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Information on EC 2.4.2.19 - nicotinate-nucleotide diphosphorylase (carboxylating) and Organism(s) Homo sapiens and UniProt Accession Q15274
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2.4.2.19 nicotinate-nucleotide diphosphorylase (carboxylating)IUBMB Comments
The reaction is catalysed in the opposite direction. Since quinolinate is synthesized from L-tryptophan in eukaryotes, but from L-aspartate in some prokaryotes, this is the first NAD+ biosynthesis enzyme shared by both eukaryotes and prokaryotes .
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Word Map
- 2.4.2.19
-
nicotinic
-
3-hydroxyanthranilic
-
phthalic
- tiazofurin
-
excitotoxin
- kynureninase
-
5-phosphoribosyl-1-pyrophosphate
-
4.1.1.45
-
phosphoribosyltransferases
-
prtases
- aminocarboxymuconate-semialdehyde
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
quinolinate phosphoribosyltransferase, quinolinic acid phosphoribosyltransferase, qaprtase, qprtase, nad pyrophosphorylase, quinolinate phosphoribosyl transferase, hqprtase, spnadc, quinolate phosphoribosyltransferase, quinolinate phosphoribosyltransferase 2, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
general stress protein 70
-
-
-
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GSP70
-
-
-
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NAD pyrophosphorylase
-
-
-
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NadC
-
-
-
-
nicotinate mononucleotide pyrophosphorylase (carboxylating) (EC 2.4.2.19)
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-
-
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nicotinate-nucleotide pyrophosphorylase (carboxylating)
-
-
-
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nicotinate-nucleotide:pyrophosphate phospho-alpha-D-ribosyltransferase (decarboxylating)
-
-
-
-
pyrophosphorylase, nicotinate mononucleotide (carboxylating)
-
-
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QAPRTase
-
-
-
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QPRTase
-
-
-
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quinolinate phosphoribosyltransferase
quinolinate phosphoribosyltransferase (decarboxylating)
-
-
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quinolinate phosphoribosyltransferase [decarboxylating]
-
-
-
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quinolinic acid phosphoribosyltransferase
-
-
-
-
quinolinic phosphoribosyltransferase
-
-
-
-
quinolinate phosphoribosyltransferase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pentosyl group transfer
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
nicotinate-D-ribonucleotide:diphosphate phospho-alpha-D-ribosyltransferase (carboxylating)
The reaction is catalysed in the opposite direction. Since quinolinate is synthesized from L-tryptophan in eukaryotes, but from L-aspartate in some prokaryotes, this is the first NAD+ biosynthesis enzyme shared by both eukaryotes and prokaryotes [3].
CAS REGISTRY NUMBER
COMMENTARY
37277-74-0
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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
phosphoribosyl diphosphate + quinolinic acid
nicotinate mononucleotide + diphosphate + CO2
-
-
-
r
pyridine-2,3-dicarboxylate + 5-phospho-alpha-D-ribose 1-diphosphate
beta-nicotinate D-ribonucleotide + diphosphate + CO2
-
-
-
?
pyridine-2,3-dicarboxylate + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinate D-ribonucleotide + diphosphate + CO2
type II phosphoribosyltransfer followed by irreversible decarboxylation, involved in catabolism of quinolinic acid and in NAD+ de novo synthesis
-
-
ir
quinolinic acid + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinic acid mononucleotide + diphosphate + CO2
pyridine-2,3-dicarboxylate + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinate D-ribonucleotide + diphosphate + CO2
quinolinic acid + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinic acid mononucleotide + diphosphate + CO2
-
-
-
?
quinolinic acid + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinic acid mononucleotide + diphosphate + CO2
-
-
-
-
?
quinolinic acid + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinic acid mononucleotide + diphosphate + CO2
6 mM MgCl2, pH7.2, 37°C, 0.3 mM quinolinic acid, HPLC-based assay: 7 microgram purified enzyme, 1 mM 5-phospho-alpha-D-ribose 1-diphosphate, 20 min, UV-based assay: 14 microgram purified enzyme, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, 30 min
HPLC-based assay: 254 nm (quantification of nicotinic acid mononucleotide and quinolinic acid), UV-based assay: 266 nm (quantification of nicotinic acid mononucleotide)
-
ir
pyridine-2,3-dicarboxylate + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinate D-ribonucleotide + diphosphate + CO2
-
-
-
?
pyridine-2,3-dicarboxylate + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinate D-ribonucleotide + diphosphate + CO2
-
-
-
ir
additional information
?
