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Information on EC 2.5.1.72 - quinolinate synthase
for references in articles please use BRENDA:EC2.5.1.72
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EC Tree 2 Transferases
2.5 Transferring alkyl or aryl groups, other than methyl groups
2.5.1 Transferring alkyl or aryl groups, other than methyl groups (only sub-subclass identified to date)
2.5.1.72 quinolinate synthase
IUBMB Comments
An iron-sulfur protein that requires a [4Fe-4S] cluster for activity . Quinolinate synthase catalyses the second step in the de novo biosynthesis of NAD+ from aspartate in some bacteria, with EC 1.4.3.16 (L-aspartate oxidase) catalysing the first step and EC 2.4.2.19 [nicotinate-nucleotide diphosphorylase (carboxylating)] the third step. In Escherichia coli, two of the residues that are involved in the [4Fe-4S] cluster binding appear to undergo reversible disulfide-bond formation that regulates the activity of the enzyme .
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
- 2.5.1.72
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nada
- nicotinamide
- dihydroxyacetone
- iminoaspartate
-
iron-sulfur
-
pyrococcus
- dhap
- horikoshii
- qa
-
cluster-containing
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oxygen-sensitive
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desulfurase
- drug development
- synthesis
Reaction Schemes
showSynonyms
quinolinate synthase, quinolinate synthetase, sufe3, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Fe4S4 quinolinate synthase
NadA
quinolinate synthetase
SufE3
-
bifunctional enzyme, quinolinate synthase activity and stimulation of CpNifS cysteine desulfurase activity
TM_1644
quinolinate synthetase
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-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
glycerone phosphate + iminosuccinate = pyridine-2,3-dicarboxylate + 2 H2O + phosphate
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glycerone phosphate + iminosuccinate = pyridine-2,3-dicarboxylate + 2 H2O + phosphate
model of the catalytic state. Elimination of phosphate from dihydroxyacetone phosphate may precede the condensation reaction
glycerone phosphate + iminosuccinate = pyridine-2,3-dicarboxylate + 2 H2O + phosphate
reaction mechanism with an early release of phosphate from dihydroxyacetone phosphate, that only, not glycerol 3-phosphate, can condense with iminoaspartate to form quinolinate. The NadA three-dimensional structure shows that there is no room in the active site to accommodate a condensation product on which the phosphate group from dihydroxyacetone phosphate is still present, overview. The enzyme has a triose phosphate isomerase activity catalyzing the reversible isomerization of glycerol 3-phosphate into dihydroxyacetone phosphate in an Fe/S-dependent manner
glycerone phosphate + iminosuccinate = pyridine-2,3-dicarboxylate + 2 H2O + phosphate
reaction mechanism with an early release of phosphate from dihydroxyacetone phosphate, that only, not glycerol 3-phosphate, can condense with iminoaspartate to form quinolinate. The NadA three-dimensional structure shows that there is no room in the active site to accommodate a condensation product on which the phosphate group from dihydroxyacetone phosphate is still present, overview. The enzyme has a triose phosphate isomerase activity catalyzing the reversible isomerization of glycerol 3-phosphate into dihydroxyacetone phosphate in an Fe/S-dependent manner
glycerone phosphate + iminosuccinate = pyridine-2,3-dicarboxylate + 2 H2O + phosphate
the presence of the Fe4S4 cluster generates an internal tunnel and a cavity to bind the substrate and and dehydrate it, which is initiated by the conserved residue Tyr21. Tyr21 is close to a conserved Thr-His-Glu. All of these residues are essential for activity and Tyr21 deprotonation, to form the reactive nucleophilic phenoxide anion, is mediated by the triad. NadA displays a dehydration mechanism significantly different from the one found in archetypical dehydratases such as aconitase, which use a serine residue deprotonated by an oxyanion hole
