tetrahydrofolate ligase (EC 6.3.4.3) activity. In some prokaryotes, it occurs as a bifunctional enzyme that also has dehydrogenase (EC 1.5.1.5) activity or formimidoyltetrahydrofolate cyclodeaminase (EC 4.3.1.4) activity.
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Leishmania major
UNIPROT: Q4Q9F9
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The taxonomic range for the selected organisms is: Leishmania major
The enzyme appears in selected viruses and cellular organisms
Synonyms
mthfd2, cyclohydrolase, methenyltetrahydrofolate cyclohydrolase, 5,10-methenyltetrahydrofolate cyclohydrolase, mthfd2l, 5,10-methenyl-thf cyclohydrolase, methylenetetrahydrofolate dehydrogenase/cyclohydrolase, nad-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase, dhch1, methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase
-
N5,N10-methylenetetrahydrofolate dehydrogenase/N5,N10-methenyltetrahydrofolate cyclohydrolase
-
5,10-methenyl-H4folate cyclohydrolase
-
-
-
-
5,10-methenyltetrahydrofolate cyclohydrolase/5,10-methylene tetrahydrofolate dehydrogenase
-
-
Citrovorum factor cyclodehydrase
-
-
-
-
cyclohydrolase
-
-
-
-
DHCH 1
-
isozyme
formyl-methenyl-methylenetetrahydrofolate synthetase (combined)
-
-
-
-
methenyl-THF cyclohydrolase
-
-
-
-
methylene tetrahydrofolate dehydrogenase/cyclohydrolase
-
-
methylene-tetrahydrofolate dehydrogenase/cyclohydrolase
-
bifunctional enzyme
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis
-
-
amidine hydrolysis
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
5,10-methenyltetrahydrofolate 5-hydrolase (decyclizing)
In eukaryotes, the enzyme occurs as a trifunctional enzyme that also has methylenetetrahydrofolate dehydrogenase (NADP+) (EC 1.5.1.5) and formate---tetrahydrofolate ligase (EC 6.3.4.3) activity. In some prokaryotes, it occurs as a bifunctional enzyme that also has dehydrogenase (EC 1.5.1.5) activity or formimidoyltetrahydrofolate cyclodeaminase (EC 4.3.1.4) activity.
CAS REGISTRY NUMBER
COMMENTARY hide
9027-97-8
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
N5,N10-methenyltetrahydrofolate + H2O
N10-formyltetrahydrofolate
show the reaction diagram
-
-
-
?
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
N5,N10-methenyltetrahydrofolate + H2O
N10-formyltetrahydrofolate
show the reaction diagram
-
-
-
?
5,10-methenyltetrahydrofolate + H2O
10-formyltetrahydrofolate
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NADP+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
5,6,7,8-tetrahydro-N5,N10-carbonylfolic acid
i.e. LY354899
di-2'-deoxyadenosine 5',5''-P1,P5,alpha,beta-methylene-delta,epsilon-methylene-pentaphosphate-gamma-borano
-
di-2'-deoxyadenosine 5',5''-P1,P5,alpha,beta-methylene-gamma,delta-methylene-tetraphosphate
-
diadenosine 5',5''-P1,P5,alpha,beta-methylene-delta,epsilon-methylene-pentaphosphate-gamma-borano
-
P1,P4-bis(5'-adenosyl)-alpha,beta-gamma,delta-bismethylene-tetraphosphate
-
N5,N10-carbonyl tetrahydrofolate
-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.018
5,6,7,8-tetrahydro-N5,N10-carbonylfolic acid
, pH 7.3, 37°C
0.009
di-2'-deoxyadenosine 5',5''-P1,P5,alpha,beta-methylene-delta,epsilon-methylene-pentaphosphate-gamma-borano
with NPP1, pH 7.3, 37°C
0.051
di-2'-deoxyadenosine 5',5''-P1,P5,alpha,beta-methylene-gamma,delta-methylene-tetraphosphate
with NPP1, pH 7.3, 37°C
0.02
diadenosine 5',5''-P1,P5,alpha,beta-methylene-delta,epsilon-methylene-pentaphosphate-gamma-borano
with NPP1, pH 7.3, 37°C
0.013
P1,P4-bis(5'-adenosyl)-alpha,beta-gamma,delta-bismethylene-tetraphosphate
with NPP1, pH 7.3, 37°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.013
