Information on EC 4.1.2.25 - dihydroneopterin aldolase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
4.1.2.25
-
RECOMMENDED NAME
GeneOntology No.
dihydroneopterin aldolase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
7,8-dihydroneopterin = 6-(hydroxymethyl)-7,8-dihydropterin + glycolaldehyde
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
elimination
-
-
of an aldehyde, C-C bond cleavage
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
6-hydroxymethyl-dihydropterin diphosphate biosynthesis
-
-
6-hydroxymethyl-dihydropterin diphosphate biosynthesis I
-
-
6-hydroxymethyl-dihydropterin diphosphate biosynthesis II (archaea)
-
-
6-hydroxymethyl-dihydropterin diphosphate biosynthesis III (Chlamydia)
-
-
Folate biosynthesis
-
-
Metabolic pathways
-
-
tetrahydromethanopterin biosynthesis
-
-
SYSTEMATIC NAME
IUBMB Comments
7,8-dihydroneopterin glycolaldehyde-lyase [6-(hydroxymethyl)-7,8-dihydropterin-forming]
The enzyme participates in folate (in bacteria, plants and fungi) and methanopterin (in archaea) biosynthesis. The enzymes from the bacterium Escherichia coli and the plant Arabidopsis thaliana also catalyse the epimerisation of the 2' hydroxy-group (EC 5.1.99.8, 7,8-dihydroneopterin epimerase) [2,3]. The enzyme from the bacterium Mycobacterium tuberculosis is trifunctional and also catalyses EC 5.1.99.8 and EC 1.13.11.81, 7,8-dihydroneopterin oxygenase [6]. The enzyme from the yeast Saccharomyces cerevisiae also catalyses the two subsequent steps in the folate biosynthesis pathway - EC 2.7.6.3, 2-amino-4-hydroxy-6-(hydroxymethyl)dihydropteridine diphosphokinase, and EC 2.5.1.15, dihydropteroate synthase [4].
CAS REGISTRY NUMBER
COMMENTARY hide
37290-59-8
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
strain MG1655
-
-
Manually annotated by BRENDA team
no activity in mammalia
-
-
-
Manually annotated by BRENDA team
no activity in Plasmodium falciparum
Plasmodium falciparum cell extracts have SHMT and PPPK-DHPS but not DHNA activities
-
-
Manually annotated by BRENDA team
multifunctional Fas enzyme with the activity of the first three enzymes of the folate synthesis pathway: dihydroneopterin aldolase, hydroxymethyldihydropterin pyrophosphokinase and dihydropteroate synthase
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
-
in isoform folA1 conditional mutant germlings incubated at 30C for 16 h, the number of nuclei at is comparable with that of wild type germlings. At the restrictive temperature of 44C, however, 60% of the conidiospores have a single nucleus while wild-type germlings normally undergo two or three nuclear divisions under these conditions. Mutant cells exit from M phase, arrest at 44C, traverse mitosis and G1 phase, and arrest in S phase in the presence of hydroxyurea. The addition of 1.8 mM folic acid does not improve growth of folA1 mutant strains at 44C, nor does it improve their growth at 30C. A mutation in folA can suppress fungal transcription factor crzAD calcium toxicity
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8-dihydropteridine
2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine + glycolaldehyde
show the reaction diagram
2-Amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8-dihydropteridine
?
show the reaction diagram
2-amino-4-hydroxy-6-(L-threo-1,2,3-trihydroxypropyl)-7,8-dihydropteridine
?
show the reaction diagram
6-hydroxymethyl-7,8-dihydropterin
?
show the reaction diagram
6-hydroxymethyl-7,8-dihydropterin + glycolaldehyde
7,8-dihydroneopterin + 7,8-dihydromonapterin
show the reaction diagram
-
reaction is reversible, and C-C bond formation has both 7,8-dihydroneopterin and 7,8-dihydromonapterin as products plus 7,8-dihydroxanthopterin
-
r
7,8-dihydro-L-monapterin
?
