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Information on EC 3.2.2.6 - ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase and Organism(s) Homo sapiens
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3.2.2.6 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolaseIUBMB Comments
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.
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Word Map
- 3.2.2.6
-
cadpr
-
ryanodine
- aplysia
- inositol
-
naadp
-
ectoenzyme
-
ca2+-mobilizing
- californica
- gdp-ribose
- nadase
- beta-nad+
-
urchin
- diphosphoribose
-
calcium-mobilizing
-
8-br-cadpr
- oxytocin
-
ca2+-releasing
-
anti-cd38
-
trisphosphate
-
8-bromo-cadpr
-
ca2+-induced
- nad+-glycohydrolase
- ngd+
-
ryanodine-sensitive
-
cd38-deficient
-
cadpr-mediated
-
cadpr-induced
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
adp-ribosyl cyclase, adpr cyclase, nad(p)ase, nad(p)-glycohydrolase, bcd38, adp-ribosyl cyclase/cyclic adp-ribose hydrolase, nad(p)+ glycohydrolase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
CD38
NAD(P) nucleosidase
NAD(P)+ glycohydrolase
-
-
-
-
NAD(P)-glycohydrolase
-
-
-
-
NAD(P)ase
-
-
-
-
nicotinamide adenine dinucleotide (phosphate) glycohydrolase
-
-
-
-
nicotinamide adenine dinucleotide (phosphate) nucleosidase
-
-
-
-
nucleosidase, nicotinamide adenine dinucleotide (phosphate)
-
-
-
-
triphosphopyridine nucleotidase
-
-
-
-
CD38
-
-
-
-
NAD(P) nucleosidase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
NAD+ + H2O = ADP-D-ribose + nicotinamide + H+
also catalyses transfer of ADP-ribose(P) residues
-
NAD+ + H2O = ADP-D-ribose + nicotinamide + H+
reaction mechanism, overview
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of N-glycosyl bond
-
-
-
-
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.
CAS REGISTRY NUMBER
COMMENTARY
9025-46-1
-
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
3-acetylpyridine + adenosine diphosphoribose
3-acetylpyridine adenine dinucleotide + phosphate
-
transglycosylation activity, very poor hydrolytic activity with this substrate
-
-
?
cyclic ADP-ribose + H2O
adenosine diphosphoribose + ?
-
i.e. ADPR activity
-
-
?
NADP+ + H2O
ADP-ribose-P + nicotinamide
-
80% activity compared to the activity with NAD+
-
-
?
nicotinamide 1,N6-ethenoadenine dinucleotide + H2O
?
-
i.e. epsilonNAD+, used for a fluorometric assay
-
-
?
3-pyridinealdehyde hypoxanthine dinucleotide + H2O
?
-
60% activity compared to the activity with NAD+
-
-
?
NAD+ + H2O
ADP-D-ribose + nicotinamide
overall reaction
-
-
?
NAD+ + H2O
ADP-D-ribose + nicotinamide
via a stepwise reaction mechanism
-
-
?
additional information
?
-
-
the formation of an enzyme-ADP-ribosyl intermediary complex is common to all reaction pathways
-
-
?
additional information
?
-
-
enzyme is involved in the regulation of intracellular concentration of adenosine diphosphoribose
-
-
?
additional information
?
-
-
enzyme is multicatalytic, it also catalyzes the synthesis of cyclic ADP-ribose from NAD+ and the hydrolysis to adenosine diphosphoribose
-
-
?
additional information
?
-
-
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)
-
-
?
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
additional information
?
-
-
enzyme is involved in the regulation of intracellular concentration of adenosine diphosphoribose
-
-
?
NAD+ + H2O
ADP-D-ribose + nicotinamide
overall reaction
-
-
?