-
no detectable activity for mutants R161Q, R138Q, K171A, K171S, K139A, K139S, 6 mM MgCl2, pH7.2, 37°C, 0.3 mM quinolinic acid, UV-based assay: 14 microgram purified enzyme, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, 30 min
-
-
?
additional information
?
-
-
no detectable activity for mutants R161Q, R138Q, K171A, K171S, K139A, K139S, 6 mM MgCl2, pH7.2, 37°C, 0.3 mM quinolinic acid, UV-based assay: 14 microgram purified enzyme, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, 30 min
-
-
?
additional information
?
-
-
key enzyme in catabolism of quinolinate. Quinolinate acts as a most potent endogenous exitotoxin to neurons. Elevation of quinolinate levels in the brain has been linked to the pathogenesis of neurodegenerative disorders
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-
?
NATURAL SUBSTRATE
NATURAL 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
phosphoribosyl diphosphate + quinolinic acid
nicotinate mononucleotide + diphosphate + CO2
-
-
-
r
pyridine-2,3-dicarboxylate + 5-phospho-alpha-D-ribose 1-diphosphate
beta-nicotinate D-ribonucleotide + diphosphate + CO2
-
-
-
?
pyridine-2,3-dicarboxylate + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinate D-ribonucleotide + diphosphate + CO2
type II phosphoribosyltransfer followed by irreversible decarboxylation, involved in catabolism of quinolinic acid and in NAD+ de novo synthesis
-
-
ir
quinolinic acid + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinic acid mononucleotide + diphosphate + CO2
additional information
?
-
-
key enzyme in catabolism of quinolinate. Quinolinate acts as a most potent endogenous exitotoxin to neurons. Elevation of quinolinate levels in the brain has been linked to the pathogenesis of neurodegenerative disorders
-
-
?
quinolinic acid + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinic acid mononucleotide + diphosphate + CO2
-
-
-
?
quinolinic acid + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinic acid mononucleotide + diphosphate + CO2
-
-
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
5-phospho-alpha-D-ribose 1-diphosphate
substrate inhibition, mixed inhibition (competitive and non-competitive) above 0.3 mM 5-phospho-alpha-D-ribose 1-diphosphate
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0232
5-phospho-alpha-D-ribose 1-diphosphate
+/-0.0036 mM, wild-type, 0.3 mM quinolinic acid, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm, 30 min, 37°C, KM for 5-phospho-alpha-D-ribose 1-diphosphate increases with decreasing quinolinic acid concentration
0.0216
quinolinic acid
+/-0.003 mM, wild-type, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm, 30 min, 37°C, affinity to quinolinic acid is independent of 5-phospho-alpha-D-ribose 1-diphosphate concentration
0.319
quinolinic acid
+/-0.060 mM, mutant R161A, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm, 30 min, 37°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
5-phospho-alpha-D-ribose 1-diphosphate
Vmax = 0.93(+/-0.03) microM/min, wild-type, 0.3 mM quinolinic acid, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm, Vmax increases with increasing 5-phospho-alpha-D-ribose 1-diphosphate concentrations up to 5 mM
additional information
5-phospho-alpha-D-ribose 1-diphosphate
-
Vmax = 0.93(+/-0.03) microM/min, wild-type, 0.3 mM quinolinic acid, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm, Vmax increases with increasing 5-phospho-alpha-D-ribose 1-diphosphate concentrations up to 5 mM
additional information
quinolinic acid
Vmax = 0.71(+/-0.0) microM/min, mutant R161A, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm
additional information
quinolinic acid
-
Vmax = 0.71(+/-0.0) microM/min, mutant R161A, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm
additional information
quinolinic acid
Vmax = 1.19(+/-0.05) microM/min, wild-type, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm
additional information
quinolinic acid
-
Vmax = 1.19(+/-0.05) microM/min, wild-type, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.09
wild-type, 0.1 mM 5-phospho-alpha-D-ribose 1-diphosphate, UV-based assay measuring nicotinic acid mononucleotide formation at 266 nm, 30 min, 37°C, same order of magnitude as bacterial enzymes, 100% relative activity
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