glycerone phosphate + iminosuccinate = pyridine-2,3-dicarboxylate + 2 H2O + phosphate
the presence of the Fe4S4 cluster generates an internal tunnel and a cavity to bind the substrate and and dehydrate it, which is initiated by the conserved residue Tyr21. Tyr21 is close to a conserved Thr-His-Glu. All of these residues are essential for activity and Tyr21 deprotonation, to form the reactive nucleophilic phenoxide anion, is mediated by the triad. NadA displays a dehydration mechanism significantly different from the one found in archetypical dehydratases such as aconitase, which use a serine residue deprotonated by an oxyanion hole
Thermotoga maritima MSB8 / DSM 3109 / ATCC 43589
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PATHWAY SOURCE
PATHWAYS
BRENDA
MetaCyc
NAD de novo biosynthesis I, NAD de novo biosynthesis III, NAD de novo biosynthesis IV (anaerobic), nicotine biosynthesis, superpathway of nicotine biosynthesis
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SYSTEMATIC NAME
IUBMB Comments
glycerone phosphate:iminosuccinate alkyltransferase (cyclizing)
An iron-sulfur protein that requires a [4Fe-4S] cluster for activity [1]. Quinolinate synthase catalyses the second step in the de novo biosynthesis of NAD+ from aspartate in some bacteria, with EC 1.4.3.16 (L-aspartate oxidase) catalysing the first step and EC 2.4.2.19 [nicotinate-nucleotide diphosphorylase (carboxylating)] the third step. In Escherichia coli, two of the residues that are involved in the [4Fe-4S] cluster binding appear to undergo reversible disulfide-bond formation that regulates the activity of the enzyme [5].
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CAS REGISTRY NUMBER
COMMENTARY
39434-08-7
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
dihydroxyacetone phosphate + iminoaspartate
? + H2O + phosphate
-
Substrates: -
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?
dihydroxyacetone phosphate + iminoaspartate
? + H2O + phosphate
-
Substrates: -
Products: -
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?
dihydroxyacetone phosphate + iminoaspartate
? + H2O + phosphate
-
Substrates: -
Products: -
Products: -
?
dihydroxyacetone phosphate + iminoaspartate
? + H2O + phosphate
-
Substrates: -
Products: -
Products: -
?
glycerone phosphate + iminosuccinate
pyridine-2,3-dicarboxylate + 2 H2O + phosphate
Substrates: -
Products: -
Products: -
?
glycerone phosphate + iminosuccinate
pyridine-2,3-dicarboxylate + 2 H2O + phosphate
-
Substrates: -
Products: -
Products: -
?
glycerone phosphate + iminosuccinate
pyridine-2,3-dicarboxylate + 2 H2O + phosphate
-
Substrates: condensation of dihydroxyacetone phosphate (DHAP) and aspartate-enamine by the action of quinolinate synthase, NadA
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Products: -
?
glycerone phosphate + iminosuccinate
pyridine-2,3-dicarboxylate + 2 H2O + phosphate
Substrates: -
Products: -
Products: -
?
glycerone phosphate + iminosuccinate
pyridine-2,3-dicarboxylate + 2 H2O + phosphate
Thermotoga maritima MSB8 / DSM 3109 / ATCC 43589
Substrates: -
Products: -
Products: -
?
additional information
?
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-
Substrates: residues C291 and C294 of the C291XXC294XXC297 motif undergo reversible disulfide formation, which regulates the activity of the enzyme
Products: -
Products: -
?
additional information
?
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Substrates: the enzyme has a triose phosphate isomerase activity catalyzing the reversible isomerization of glycerol 3-phosphate into dihydroxyacetone phosphate in an Fe/S-dependent manner. Only dihydroxyacetone phosphate can then condense with iminoaspartate to form quinolinate. If glycerol 3-phosphate is not converted to dihydroxyacetone phosphate no quinolinate can be produced. The enzyme as triose phosphate isomerase is more efficient in the direction of dihydroxyacetone phosphate production
Products: -
Products: -
?
additional information
?