NAD+ + H2O
ADP-D-ribose + nicotinamide
via a stepwise reaction mechanism
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ag+
Ag+
-
50% inhibition of NADase and 300% activation of adenosine diphosphate cyclase
Ag+
-
at 2 mM 50% inhibition of NADase activity and 300% activation of ADPR activity
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-[2-azido-2-deoxy-5-O-phosphono-D-threo-pentofuranosyl]-3-carbamoylpyridinium
inhibition of the NADase activity
1-[5-O-[(benzyloxy)(hydroxy)phosphoryl]-2-deoxy-2-fluoro-L-erythro-pentofuranosyl]-3-carbamoylpyridinium
inhibition of the NADase activity
1-[5-O-[butoxy(hydroxy)phosphoryl]-2-deoxy-2-fluoro-D-threo-pentofuranosyl]-3-carbamoylpyridinium
inhibition of the NADase activity
3-carbamoyl-1-[2-chloro-2-deoxy-5-O-phosphono-D-threo-pentofuranosyl]pyridinium
inhibition of the NADase activity
3-carbamoyl-1-[2-deoxy-2-fluoro-5-O-phosphono-D-threo-pentofuranosyl]pyridinium
inhibition of the NADase activity
3-carbamoyl-1-[2-deoxy-2-fluoro-5-O-phosphono-L-threo-pentofuranosyl]pyridinium
inhibition of the NADase activity
3-carbamoyl-1-[2-deoxy-2-fluoro-5-O-thiophosphono-L-erythro-pentofuranosyl]pyridinium
inhibition of the NADase activity
3-carbamoyl-1-[2-deoxy-2-fluoro-5-O-[(hexyloxy)(hydroxy)phosphoryl]-D-threo-pentofuranosyl]pyridinium
inhibition of the NADase activity
3-carbamoyl-1-[2-deoxy-2-fluoro-5-O-[hydroxy(2-phenylethoxy)phosphoryl]-L-erythro-pentofuranosyl]pyridinium
inhibition of the NADase activity
3-carbamoyl-1-[2-deoxy-2-fluoro-D-threo-pentofuranosyl]pyridinium
inhibition of the NADase activity
3-carbamoyl-1-[2-deoxy-5-O-(diethoxyphosphoryl)-2-fluoro-D-threo-pentofuranosyl]pyridinium
inhibition of the NADase activity
3-carbamoyl-1-[2-deoxy-5-O-[(ethenyloxy)(propoxy)phosphoryl]-2-fluoro-D-threo-pentofuranosyl]pyridinium
inhibition of the NADase activity
3-carbamoyl-1-[3-deoxy-3-fluoro-5-O-phosphono-L-threo-pentofuranosyl]pyridinium
inhibition of the NADase activity
Ag+
-
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
arabinosyl 2'-fluoro-2'-deoxy-NAD
-
suicide substrate that inhibits CD38 ectoenzyme activity
arabinosyl-2'-fluoro-2'-deoxynicotinamide mononucleotide
inhibition of the NADase activity
Hg2+
-
complete inhibition at 2 mM; inhibition of NADase and adenosine diphosphate cyclase
Pb2+
-
complete inhibition at 2 mM; inhibition of NADase and adenosine diphosphate cyclase
Sn2+
-
complete inhibition at 2 mM; inhibition of NADase and adenosine diphosphate cyclase
additional information
-
not inhibited by rac-taxifolin, rac-catechin, piceatannol, and trans-resveratrol
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0321
5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromenium
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0218
cyanidin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0146
delphinidin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0703
fisetinidin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0063
kuromanin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0082
luteolin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.006
luteolinidin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.017
malvidin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0248
myricetin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0163
pelargonidin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0209
peonidin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0392
petunidin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0486
quercetagetin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0142
quercetagetinidin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0379
quercetin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
0.0379
robinetin
Homo sapiens
-
at 37°C in 10 mM potassium phosphate buffer, pH 7.4, containing 0.05% (w/v) emulphogene
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
activity is 4times higher in Burkitt's lymphoma-derived cell lines than in nonmalignant control lines
the enzymeis induced by retinoic acid, no activity in untreated cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
CD38 is predominately on the plasma membrane of Raji and retinoic acid-treated HL-60 cells
-
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
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
ablation of the CD38 gene in mice causes multiple physiological defects, including impaired oxytocin release, that result in altered social behavior
physiological function
additional information
physiological function
-
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
physiological function
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+
physiological function
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
physiological function
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
additional information
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
additional information
structure-function relationship anaysis, overview. Covalent intermediates are formed with the catalytic residue, Glu226
