Information on EC 2.4.2.12 - nicotinamide phosphoribosyltransferase and Organism(s) Mus musculus and UniProt Accession Q99KQ4

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Mus musculus
UNIPROT: Q99KQ4


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


The taxonomic range for the selected organisms is: Mus musculus

EC NUMBER
COMMENTARY hide
2.4.2.12
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RECOMMENDED NAME
GeneOntology No.
nicotinamide phosphoribosyltransferase
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pentosyl group transfer
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pentosyl group transfer
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
NAD biosynthesis III
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Nicotinate and nicotinamide metabolism
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Metabolic pathways
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SYSTEMATIC NAME
IUBMB Comments
nicotinamide-D-ribonucleotide:diphosphate phospho-alpha-D-ribosyltransferase
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CAS REGISTRY NUMBER
COMMENTARY hide
9030-27-7
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
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enzyme inhibition induces NAD depletion in various mouse organs but selectively causes dramatic atrophy of the spleen red pulp
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
nicotinamide + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinamide D-ribonucleotide + diphosphate
show the reaction diagram
nicotinamide + alpha-D-5-phosphoribosyl 1-diphosphate
nicotinamide mononucleotide + diphosphate
show the reaction diagram
nicotinamide clearance
NMN synthesis is rate-limiting step for NAD+ synthesis
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r
nicotinamide + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinamide D-ribonucleotide + diphosphate
show the reaction diagram
nicotinamide + 5-phosphoribosyl 1-diphosphate
nicotinamide mononucleotide + diphosphate
show the reaction diagram
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-
-
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?
additional information
?
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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
nicotinamide + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinamide D-ribonucleotide + diphosphate
show the reaction diagram
Q99KQ4
key enzyme in the regulation of NAD+ biosynthesis, regulates the silent regulator protein 2, i.e. Sir2, activity, the enzyme has a metabolic regulatory function by up- and downregulation of proteins, overview
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?
nicotinamide + alpha-D-5-phosphoribosyl 1-diphosphate
nicotinamide mononucleotide + diphosphate
show the reaction diagram
Q99KQ4
nicotinamide clearance
NMN synthesis is rate-limiting step for NAD+ synthesis
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r
nicotinamide + 5-phospho-alpha-D-ribose 1-diphosphate
nicotinamide D-ribonucleotide + diphosphate
show the reaction diagram
additional information
?
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NMPRTase is a crucial enzyme in the salvage pathway of NAD+ biosynthesis and has important functions in regulating NAD+ levels in cells undergoing substantial NAD+ turnover
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
APO866
also known as FK866, (E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-(pyridine-3-yl)-acrylamide, 10 mg/kg, DBA/1 mice: beneficial effects on collagen-induced arthritis (CIA) due to impaired secretion of inflammatory cytokines (reduction of the mean arthritic score and number of affected paws from mice with CIA as well as decrease in local levels of IL-1beta and IL-6 but no impact on IL-10, IFN-gamma, CCL5 and IL-12p70 levels, decrease in inflammatory infiltrate and hyperplasia in knees and paws from mice with CIA) but not due to toxicity (no premature death of individuals, no impact on histology of liver, spleen, lung, gut, kidney, inguinal lymph nodes and brain, normal liver alanine aminotransferase levels, no enhanced apoptosis in arthritic paws) and not due to impact on anti-collagen immune response (similar anti-collagen IgG levels); also known as FK866, (E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-(pyridine-3-yl)-acrylamide, 10 mg/kg, isolated peritoneal exudate inflammatory cells (PEC) from C57BL/6 mice: time-dependent NAD depletion (lowest at 9 h, recovery after 14 h), addition of 10 mM NMN abolishes a reduction of intracellular NAD+ concentration as well as TNFalpha and IL-6 secretion (pro-inflammatory cytokines) in PECs induced by in vivo or in vitro stimulation of inflammatory response with 5 microgram/ml Pansorbin (Staphylococcus aureus cells, SAC) or 100 ng/ml lipopolysaccharide (LPS)
(4',5,7-trihydroxyflavone)-(3'->8)-(4',5,7-trihydroxyflavone)
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(4',7-dimethoxy-5-hydroxyflavone)-(3'->8)-(4',7-dimethoxy-5-hydroxyflavone)
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FK-866
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i.e. (2E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-phenylprop-2-enamide
FK866
gallotanine
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i.e. (2R,3S,5R,6S)-tetrahydro-2H-pyran-2,3,4,5,6-pentaylpentakis(oxycarbonyl-5,6-dihydroxybenzene-3,1-diyl) pentakis(3,4,5-trihydroxybenzoate)
GMX1777