show the reaction diagram
7,8-dihydromonapterin
6-hydroxymethyl-7,8-dihydropterin + glycolaldehyde
show the reaction diagram
7,8-Dihydromonapterin
?
show the reaction diagram
7,8-dihydroneopterin
6-hydroxymethyl-7,8-dihydropterin + glycolaldehyde
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
2-Amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8-dihydropteridine
?
show the reaction diagram
7,8-dihydroneopterin
6-hydroxymethyl-7,8-dihydropterin + glycolaldehyde
show the reaction diagram
additional information
?
-
-
enzyme in folate biosynthesis
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-Amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine
-
competitive
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(1-hydroxycyclohexylmethyl)benzamide
-
IC50: 0.00074 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(2,2-bis-hydroxymethylbutyl)benzamide
-
IC50: 0.00095 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(2,3-dihydrobenzofuran-5-ylmethyl)benzamide
-
IC50: 0.00055 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(3,5-bistrifluoromethylbenzyl)benzamide
-
IC50: 0.001 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(3,5-dichlorobenzyl)benzamid
-
IC50: 0.000068 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(3-hydroxy-2,2-dimethylpropyl)benzamide
-
IC50: 0.00073 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(3-hydroxypropyl)benzamide
-
IC50: 0.0023 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(4-hydroxybutyl)benzamide
-
IC50: 0.002 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(4-phenoxybenzyl)benzamide
-
IC50: 0.022 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-benzo[1,3]dioxol-5-ylmethylbenzamide
-
IC50: 0.00031 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-biphenyl-4-ylmethylbenzamide
-
IC50: 0.025 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-cis-(2-hydroxycycloheptylmethyl)benzamide
-
IC50: 0.00035 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-cis-(2-hydroxycyclohexylmethyl)benzamide
-
IC50: 0.00041 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-trans-(2-hydroxycyclohexylmethyl)benzamide
-
IC50: 0.00032 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-[2-(2-hydroxymethylphenylsulfanyl)benzyl]-benzamide
-
IC50: 0.00003 mM
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)benzoic acid
-
IC50: 0.0015 mM
6-Formyl-dihydropterin
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-
6-Methyl-dihydropterin
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-
7,8-dihydrobiopterin
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builds a complex with the enzyme
dihydrofolic acid
Dihydropteroic acid
-
slight
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
EDTA
-
increases activity
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0023 - 0.064
2-amino-4-hydroxy-6-(D-erythro-1,2,3-trihydroxypropyl)-7,8-dihydropteridine
0.00076 - 9.8
7,8-dihydro-L-monapterin
0.00017 - 0.057
7,8-dihydromonapterin
0.00016 - 9.7
7,8-dihydroneopterin
10
glycoaldehyde
-
apparent value
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0000023 - 0.089
7,8-dihydro-L-monapterin
0.006
7,8-dihydromonapterin
Mycobacterium tuberculosis
P9WNC5
pH 7.0, 22C
0.0000022 - 0.082
7,8-dihydroneopterin
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
38
7,8-dihydromonapterin
Mycobacterium tuberculosis
P9WNC5
pH 7.0, 22C
16051
36
7,8-dihydroneopterin
Mycobacterium tuberculosis
P9WNC5
pH 7.0, 22C
3544
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00074
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(1-hydroxycyclohexylmethyl)benzamide
Staphylococcus aureus
-
IC50: 0.00074 mM
0.00095
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(2,2-bis-hydroxymethylbutyl)benzamide
Staphylococcus aureus
-
IC50: 0.00095 mM
0.00055
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(2,3-dihydrobenzofuran-5-ylmethyl)benzamide
Staphylococcus aureus
-
IC50: 0.00055 mM
0.001
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(3,5-bistrifluoromethylbenzyl)benzamide
