This multiunctional enzyme acts on NAD+, catalysing both the synthesis and hydrolysis of cyclic ADP-ribose, a calcium messenger that can mobilize intracellular Ca2+ stores and activate Ca2+ influx to regulate a wide range of physiological processes. In addition, the enzyme also catalyses EC 2.4.99.20, 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase. It is also able to act on beta-nicotinamide D-ribonucleotide. cf. EC 3.2.2.5, NAD+ glycohydrolase.
structure-function analysis and reaction mechanism, overview. The nicotinamide-ribosyl bond of NAD+ is cleaved via a dissociative process with a late transition state, leading to a ribooxocarbenium ion reaction intermediate stabilized by the side-chain of invariant Glu218. This rate-determining step is followed by two nucleophilic reactions in competition: (i) an intermolecular pathway involving a rapid trapping from the b-face of this intermediate by a water molecule (NAD+ glycohydrolase activity) or by competing neutral nucleophiles such as pyridines (transglycosidation reactions) or alcohols (e.g., methanolysis), and (ii) an intramolecular reaction between N1 of the adenine ring and C19 (anomeric carbon) of the oxocarbenium ion leading to the formation of cyclic ADP-ribose (ADP-ribosyl cyclase activity). This latter reaction represents a kinetically minor step relative to solvolysis
substrate binding with a crucial role of Glu218, which orients the substrate for cleavage by interacting with the N-ribosyl 2'-OH group of NAD+, stepwise ordered uni-bi kinetic mechanism, overview. Residues Trp118, Glu138, Asp147, Trp181 stabilize the ribooxocarbenium ion-like transition state mostly by electrostatic interactions
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SYSTEMATIC NAME
IUBMB Comments
NAD+ glycohydrolase (cyclic ADP-ribose-forming)
This multiunctional enzyme acts on NAD+, catalysing both the synthesis and hydrolysis of cyclic ADP-ribose, a calcium messenger that can mobilize intracellular Ca2+ stores and activate Ca2+ influx to regulate a wide range of physiological processes. In addition, the enzyme also catalyses EC 2.4.99.20, 2'-phospho-ADP-ribosyl cyclase/2'-phospho-cyclic-ADP-ribose transferase. It is also able to act on beta-nicotinamide D-ribonucleotide. cf. EC 3.2.2.5, NAD+ glycohydrolase.
bovine CD38/NAD+ glycohydrolase catalyzes the hydrolysis of NAD+ to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism
selectivity in favor of methanolysis by wild-type enzyme and mutant E138A. 1'-Azido ADP-ribose is the reaction product obtained in the presence of azide. the ADP-ribosyl cyclase activity of wild-type bCD38 isminimal
selectivity in favor of methanolysis by wild-type enzyme and mutant E138A. 1'-Azido ADP-ribose is the reaction product obtained in the presence of azide. the ADP-ribosyl cyclase activity of wild-type bCD38 isminimal
CD38 is a multifunctional enzyme catalyzing the conversion of NAD(P)+ to three metabolites (cyclic ADP-ribose, nicotinic acid adenine dinucleotide phosphate and ADP-ribose)
CD38 is a NAD+-dependent, multifunctional ectoenzyme that cannot only generate cyclic ADP-ribose from NAD+ but also hydrolyze cyclic ADP-ribose to ADP-ribose and transport cyclic ADP-ribose into cells
enzyme may be induced by presence of protein in the culture medium. Low concentrations of sucrose or glucose, 0.1%, casamino acids or some amino acids such as Met, Cys, Phe and Trp strongly repress enzyme synthesis
bovine CD38/NAD+ glycohydrolase catalyzes the hydrolysis of NAD+ to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism
CD38 is a NAD+-dependent, multifunctional ectoenzyme that cannot only generate cyclic ADP-ribose from NAD+ but also hydrolyze cyclic ADP-ribose to ADP-ribose and transport cyclic ADP-ribose into cells
enzyme may be induced by presence of protein in the culture medium. Low concentrations of sucrose or glucose, 0.1%, casamino acids or some amino acids such as Met, Cys, Phe and Trp strongly repress enzyme synthesis
50% inhibition of NADase and 300% activation of adenosine diphosphate cyclase; at 2 mM 50% inhibition of NADase activity and 300% activation of cADPR activity
An enzymatic alteration secondary to adenylyl cyclase deficiency in the cr-1 (crisp) mutant of Neurospora crassa: nicotinamide adenine dinucleotide (phosphate) glycohydrolase overproduction.