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). IL18R_HUMAN
541
1
62304
Swiss-Prot
Secretory Pathway (Reliability: 2)
CD38_HUMAN
300
1
34328
Swiss-Prot
other Location (Reliability: 5)
I18RA_HUMAN
599
1
68310
Swiss-Prot
Secretory Pathway (Reliability: 3)
IL1AP_HUMAN
570
1
65418
Swiss-Prot
Secretory Pathway (Reliability: 1)
SARM1_HUMAN
724
0
79388
Swiss-Prot
Secretory Pathway (Reliability: 4)
BST1_HUMAN
318
1
35724
Swiss-Prot
Secretory Pathway (Reliability: 1)
ILRL1_HUMAN
556
1
63358
Swiss-Prot
Secretory Pathway (Reliability: 1)
ILRL2_HUMAN
575
1
65405
Swiss-Prot
Secretory Pathway (Reliability: 1)
IL1R1_HUMAN
569
1
65402
Swiss-Prot
Secretory Pathway (Reliability: 1)
IRPL1_HUMAN
696
1
79969
Swiss-Prot
Secretory Pathway (Reliability: 2)
IRPL2_HUMAN
686
1
78670
Swiss-Prot
Secretory Pathway (Reliability: 1)
B4DMR7_HUMAN
94
0
10759
TrEMBL
other Location (Reliability: 4)
A0A386NEX7_HUMAN
333
1
37496
TrEMBL
Secretory Pathway (Reliability: 1)
Q05B42_HUMAN
617
0
67941
TrEMBL
other Location (Reliability: 2)
B2R880_HUMAN
300
1
34313
TrEMBL
other Location (Reliability: 5)
A6NC48_HUMAN
333
1
37482
TrEMBL
Secretory Pathway (Reliability: 1)
H0Y984_HUMAN
186
0
21083
TrEMBL
other Location (Reliability: 3)
H0Y9Q9_HUMAN
97
0
11098
TrEMBL
other Location (Reliability: 1)
B4E006_HUMAN
160
1
17929
TrEMBL
Secretory Pathway (Reliability: 5)
Q0D2N8_HUMAN
710
0
77782
TrEMBL
other Location (Reliability: 4)
H0Y950_HUMAN
151
0
17417
TrEMBL
other Location (Reliability: 5)
H0Y8G4_HUMAN
155
0
17563
TrEMBL
other Location (Reliability: 1)
TLR1_HUMAN
786
0
90291
Swiss-Prot
other Location (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
native enzyme shows high molecular weight and elutes in the void volumes from a Superose 12 gel filtration column
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E226D
E226Q
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
SDS, even at micromolar concentration, leads to complete inactivation of the enzyme
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
4°C to -196°C, 10 mM Tris-HCl, pH 8.0, 0.1% Triton X-100, at least 1 month, stable
-
4°C, -20°C, -80°C or -196°C, pH 8.0, 0.1% Triton X-100, 10 mM Tris-HCl, stable for at least 1 month
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
native enzyme 480fold from serum by ammonium sulfate fractionation, affinity chromatography, gel filtration, and isoelectric focusing, and again gel filtration, to homogeneity
partially from spleen microsomal membranes after solubilization with Triton X-100, chromatography methods, 133fold
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
no induction of CD38 mRNA by senescence itself. Cytokines and chemokines expressed by senescent cells induce CD38 expression in macrophages
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
80% renaturation of urea and SDS denatured enzyme by treatment with Triton X-100 in a 20:1 v/w ratio with SDS
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Skala, H.; Lenoir, G.M.; Pichard, A.L.; Vuillaume, M.; Dreyfus, J.C.
Elevated NAD(P) glycohydrolase activity: a possible enzymatic marker for malignancy in Burkitt's lymphoma cells
Blood
60
912-917
1982
Homo sapiens
Orsomando, G.; Polzonetti, V.; Natalini, P.
NAD(P)+-glycohydrolase from human spleen: a multicatalytic enzyme
Comp. Biochem. Physiol. B
126
89-98
2000
Homo sapiens
Berthelier, V.; Tixier, J.M.; Muller-Steffner, H.; Schuber, F.; Deterre, P.
Human CD38 is an authentic NAD(P)+ glycohydrolase
Biochem. J.
330
1383-1390
1998
Homo sapiens
-
Kellenberger, E.; Kuhn, I.; Schuber, F.; Muller-Steffner, H.
Flavonoids as inhibitors of human CD38
Bioorg. Med. Chem. Lett.
21
3939-3942
2011
Homo sapiens
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
Exp. Cell Res.
317
910-919
2011
Homo sapiens
Jiang, H.; Sherwood, R.; Zhang, S.; Zhu, X.; Liu, Q.; Graeff, R.; Kriksunov, I.A.; Lee, H.C.; Hao, Q.; Lin, H.
Identification of ADP-ribosylation sites of CD38 mutants by precursor ion scanning mass spectrometry
Anal. Biochem.
433
218-226
2013
Homo sapiens (P28907)
Kwong, A.; Chen, Z.; Zhang, H.; Leung, F.; Lam, C.; Ting, K.; Zhang, L.; Hao, Q.; Zhang, L.; Lee, H.
Catalysis-based inhibitors of the calcium signaling function of CD38
Biochemistry
51
555-564
2012
Homo sapiens (P28907), Mus musculus (P56528), Rattus norvegicus
Shrimp, J.H.; Hu, J.; Dong, M.; Wang, B.S.; MacDonald, R.; Jiang, H.; Hao, Q.; Yen, A.; Lin, H.
Revealing CD38 cellular localization using a cell permeable, mechanism-based fluorescent small-molecule probe
J. Am. Chem. Soc.
136
5656-5663
2014
Homo sapiens (P28907)
Coskun, O.; Nurten, R.
Purification of NAD+ glycohydrolase from human serum
Oncol. Lett.
6
227-231
2013
Homo sapiens (P28907)
Chini, C.; Hogan, K.A.; Warner, G.M.; Tarrago, M.G.; Peclat, T.R.; Tchkonia, T.; Kirkland, J.L.; Chini, E.
The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline
Biochem. Biophys. Res. Commun.
513
486-493
2019
Homo sapiens (P28907)
EXTERNAL LINKS (specific for EC-Number 3.2.2.6)
Transporter Classification Database (TCDB): 8.A.23.1.11
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