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i.e. 1-[2-(2-(2-(2-methoxyethoxy)-ethoxy)ethoxy)-ethoxy-carbonyloxymethyl]-4-[N'-cyano-N''-(6-(4-chlorophenyl)-hexyl)-N-guanidino]pyridinium chloride, prodrug of GMX1778. A dose of 75 mg/kg administered over a 24 h intravenous infusion produces GMX1778 steady-state plasma levels of about 1 microg/ml and causes nicotinamide dinucleotide levels to decrease significnantly in tumors. Nicotinic acid protects mice treated with a lethal dose of GMX1777
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.92
nicotinamide
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pH 7.4, 37°C, recombinant enzyme
0.00124
nicotinamide
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.02
nicotinamide
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pH 7.4, 37°C, recombinant enzyme
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0066
(4',5,7-trihydroxyflavone)-(3'->8)-(4',5,7-trihydroxyflavone)
Mus musculus;
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pH 7.5, 37°C
0.0175
(4',7-dimethoxy-5-hydroxyflavone)-(3'->8)-(4',7-dimethoxy-5-hydroxyflavone)
Mus musculus;
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pH 7.5, 37°C
0.0000009
FK-866
Mus musculus;
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i.e. (2E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-phenylprop-2-enamide, pH 7.5, 37°C
0.0013
gallotanine
Mus musculus;
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i.e. (2R,3S,5R,6S)-tetrahydro-2H-pyran-2,3,4,5,6-pentaylpentakis(oxycarbonyl-5,6-dihydroxybenzene-3,1-diyl) pentakis(3,4,5-trihydroxybenzoate), pH 7.5, 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
positive staining in blood vessels from arthritic joints as revealed by immunohistochemistry using rat monoclonal anti-murine NAMPT antibody
Manually annotated by BRENDA team
some positive staining in cells of both normal and arthritic joints as revealed by immunohistochemistry using rat monoclonal anti-murine NAMPT antibody
Manually annotated by BRENDA team
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enzyme and Sir2 expression levels
Manually annotated by BRENDA team
massive expression in synoviocytes of the synovial lining layer, sub-intimal synovium and pannus in joints from mice with type II collagen induced arthritis (CIA) compared to non-arthritic naive DBA/1 mice as revealed by immunohistochemistry using rat monoclonal anti-murine NAMPT antibody, some positive staining in chondrocytes from normal and arthritic joints and in blood vessels and inflammatory cells from arthritic joints
Manually annotated by BRENDA team
elevated levels in mice with type II collagen induced arthritis (CIA) compared to non-arthritic naive DBA/1 mice as revealed by ELISA using a mouse visfatin/PBEF ELISA kit
Manually annotated by BRENDA team
(PEC) isolated from naive C57BL/6 mice of from lipopolysaccharide-treated mice
Manually annotated by BRENDA team
elevated levels upon type II collagen induced arthritis (CIA) compared to non-arthritic naive DBA/1 mice as revealed by ELISA using a mouse visfatin/PBEF ELISA kit
Manually annotated by BRENDA team
additional information
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ubiquitous in all tissues
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
UNIPROT
ORGANISM
Mus musculus;
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
crystal structures at up to 2.1 A resolution of NMPRTase, alone and in complex with the reaction product nicotinamide mononucleotide or the inhibitor FK866. Crystals of wild-type murine NMPRTase free enzyme are obtained by sitting drop vapor diffusion at 4°C
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography
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immobilized metal ion affinity chromatography
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
DNA sequence determination and analysis, phylogenetic analysis, expression of His-tagged enzyme and of enzyme fused to Sir2 in Escherichia coli strain BL21(DE3)
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expressed in Escherichia coli BL21-CodonPlus(DE3)-RIL
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expression in Escherichia coli
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pre-B-cell colony enhancing factor
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
expression of Nampt in the heart is significantly decreased by ischemia, ischemia/reperfusion and pressure overload. Downregulation of Nampt increases caspase 3 cleavage, cytochrome c release, and TUNEL-positive cells, which are inhibited in the presence of Bcl-xL, but do not increase hairpin 2–positive cells, suggesting that endogenous Nampt negatively regulates apoptosis but not necrosis. Downregulation of Nampt also impairs autophagic flux
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upon aging: enzyme level increases in serum but decreases in brain, decreases in cortex and hippocampus but remains unchanged in cerebellum and striatum in brain, and increases in microglia but likely decreases in neuron
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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a dose of 75 mg/kg GMX1777, i.e. 1-[2-(2-(2-(2-methoxyethoxy)-ethoxy)ethoxy)-ethoxy-carbonyloxymethyl]-4-[N'-cyano-N''-(6-(4-chlorophenyl)-hexyl)-N-guanidino]pyridinium chloride, prodrug of GMX1778, administered over a 24 h intravenous infusion produces GMX1778 steady-state plasma levels of about 1 microg/ml and causes nicotinamide dinucleotide levels to decrease significnantly in tumors. Nicotinic acid protects mice treated with a lethal dose of GMX1777