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Substrates: the enzyme has a triose phosphate isomerase activity catalyzing the reversible isomerization of glycerol 3-phosphate into dihydroxyacetone phosphate in an Fe/S-dependent manner. Only dihydroxyacetone phosphate can then condense with iminoaspartate to form quinolinate. If glycerol 3-phosphate is not converted to dihydroxyacetone phosphate no quinolinate can be produced. The enzyme as triose phosphate isomerase is more efficient in the direction of dihydroxyacetone phosphate production
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Products: -
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
glycerone phosphate + iminosuccinate
pyridine-2,3-dicarboxylate + 2 H2O + phosphate
Substrates: -
Products: -
Products: -
?
glycerone phosphate + iminosuccinate
pyridine-2,3-dicarboxylate + 2 H2O + phosphate
-
Substrates: -
Products: -
Products: -
?
glycerone phosphate + iminosuccinate
pyridine-2,3-dicarboxylate + 2 H2O + phosphate
Substrates: -
Products: -
Products: -
?
glycerone phosphate + iminosuccinate
pyridine-2,3-dicarboxylate + 2 H2O + phosphate
Thermotoga maritima MSB8 / DSM 3109 / ATCC 43589
Substrates: -
Products: -
Products: -
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4Fe-4S-center
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inhibitor 4,5-dithiohydroxyphthalic acid coordinates to the enzyme [4Fe-4S] cluster through a differentiated iron site
iron-sulfur centre
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enzyme carries a higly oxygen-sensiteve [4Fe-4S] cluster at the NadA domain
iron-sulfur centre
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enzyme contains a [4Fe-4S]-cluster, coordinated by residues C110, C230, C320. 3.8 mol iron per mol of enzyme, 3.3 mol sulfur per mol of enzyme
iron-sulfur centre
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protein contains 3-3.5 mol iron and 3-3.5 mol sulfur per mol. Majority of the iron is in the form of a [4Fe-4S]2+ cluster. The cluster is absolutely required for activity
iron-sulfur centre
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protein contains a [4Fe-4S] cluster absolutely required for activity
iron-sulfur centre
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protein contains a [4Fe-4S] cluster absolutely required for activity
iron-sulfur centre
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protein contains a [4Fe-4S] cluster absolutely required for activity
iron-sulfur centre
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protein contains a [4Fe-4S]2+ cluster plus a small amount of a [3Fe-4S]+ cluster species. Protein contains 5 mol of iron and 2.8 mol of sulfur per mol
iron-sulfur centre
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sequence contains a Cys-W-X-Cys-Y-Z-Cys sequence characteristic for (Fe-S)4-containing proteins. Enzyme is inhibited by Fe(II)-chelating agents
[4Fe-4S]-center
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NadA contains a [4Fe-4S] cluster cofactor with a unique, non-cysteinyl-ligated, iron ion (Fea), which binds the hydroxyl group of a postulated intermediate in the last step of the reaction to facilitate a dehydration. N1 and the C7 carboxylate group of quinolinate ligate to Fea in a bidentate fashion placing the C5 hydroxyl group of the postulated final intermediate distal to Fea and virtually incapable of coordinating to it
[4Fe-4S]-center
inhibitors 4-mercaptophthalic acid, 6-mercaptopyridine-2,3-dicarboxylic acid and 5-mercaptopyrazine-2,3-dicarboxylic acid bind to the catalytic iron site of the [4Fe-4S] cluster through their thiolate
[4Fe-4S]-center
substrate dihydroxyacetone phosphate chelates the cluster
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4Fe-4S cluster
the enzyme requires a [4Fe4S] cluster for full activity
Fe2+
Iron
[4Fe-4S] cluster
Iron
-
enzyme contains a [4Fe-4S]-cluster, coordinated by residues C110, C230, C320. 3.8 mol iron per mol of enzyme
Iron
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protein contains a [4Fe-4S] cluster absolutely required for activity. 3 iron ions per polypeptide
Iron
-
protein contains a [4Fe-4S]2+ cluster plus a small amount of a [3Fe-4S]+ cluster species. Protein contains 5 mol of iron and 2.8 mol of sulfur per mol
Iron
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sequence contains a Cys-W-X-Cys-Y-Z-Cys sequence characteristic for (Fe-S)4-containing proteins. Enzyme is inhibited by Fe(II)-chelating agents