CD38 is a type II membrane protein with an extracellular C-terminal enzymatic domain with NADase/NADPase and ADPR cyclase activity and a short cytoplasmic N-terminal tail
CD38 knockout mice manifest multiple defects relating to Ca2+ signaling, including that of insulin secretion, hormonal signaling in pancreatic acinar cells, migration of dendritic cell precursors, bone resorption, airway responsiveness, alpha-adrenoceptor signaling in aorta, cardiac hypertrophy, susceptibility to bacterial infection, as well as social behavior in mice through modulation of oxytocin secretion
CD38 reductions lead to microglial apoptosis. inhibition of CD38/cADPR-dependent signaling by CD38 silencing or 8-bromo-cADPR, a ryanodine receptor antagonist, produced significant ATP release from BV2 microglia. Cx43 small interfering RNA and Cx43 hemichannel blocker 18-alpha-glycyrrhetinic acid completely prevented the CD38 silencing or 8-bromo-cADPR-induced ATP release. Prevention of the ATP release might also be due to P2X7 receptor antagonists. Key role of ATP release in the microglial apoptosis induced by decreased CD38/cADPR-dependent signaling, overview
leukocyte antigen CD38 expression is an early marker of all-trans retinoic acid-stimulated differentiation in the leukemic cell line HL-60 where CD38 promotes induced myeloid maturation when overexpressed. The ability of CD38 to propel all-trans retinoic acid-induced myeloid differentiation and G1/0 arrest is unimpaired by loss of its ectoenzymeactivity
CD38 is an ectoenzyme that consumes NAD+ to produce cyclic ADP-ribose, a potent agonist of ryanodine receptors. Basal CD38/cyclic ADP-ribose-dependent signaling plays a key role in ATP release, which mediates basal survival of microglia, overview
CD38 is an NAD+-metabolizing enzyme in mammals, a type II transmembrane protein that converts NAD+ primarily to adenosine diphosphate ribose and a small amount of cyclic adenosine diphosphate ribose. The major enzymatic function of the enzyme is to hydrolyze extracellular rather than intracellular NAD+
the enzyme is a signaling enzyme responsible for catalyzing the synthesis of cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate, both are universal Ca2+ messenger molecules
the enzyme is a signaling enzyme responsible for catalyzing the synthesis of cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate, both are universal Ca2+ messenger molecules
the enzyme is a signaling enzyme responsible for catalyzing the synthesis of cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate, both are universal Ca2+ messenger molecules
in cultured macrophages, lipopolysaccharide LPS can upregulate CD38 expression in time- and dose-dependent manner. Knocking down or blockade of CD38 in macrophages inhibits LPS-induced macrophage M1 polarization accompanied by diminished NF-kappaB signaling activation. In a mouse model with LPS-induced acute kidney injury, blocking CD38 with quercetin significantly relieves kidney dysfunction, kidney pathological changes as well as inflammatory cell accumulation
senescent cells do not have high expression of CD38. The senescent associated secretory phenotype factors secreted by senescent cells induce CD38 mRNA and protein expression and increase CD38-NADase activity in non-senescent cells such as endothelial cells or bone marrow derived macrophages
D226/Q226 and K129 residues of the two CD38 enzyme are the ADP-ribosylation sites. 6-Alkyne-F-araNAD, 6-alkyne-NAD, and Rh-N3 are used in the labeling reactions of CD38 wild-type and mutants, overview
structure-function analysis, overview. The enzyme catalyzes the formation of beta-1'-O-methyl ADP-ribose in presence of methanol, solvolysis does not affect the overall turnover rate of NAD+ by the wild-type enzyme. Precise role of key conserved active site residues Trp118, Glu138, Asp147, Trp181 and Glu218, effects of experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. Binding of 2'-fluorinated analogs of NAD+ and trappping of the reaction intermediate, detailed overview. Catalytic residue Glu138 is part of the TLEDTL signature domain, Asp147 is a highly conserved residue in the enzyme and is important for the catalytic parameters. Cooperative contribution of Trp118 and Trp181 to catalysis