key enzyme in the de novo nicotinamide adenine dinucleotide synthesis pathway
physiological function
physiological function
interacts with active-caspase-3, depletion of quinolinate phosphoribosyltransferase protein increases intracellular caspase-3 activity, quinolinate phosphoribosyltransferase-depleted cells are highly sensitive to spontaneous cell death, quinolinate phosphoribosyltransferase protein prevents spontaneous cell death through inhibition of overproduction of active-caspase-3, identified as a caspase-3 binding protein, not a substrate for caspase-3
physiological function
the enzyme is essential for maintaining the homeostasis of quinolinic acid in the brain
physiological function
the enzyme inhibits hepatitis C virus replication via reduction of cellular lipogenesis
physiological function
the enzyme with anti-apoptotic properties is a direct target gene of Wilms' tumor gene 1 in leukemic cells. Enzyme overexpression in K-562 leukemic cells increases resistance to imatinib
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). NADC_HUMAN
297
0
30846
Swiss-Prot
Secretory Pathway (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hexamer
hexamer
according to gel filtration, 3 canonical (AB) dimers (formed by two-fold rotation placing N-terminus of monomer A next to C-terminus of monomer B) related to each other by 3-fold rotation axis, hexameric D3 symmetry, active sites in close proximity at interface between monomers A and monomers B
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
apoenzyme and in complex with phthalic acid, sitting drop vapor diffusion method, using 50 mM MES pH 6.5, 0.1 M NaH2PO4, 0.1 M K H2PO4, and 1.6-2.1 M NaCl
apoenzyme and in complex with quinolinic acid or nicotinic acid mononucleotide, hanging drop vapor diffusion method, using
PDB code: 2jbm (apo-hQPRTase), alpha/beta barrel fold (12 beta strands + 11 alpha helices) with N-terminal domain (residues 1-112, 279-291) and C-terminal domain (residues 113-278), similar to bacterial QPRTases (PDB: 1x1o), active site at alpha/beta open sandwich structure that faces an alpha/beta barrel of the adjacent subunit harbouring the quinolinic acid binding site (Arg102, Arg138, Arg161, Lys139, Lys171, pocket at the centre of the barrel), space group P2(1)2(1)2(1), unit-cell parameters: a = 111.5 A, b = 179.5 A, c = 194.7 A, 12 monomers in asymmetric unit arranged as 2 hexamers of D3 symmetry, sitting-drop vapour diffusion: 5 days, 20°C, 2 microlitre protein solution (10 mg/ml, pH7.5) + 2 microlitre precipitant (0.6 M potassium/sodium tartrate, 0.1 M sodium HEPES pH7.6), resolution of 2 A, phase determination using multiple wavelength anomalous diffraction on crystals of the Se-Met variant
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
R102A
10% remaining activity, R102 is part of quinolinic acid binding site, denotes from the other subunit in the canonical dimer
R102Q
10% remaining activity, R102 is part of quinolinic acid binding site, denotes from the other subunit in the canonical dimer
R161A
R161A
20% remaining activity, R161 is part of quinolinic acid binding site and important for substrate binding
R161A
the mutation abolishes substrate binding and enzyme activity with a 20% capacity of wild type enzyme
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate precipitation, dye ligand chromatography (Blue-Sepharose), ion exchange chromatography
nickel affinity chromatography, TEV protease cleavage followed by nickel affinity chromatography, gel filtration, selenomethionine variant of hQPRTase purified in presence of 5 mM beta-mercaptoethanol
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
in pEHISTEV (pBS-hQPRT as template) for expression in Escherichia coli BL21(DE3) or mutagenesis, expression with N-terminal hexa-His tag and TEV protease cleavage site, two extra N-terminal residues (Gly, Ala) remain after removal of hexa-His tag
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
overexpression of Wilms' tumor gene 1 in hematopoietic progenitor cells and cell lines results in an increase of enzyme expression
the enzyme is significantly reduced in livers of patients with persistent hepatitis C virus infection
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Okuno, E.; White, R.J.; Schwarcz, R.