Staphylococcus aureus
-
IC50: 0.001 mM
0.000068
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(3,5-dichlorobenzyl)benzamid
Staphylococcus aureus
-
IC50: 0.000068 mM
0.00073
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(3-hydroxy-2,2-dimethylpropyl)benzamide
Staphylococcus aureus
-
IC50: 0.00073 mM
0.0023
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(3-hydroxypropyl)benzamide
Staphylococcus aureus
-
IC50: 0.0023 mM
0.002
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(4-hydroxybutyl)benzamide
Staphylococcus aureus
-
IC50: 0.002 mM
0.022
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-(4-phenoxybenzyl)benzamide
Staphylococcus aureus
-
IC50: 0.022 mM
0.00031
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-benzo[1,3]dioxol-5-ylmethylbenzamide
Staphylococcus aureus
-
IC50: 0.00031 mM
0.025
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-biphenyl-4-ylmethylbenzamide
Staphylococcus aureus
-
IC50: 0.025 mM
0.00035
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-cis-(2-hydroxycycloheptylmethyl)benzamide
Staphylococcus aureus
-
IC50: 0.00035 mM
0.00041
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-cis-(2-hydroxycyclohexylmethyl)benzamide
Staphylococcus aureus
-
IC50: 0.00041 mM
0.00032
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-trans-(2-hydroxycyclohexylmethyl)benzamide
Staphylococcus aureus
-
IC50: 0.00032 mM
0.00003
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)-N-[2-(2-hydroxymethylphenylsulfanyl)benzyl]-benzamide
Staphylococcus aureus
-
IC50: 0.00003 mM
0.0015
3-(5-amino-7-hydroxy-[1,2,3]triazolo[4,5-d]pyrimidin-2-yl)benzoic acid
Staphylococcus aureus
-
IC50: 0.0015 mM
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Escherichia coli (strain K12)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
62300
apo-enzyme, mass spectrometry
100000
-
gel filtration
104000
110000
-
sedimentation equilibrium centrifugation
119000
-
independent monofunctional activity FasAB-Met23, gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
octamer
tetramer
trimer
-
or tetramer, 4 * or 3 * 31000, bifunctional enzyme with dihydroneopterin aldolase activity and hydroxymethyldihydropterin pyrophosphokinase activity, dihydroneopterin aldolase activity requires the multimeric protein, whereas pyrophosphokinase is expressed by the monomeric form, SDS-PAGE
additional information
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
sitting-drop vapour-diffusion method by mixing 2 ml of a solution containing 11.5 mg of protein per ml with an equal volume of reservoir solution containing 0.1 M Tris hydrochloride (pH 7.2), 21% polyethylene glycol (PEG 2000 MME), and 115 mM cyclohexyl-butanoyl-N-hydroxyethylglucamide. Diffraction data are collected to a resolution of 2.2 A. The crystals belonged to space group P1 with the unit cell constants a = 63.5 A, b = 84.2 A, c = 89.1 A, alpha = 90.14, beta = 89.9, gamma = 76.2, and has a solvent content of 42%
hanging drop vapour diffusion method, co-crystallization with monapterin or neopterin, in 1.4 M sodium acetate, 0.2 M imidazole, 0.1 M sodium cacodylate (pH 6.5), at 19C; in complex with neopterin, an analog of dihydroneoptierin, and with monapterin, to 1.7 A and 1.68 A resolution, respectively. Active site residues E22, K100, and Y54 function coordinately during catalysis
hanging drop vapour diffusion method with 50 mM MOPS/NaOH (pH 7.0), 17.5% (w/v) methoxy-PEG 2000, 400 mM NaCl, 10 mM MgCl2, 2 mM dithiothreitol, 1 mM EDTA and 5% (v/v) glycerol
-
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
100
-
5 min, stable
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
DEAE-cellulose column chromatography and Bio-Gel A 0.5 m gel filtration
DEAE-cellulose column chromatography and Bio-Gel A-0.5m gel filtration
-
Mono Q 10/10 column chromatography, Superdex 200 gel filtration
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native and recombinant independent monofunctional activity FasAB-Met23
-