Iron
-
protein contains a [4Fe-4S] cluster absolutely required for activity
Iron
-
protein contains a [4Fe-4S] cluster absolutely required for activity
[4Fe-4S] cluster
an [4Fe-4S] cluster-containing enzyme. The Fe/S cluster of NadA (both Fe4S4 and Fe2S2) might play a significant structural role in NadA that could affect the triose phosphate isomerase activity
[4Fe-4S] cluster
an [4Fe-4S] cluster-containing enzyme. The Fe/S cluster of NadA (both Fe4S4 and Fe2S2) might play a significant structural role in NadA that could affect the triose phosphate isomerase activity
[4Fe-4S] cluster
the presence of the [4Fe-4S] cluster generates an internal tunnel and a cavity
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4,5-dithiohydroxyphthalic acid
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structural analogue of the 5-hydroxy-4,5-dihydropyridine-2,3-dicarboxylic acid intermediate. Compound coordinates to the enzyme [4Fe-4S] cluster through a differentiated iron site, thus leading to the inhibition of quinolate formation. Compound is inhibitory in vitro and in vivo
O2
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complete loss of activity upon purification of enzyme in aerobic conditions or exposure to oxygen overnight
O2
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the activity of the enzyme within Escherichia coli is diminished by exposure of the cells to 4.2 atm O2, while the activity in extracts is rapidly decreased by 0.2 atm O2. Inactivation in extracts can be gradually reversed during anaerobic incubation, but is blocked by alpha, alpha'-dipyridyl or by 1,10-phenanthroline
Phosphoglycolic acid
significantly inhibits the enzyme's triose phosphate isomerase activity at 1 mM
Phosphoglycolic acid
significantly inhibits the enzyme's triose phosphate isomerase activity at 1 mM
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Dehydration
Dual activity of quinolinate synthase: triose phosphate isomerase and dehydration activities play together to form quinolinate.
Dehydration
Quinolinate synthetase: the oxygen-sensitive site of de novo NAD(P)+ biosynthesis.
Dehydration
The Crystal Structure of Fe4S4 Quinolinate Synthase Unravels an Enzymatic Dehydration Mechanism That Uses Tyrosine and a Hydrolase-Type Triad.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.007
4,5-dithiohydroxyphthalic acid
Escherichia coli
-
pH not specified in the publication, temperature not specified in the publication
0.013
4-mercaptophthalic acid
Escherichia coli
pH not specified in the publication, temperature not specified in the publication
0.032
5-mercaptopyrazine-2,3-dicarboxylic acid
Escherichia coli
pH not specified in the publication, temperature not specified in the publication
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.05
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25°C, presence of fumarate as electron acceptor for NadB in the coupled assay
additional information
additional information
-
discontinuous enzymatic assay that couples the production of iminoaspartate by NadB with the condensation between DHAP and iminoaspartate to form quinolinic acid catalyzed by NadA. The assay is linear up to 0.25 mg of NadA, 10 microg of NadB is the lowest amount suitable to measure NadA activity, and under anaerobic conditions, NadA activity becomes independent of fumarate concentration, starting from 1 mM fumarate, but decreases at concentrations higher than 2 mM fumarate, due to inhibition of NadB by fumarate
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.5
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional enzyme, quinolinate synthase activity and stimulation of CpNifS cysteine desulfurase activity. Encoded by OLD5, onset of leaf death5
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brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
additional information
-
three strictly conserved amino acids, Glu198, Tyr109, and Tyr23, are in close proximity to the bound product. Substitution of these amino acids with Gln, Phe, and Phe, respectively, leads to complete loss of activity
physiological function
quinolinate synthase is a Fe4S4 cluster-containing dehydrating enzyme involved in the synthesis of quinolinic acid, the universal precursor of the essential nicotinamide adenine dinucleotide coenzyme
physiological function
quinolinate synthase is an [4Fe-4S] cluster-containing dehydrating enzyme involved in synthesis of quinolinic acid, the universal precursor of the essential coenzyme nicotinamide adenine dinucleotide