Quinolinic acid phosphoribosyltransferase: purification and partial characterization from human liver and brain
J. Biochem.
103
1054-1059
1988
Homo sapiens
Fukuoka, S.I.; Nyaruhucha, C.M.; Shibata, K.
Characterization and functional expression of the cDNA encoding human brain quinolinate phosphoribosyltransferase
Biochim. Biophys. Acta
1395
192-201
1998
Homo sapiens
Liu, H.; Woznica, K.; Catton, G.; Crawford, A.; Botting, N.; Naismith, J.H.
Structural and kinetic characterization of quinolinate phosphoribosyltransferase (hQPRTase) from Homo sapiens
J. Mol. Biol.
373
755-763
2007
Homo sapiens (Q15274), Homo sapiens
Kang, G.B.; Kim, M.K.; Youn, H.S.; An, J.Y.; Lee, J.G.; Park, K.R.; Lee, S.H.; Kim, Y.; Fukuoka, S.; Eom, S.H.
Crystallization and preliminary X-ray crystallographic analysis of human quinolinate phosphoribosyltransferase
Acta Crystallogr. Sect. F
67
38-40
2011
Homo sapiens
Ishidoh, K.; Kamemura, N.; Imagawa, T.; Oda, M.; Sakurai, J.; Katunuma, N.
Quinolinate phosphoribosyl transferase, a key enzyme in de novo NAD(+) synthesis, suppresses spontaneous cell death by inhibiting overproduction of active-caspase-3
Biochim. Biophys. Acta
1803
527-533
2010
Homo sapiens (Q15274)
Malik, S.S.; Patterson, D.N.; Ncube, Z.; Toth, E.A.
The crystal structure of human quinolinic acid phosphoribosyltransferase in complex with its inhibitor phthalic acid
Proteins
82
405-414
2014
Homo sapiens (Q15274), Homo sapiens
Youn, H.S.; Kim, T.G.; Kim, M.K.; Kang, G.B.; Kang, J.Y.; Lee, J.G.; An, J.Y.; Park, K.R.; Lee, Y.; Im, Y.J.; Lee, J.H.; Eom, S.H.
Structural insights into the quaternary catalytic mechanism of hexameric human quinolinate phosphoribosyltransferase, a key enzyme in de novo NAD biosynthesis
Sci. Rep.
6
19681
2016
Homo sapiens (Q15274), Homo sapiens
Ullmark, T.; Montano, G.; Jaervstrat, L.; Jernmark Nilsson, H.; Hakansson, E.; Drott, K.; Nilsson, B.; Vidovic, K.; Gullberg, U.
Anti-apoptotic quinolinate phosphoribosyltransferase (QPRT) is a target gene of Wilms tumor gene 1 (WT1) protein in leukemic cells
Biochem. Biophys. Res. Commun.
482
802-807
2017
Homo sapiens (Q15274)
Wang, Z.; Gao, Y.; Zhang, C.; Hu, H.; Guo, D.; Xu, Y.; Xu, Q.; Zhang, W.; Deng, S.; Lv, P.; Yang, Y.; Ding, Y.; Li, Q.; Weng, C.; Chen, X.; Gong, S.; Chen, H.; Niu, J.; Tang, H.
Quinolinate phosphoribosyltransferase is an antiviral host factor against hepatitis C virus infection
Sci. Rep.
7
5876
2017
Homo sapiens (Q15274), Homo sapiens
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