di-2'-deoxyadenosine 5',5''-P1,P5,alpha,beta-methylene-delta,epsilon-methylene-pentaphosphate-gamma-borano
Leishmania major
with NPP1, pH 7.3, 37°C
0.05
di-2'-deoxyadenosine 5',5''-P1,P5,alpha,beta-methylene-gamma,delta-methylene-tetraphosphate
Leishmania major
with NPP1, pH 7.3, 37°C
0.063
diadenosine 5',5''-P1,P5,alpha,beta-methylene-delta,epsilon-methylene-pentaphosphate-gamma-borano
Leishmania major
with NPP1, pH 7.3, 37°C
0.033
P1,P4-bis(5'-adenosyl)-alpha,beta-gamma,delta-bismethylene-tetraphosphate
Leishmania major
with NPP1, pH 7.3, 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.3
-
cyclohydrolase activity is monitored by following the consumption of 5,10-methylenetetrahydrofolate yielding 10-formyltetrahydrofolate
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.3
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
27
-
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
UniProt
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
additional information
-
DHCH1 is not localized in the mitochondrion or other vesicular compartments
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
three enzyme activities in the protozoan Leishmania major, namely N5,N10-methylenetetrahydrofolate dehydrogenase/N5,N10-methenyltetrahydrofolate cyclohydrolase and N10-formyltetrahydrofolate ligase produce the essential intermediate N10-formyltetrahydrofolate, folate metabolism pathway, overview
additional information
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
Q4Q9F9_LEIMA
298
0
31759
TrEMBL
other Location (Reliability: 1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
65000
recombinant detagged enzyme, gel filtration
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant apo-DHCH, hanging drop vapor diffusion, mixing of 0.002 ml 9 mg/ml protein in 50 mM Tris–HCl, 100 mM NaCl, pH 7.5, with 0.002 ml reservoir solution containing 20% PEG 3350 and 0.2 M ammonium acetate, equilibration against 0.07 ml of reservoir solution at 22°C, 3 days, X-ray diffraction structure determination and analysis at 2.7 A resolution, modelling
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme by nickel affinity chromatography, cleavage of the His-tag by TEV protease, His affinity chromatography, and gel filtration, to over 95% purity
recombinant DHCH1 protein is purified by metal-affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of the His-tagged enzyme in Escherichia coli
hexa-His tagged DHCH1 is expressed in Escherichia coli, production of a genetic knock-out
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
the bifunctional enzyme is a target for design of parasite-specific inhibitors as structure-based drugs
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Murta, S.M.; Vickers, T.J.; Scott, D.A.; Beverley, S.M.
Methylene tetrahydrofolate dehydrogenase/cyclohydrolase and the synthesis of 10-CHO-THF are essential in Leishmania major
Mol. Microbiol.
71
1386-1401
2009
Leishmania major
Manually annotated by BRENDA team
Vickers, T.; Murta, S.; Mandell, M.; Beverley, S.
The enzymes of the 10-formyl-tetrahydrofolate synthetic pathway are found exclusively in the cytosol of the trypanosomatid parasite Leishmania major
Mol. Biochem. Parasitol.
166
142-152
2009
Leishmania infantum, Leishmania major, Leishmania donovani (B8Y658), Leishmania donovani (B8Y659)
Manually annotated by BRENDA team
Eadsforth, T.C.; Cameron, S.; Hunter, W.N.
The crystal structure of Leishmania major N5,N10-methylenetetrahydrofolate dehydrogenase/cyclohydrolase and assessment of a potential drug target
Mol. Biochem. Parasitol.
181
178-185
2012
Leishmania major (Q4Q9F9), Leishmania major
Manually annotated by BRENDA team