physiological function
quinolinate synthase is an [4Fe-4S] cluster-containing dehydrating enzyme involved in synthesis of quinolinic acid, the universal precursor of the essential coenzyme nicotinamide adenine dinucleotide
physiological function
-
quinolinate synthase is involved in synthesis of quinolinic acid, the universal precursor of the essential coenzyme nicotinamide adenine dinucleotide
physiological function
Thermotoga maritima MSB8 / DSM 3109 / ATCC 43589
-
quinolinate synthase is a Fe4S4 cluster-containing dehydrating enzyme involved in the synthesis of quinolinic acid, the universal precursor of the essential nicotinamide adenine dinucleotide coenzyme
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
39300
40000
39300
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plus minor amount of monomer. 2 * 40000, SDS-PAGE, 2 * 39300, calculated
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
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plus minor amount of monomer. 2 * 40000, SDS-PAGE, 2 * 39300, calculated
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
residues C291 and C294 of the C291XXC294XXC297 motif undergo reversible disulfide formation, which regulates the activity of the enzyme. Disulfide-bond formation and reduction are effected by oxidized and reduced forms of thioredoxin, with a midpoint potential of -264 mV for the redox couple
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
both native and SeMet enzyme are crystallized using the hanging-drop vapor-diffusion method at 22°C, structure is determined at 2.8 A resolution
in presence of substrate analogue malate. Diffraction to 2.0 A resolution. Triangular architecture composed of a 3fold repeat of three-layer alphabetaalpha sandwich folding. The active site is located at the interface of the three domains and is centered on the pseudo-3fold axis. The malate molecule is tightly held near the bottom of the active site cavity
structures of NadA in complex with dihydroxyacetone phosphate, iminoaspartate analogues, and quinolinate. Dihydroxyacetone phosphate adopts a nearly planar conformation and chelates the [4Fe-4S] cluster via its keto and hydroxyl groups. The cluster may act as a Lewis acid in enediolate formation, like zinc in class II aldolases
mutant K219R/Y107F in complex with the first intermediate resulting from the condensation of dihydroxyacetone phosphate with iminoaspartate and the dihydroxyacetone phosphate analogue phosphoglycolohydroxamate, and mutant K219R/Y21F in complex with quinolinic acid. Phosphoglycolohydroxamate binds to NadA with its phosphate group at the site where the carboxylate groups of the first intermediate also bind
structures of complexes of the Y21F/K219R variant with 4-mercaptophthalic acid, 6-mercaptopyridine-2,3-dicarboxylic acid and 5-mercaptopyrazine-2,3-dicarboxylic acid, at 1.64 A, 1.9 A and 2.1 A resolution, respectively. The carboxylate groups of the inhibitors interact with active site amino acids of His19 and Ser36 (domain 1), Ser124 (domain 2) and His193 and Thr210 (domain 3), and all molecules bind to one iron of the cluster with their thiolate moiety
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C113A
C200A
C297A
K219R/Y107F
crystallization data. The mutated protein is unable to catalyze the aldo-keto isomerization and/or cyclization of the first intermediate resulting from the condensation of dihydroxyacetone phosphate with iminoaspartate that ultimately leads to quinolinic acid formation
K219R/Y107F
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crystallization data. The mutated protein is unable to catalyze the aldo-keto isomerization and/or cyclization of the first intermediate resulting from the condensation of dihydroxyacetone phosphate with iminoaspartate that ultimately leads to quinolinic acid formation
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additional information
additional information
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functional complementation of a corresponding Escherichia coli mutant. Gene disruption in Arabidospis thaliana is embryo-lethal
additional information
-
the old5 lesion does not affect quinolinate synthase activity but decreases the protein's cysteine desulfurase activity resulting in increased NAD steady state levels concomitant with increased activity of enzymes in the NAD salvage pathway