Ni-nitrilotriacetate column chromatography, DEAE-cellulose column chromatography and Bio-Gel A-0.5 m gel filtration
Ni-NTA column chromatography and Bio-Gel A-0.5m gel filtration
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21 (DE3) cells
-
expressed in Escherichia coli BL21(DE3) cells
expressed in Escherichia coli folB deletant cells
-
expressed in Escherichia coli; expression in Escherichia coli
-
expressed in Escherichia coli; expression in Escherichia coli; expression in Escherichia coli
expression in Escherichia coli
-
overexpression of the multifunctional Fas enzyme with the activity of the first three enzymes of the folate synthesis pathway: dihydroneopterin aldolase, hydroxymethyldihydropterin pyrophosphokinase and dihydropteroate synthase in cultured Spodoptera frugiperda insect cells
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overproduced as an independent monofunctional activity in Escherichia coli, FasAB-Met23
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
DHNA expression is significantly elevated only in fruit overexpressing GCHI (and accumulating pterins)
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
E21A
-
strongly reduced kcat
E73A
-
strongly reduced kcat
K98A
-
strongly reduced kcat
Y53F
-
the mutation converts the enzyme to a cofactor-independent oxygenase, which generates mainly 7,8-dihydroxanthopterin
D39E
-
FasA domain mutant D39E and FasB domain mutant G175A have no detectable activity of dihydroneopterin aldolase. The FasA domain mutants, G53A and Q63N and the FasB domain mutant Q185N, show approximately 11-fold, 16-fold and 24-fold decrease, respectively, in specific activity compared to wild-type FasAB-Met23. The activity of the FasB domain mutant D161E is similar to that of wild-type enzyme. The two mutant enzymes K96R and K218R have levels of activity comparable to wild-type enzyme
G175A
-
FasA domain mutant D39E and FasB domain mutant G175A have no detectable activity of dihydroneopterin aldolase. The FasA domain mutants, G53A and Q63N and the FasB domain mutant Q185N, show approximately 11-fold, 16-fold and 24-fold decrease, respectively, in specific activity compared to wild-type FasAB-Met23. The activity of the FasB domain mutant D161E is similar to that of wild-type enzyme. The two mutant enzymes K96R and K218R have levels of activity comparable to wild-type enzyme
E22A
-
strongly reduced kcat
E29A
-
multistage tandem mass spectrometry (MS/MS and MS3) of gas-phase fragmentation reaction of the mutant enzyme yields identical product ion spectrum to the wild-type protein
E74A
-
mutation causes dramatic changes in the affinities of the enzyme for the substrate or product analogues or the rate constants
E81A
-
multistage tandem mass spectrometry (MS/MS and MS3) of gas-phase fragmentation reaction of the mutant enzyme yields identical product ion spectrum to the wild-type protein
K100A
-
strongly reduced kcat
K100Q
-
strongly reduced kcat
K107A
-
multistage tandem mass spectrometry (MS/MS and MS3) of gas-phase fragmentation reaction of the mutant enzyme is compared to that of wild-type enzyme It yields significantly different product ion spectra dominated by cleaves occuring N-terminal to Pro
Y54F
-
the mutation converts the enzyme to a cofactor-independent oxygenase, which generates mainly 7,8-dihydroxanthopterin
Y61F
-
multistage tandem mass spectrometry (MS/MS and MS3) of gas-phase fragmentation reaction of the mutant enzyme yields identical product ion spectrum to the wild-type protein
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
-
drugs targeting folate metabolism have long been used as highly successful antimicrobial and anticancer agents
pharmacology
-
the Fas multifunctional enzyme with the activity of the first three enzymes of the folate synthesis pathway: dihydroneopterin aldolase, hydroxymethyldihydropterin pyrophosphokinase and dihydropteroate synthase is an attractive target for chemotherapy, sin
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