structure-function analysis, overview. The enzyme catalyzes the formation of beta-1'-O-methyl ADP-ribose in presence of methanol, solvolysis does not affect the overall turnover rate of NAD+ by the wild-type enzyme. Precise role of key conserved active site residues Trp118, Glu138, Asp147, Trp181 and Glu218, effects of experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. Binding of 2'-fluorinated analogs of NAD+ and trappping of the reaction intermediate, detailed overview. Catalytic residue Glu138 is part of the TLEDTL signature domain, Asp147 is a highly conserved residue in the enzyme and is important for the catalytic parameters. Cooperative contribution of Trp118 and Trp181 to catalysis
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
mono N-glycosylated forms of soluble enzyme ecto-domain (residues 32-278) and catalytic residue mutant Glu218Gln, in apo state or bound to 2'-fluorinated NAD+ derivatives aFNAD or rFNAD, hanging drop vapour diffusion method, from 20-30% PEG 4000, 50-250 mM ammonium sulfate and 100 mM sodium cacodylate, sodium acetate or MES, pH 6.0-6.5, room temperature, soaking of crystals in 1-3 mM ligand solution, X-ray diffraction structure determination and analysis at 1.8 A resolution, molecular replacement
enzyme in complex with inhibitors, hanging drop vapor diffusion method, mixing of 10 mg/ml protein in 20 mM HEPES with 5 mm ligands, with reservoir solution containing 0.1 M sodium acetate, pH 4.0, 0.2 M ammonium acetate, 3% 2-propanol, and 15% PEG 10000, X-ray diffraction structure determination and analysis, molecular replacement
site-directed mutagenesis, the mutation causes a modest increase in the rate of NAD+ transformation which is proportional to its concentration. At 4.0 M, the rate increase is about 1.2fold and the formation of beta-1'-O-methyl ADP-ribose amounts to about 80% of the total reaction products. The observed selectivity in favor of methanolysis is similar to that of wild-type enzyme. The ADP-ribosyl cyclase activity of E138A mutant is more affected by the competing nucleophile, i.e. formation of ADP-ribose and cADPR are reduced by 75% and 90% respectively at 4.0 M methanol, the mutant shows an increase in ADP cyclization and higly reduced overall activity compared to the wild-type enzyme
site-directed mutagenesis, in the presence of methanol, mutant E138Q efficiently catalyzes the formation of beta-1'-O-methyl ADP-ribose. But in contrast with mutant E138A, and like the wild-type enzyme, solvolysis does not affect the overall turnover rate of NAD+ indicating that the formation of the E.ADP-ribosyl intermediate is still rate limiting
site-directed mutagenesis, the mutant shows a decrease of the catalytic rate which is 16fold lower than the product of the effects of the two single mutations
site-directed mutagenesis, the mutant shows a decrease of the catalytic rate and a reduced sensitivity to nicotinamide inhibition compared to the wild-type enzyme
native enzyme 480fold from serum by ammonium sulfate fractionation, affinity chromatography, gel filtration, and isoelectric focusing, and again gel filtration, to homogeneity
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene cd38, eight exons, DNA and amino acid sequence determination and analysis, sequence comparison to the human enzyme, phylogenetic tree, expression in COS-7 cells
recombinant expression of bovine CD38/NAD+ glycohydrolase truncated for the first 31 amino acids that encompass the transmembrane and short intracellular domains in Pichia pastoris. The construct comprises a DNA fragment encoding the ecto-domain in the expression plasmid pPICZaA in frame with the yeast alpha-factor secretion signal sequence under the transcriptional control of the AOX1 promoter and keeping its original stop codon
A heat-stable nicotinamide-adenine dinucleotide glycohydrolase from Pseudomonas putida KB1. Partial purification and some properties of the enzyme and an inhibitory protein
Carbon source regulation of nicotinamide adenine dinucleotide (phosphate) glycohydrolase in Neurospora crassa: induction and repression of enzyme synthesis
Nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate splitting enzyme(s) of sheep and rabbit erythrocytes: their effect on the growth of Haemophilus
Congleton, J.; Jiang, H.; Malavasi, F.; Lin, H.; Yen, A.
ATRA-induced HL-60 myeloid leukemia cell differentiation depends on the CD38 cytosolic tail needed for membrane localization, but CD38 enzymatic activity is unnecessary
Identification of a major enzyme for the synthesis and hydrolysis of cyclic ADP-ribose in amphibian cells and evolutional conservation of the enzyme from human to invertebrate
The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline