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Information on EC 3.2.2.5 - NAD+ glycohydrolase and Organism(s) Homo sapiens and UniProt Accession P28907
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3.2.2.5 NAD+ glycohydrolaseIUBMB Comments
This enzyme catalyses the hydrolysis of NAD+, without associated ADP-ribosyl cyclase activity (unlike the metazoan enzyme EC 3.2.2.6, bifunctional ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase). The enzyme from Group A streptococci has been implicated in the pathogenesis of diseases such as streptococcal toxic shock-like syndrome (STSS) and necrotizing fasciitis. The enzyme from the venom of the snake Agkistrodon acutus also catalyses EC 3.6.1.5, apyrase .
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Word Map
- 3.2.2.5
-
adp-ribosylation
- adp-ribosyltransferase
- streptococcal
- pertussis
-
streptolysin
-
ectoenzyme
- aplysia
- diphtheria
-
ribosylation
-
exotoxin
- glycosylphosphatidylinositol
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isonicotinic
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glycosylphosphatidylinositol-anchored
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gpi-anchored
- cadp-ribose
- cyclases
- hemoglobinuria
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auto-adp-ribosylation
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calcium-mobilizing
- diphosphoribose
-
anti-cd38
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gpi-linked
- nmn
-
bungarus
- medicine
- fasciatus
-
nad-binding
- analysis
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holotoxins
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
nadase, cd157, nad glycohydrolase, nad-glycohydrolase, nad+ glycohydrolase, cadpr hydrolase, nad+-glycohydrolase, aa-nadase, smnace, nicotinamide adenine dinucleotide glycohydrolase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Acute lymphoblastic leukemia cells antigen CD38
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ADRC
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Antigen BP3
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-
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BP-3 alloantigen
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cADPr hydrolase
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CD157 antigen
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CD38 homolog
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CD38H
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Cyclic ADP-ribose hydrolase
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-
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diphosphopyridine nucleosidase
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-
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diphosphopyridine nucleotidase
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DPN hydrolase
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DPNase
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I-19
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Lymphocyte differentiation antigen CD38
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NAD glycohydrolase
NAD hydrolase
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NAD nucleosidase
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NAD(+) nucleosidase
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NADase
nicotinamide adenine dinucleotide glycohydrolase
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nicotinamide adenine dinucleotide nucleosidase
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NIM-R5 antigen
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T10
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NAD glycohydrolase
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NADase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
NAD+ + H2O = ADP-D-ribose + nicotinamide
residues E146, D147, and W125 work collaboratively to facilitate the formation of the Michaelis complex
NAD+ + H2O = ADP-D-ribose + nicotinamide
reaction mechanism, and structure-function relationship, overview
NAD+ + H2O = ADP-D-ribose + nicotinamide
the enzyme can also hydrolyse NADP+ to yield phospho-ADP-ribose and nicotinamide, but more slowly
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NAD+ + H2O = ADP-D-ribose + nicotinamide
the polar interactions between E226 and the substrate 2',3'-OH groups are essential for initiating catalysis. S193 has a regulatory role during catalysis and is likely to be involved in intermediate stabilization
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of N-glycosyl bond
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SYSTEMATIC NAME
IUBMB Comments
NAD+ glycohydrolase
This enzyme catalyses the hydrolysis of NAD+, without associated ADP-ribosyl cyclase activity (unlike the metazoan enzyme EC 3.2.2.6, bifunctional ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase). The enzyme from Group A streptococci has been implicated in the pathogenesis of diseases such as streptococcal toxic shock-like syndrome (STSS) and necrotizing fasciitis. The enzyme from the venom of the snake Agkistrodon acutus also catalyses EC 3.6.1.5, apyrase [3].
CAS REGISTRY NUMBER
COMMENTARY
9032-65-9
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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
NAD+ + H2O
ADP-ribose + nicotinamide
substrate binding structure, overview. Catalytically important CD38 residue Thr221 disfavors the cyclizing folding of the substrate, resulting in NADase being the dominant activity
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-
?
NAD+ + H2O
ADP-ribose + nicotinamide
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purified bifunctional enzyme has a ADP-ribosyl cyclase/NAD glycohydrolase ratio of 1/120. In situ cyclase/NAD glycohydrolase ratio measured in seminal plasma is 1/1. Physiological concentrations of zinc present in the seminal fluid, in the range of 0.6 to 4 mM, are responsible for the modulation of the cyclase/NAD glycohydrolase ratio
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?
additional information
?
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bifunctional enzyme ADP-ribose cyclase/NAD glycohydrolase, enzyme activities are regulated by zinc, enzyme is capable of both synthesis and hydrolysis of cADP-ribose
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?
additional information
?
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bifunctional enzyme ADP-ribose cyclase/NAD glycohydrolase, enzyme is capable of both synthesis and hydrolysis of cADP-ribose
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?
additional information
?
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enzyme plays a crucial role in neutrophil diapedesis. Its ligation with specific monoclonal antibodies both on neutrophils or endothelial cells results in altered neutrophil movement on the apical surface of endothelium and, ultimately, in loss of diapedesis. Following CD157 ligation, neutrophils appear disoriented, meandering toward junctions where they eventually stop without transmigrating
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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
NAD+ + H2O
ADP-ribose + nicotinamide
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purified bifunctional enzyme has a ADP-ribosyl cyclase/NAD glycohydrolase ratio of 1/120. In situ cyclase/NAD glycohydrolase ratio measured in seminal plasma is 1/1. Physiological concentrations of zinc present in the seminal fluid, in the range of 0.6 to 4 mM, are responsible for the modulation of the cyclase/NAD glycohydrolase ratio
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?
additional information
?
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bifunctional enzyme ADP-ribose cyclase/NAD glycohydrolase, enzyme activities are regulated by zinc, enzyme is capable of both synthesis and hydrolysis of cADP-ribose
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-
?
additional information
?
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enzyme plays a crucial role in neutrophil diapedesis. Its ligation with specific monoclonal antibodies both on neutrophils or endothelial cells results in altered neutrophil movement on the apical surface of endothelium and, ultimately, in loss of diapedesis. Following CD157 ligation, neutrophils appear disoriented, meandering toward junctions where they eventually stop without transmigrating
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?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zinc
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purified bifunctional enzyme has a ADP-ribosyl cyclase/NAD glycohydrolase ratio of 1/120. In situ cyclase/NAD glycohydrolase ratio measured in seminal plasma is 1/1. Physiological concentrations of zinc present in the seminal fluid, in the range of 0.6 to 4 mM, are responsible for the modulation of the cyclase/NAD glycohydrolase ratio
Zn2+
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stimulates the cyclase activity, inhibits the NAD glycohydrolase activity, zinc has a regulatory function at physiological concentrations of 0.6-4 mM, responsible for modulation of the ADP-ribose cyclase/NAD glycohydrolase activity ratio of the bifunctional enzyme in zinc-rich seminal plasma to 1:3 in situ, with the purified enzyme in absence of zinc the ratio is 1:110-120, in presence of Zn2+ it is 1:2-3, mechanism
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ADP-(2-deoxy-2-fluoro-D-arabinose)
the NAD analogue forms a covalent adduct after nicotinamide cleavage, resulting in inhibition of the enzyme activity, binding structure, overview
ADP-(2-deoxy-2-fluoro-D-ribose)
the NAD analogue forms a covalent adduct after nicotinamide cleavage, resulting in inhibition of the enzyme activity, binding structure, overview
beta-NAD+
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substrate inhibition, mediated by ADP-ribosylation, partially reversible by arginine or histidine, inhibits apoptosis in vivo
GT1b
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exogenous ganglioside, inhibition in vivo, needs to be incorporated into the cell to inhibit CD38, preferably cis interaction, i.e. CD38 and GT1b are located on the same cell, the tandem sialic acid residues linked to the internal galactose of the gangliotetraose core are crucial to the inhibition
Zn2+
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stimulates the cyclase activity, inhibits the NAD glycohydrolase activity, zinc has a regulatory function at physiological concentrations of 0.6-4 mM, responsible for modulation of the ADP-ribose cyclase/NAD glycohydrolase activity ratio of the bifunctional enzyme in zinc-rich seminal plasma to 1:3 in situ, with the purified enzyme in absence of zinc the ratio is 1:110-120, in presence of Zn2+ it is 1:2-3, mechanism
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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enzyme level and ADP-ribosylation is significantly higher in patients and are correlated with tumour stage
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high enzyme levels in serum are associated with a poor prognosis in patients with colorectal cancer
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erythrocytes from cancer patients exhibit up to fivefold higher NAD+ glycohydrolase activities than control erythrocytes from normal subjects
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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transmembrane protein with a catalytically active extracellular domain
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
CD38 has multiple activities, i.e. in cyclic ADP-ribose, cADPR, production and degradation, as well as NAD hydrolysis as NADase
physiological function
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high enzyme levels in serum are associated with a poor prognosis in patients with colorectal cancer
additional information
additional information
structural determinants for the functional evolution from a cyclase to a hydrolase, overview
additional information
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structural determinants for the functional evolution from a cyclase to a hydrolase, overview
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). CD38_HUMAN
300
1
34328
Swiss-Prot
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
upon stimulation with interleukin IL-8, CD38 associates with nonmuscle myosin heavy chain IIA. Association is dependent on protein kinase G-mediated phosphorylation of nonmuscle myosin heavy chain IIA and occurs through tyrosine kinase Lck
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CD38 in complex with ribosyl-2'-fluoro-deoxy-adenosine diphosphate or arabinosyl-2'-fluoro-deoxy-adenosine diphosphate ribose, soaking crystals in a solution containing either 5.2 mM inhibitor, and 100 mM MES, pH 6.0, 15% PEG 4000, and 30% glycerol, X-ray diffraction structure determination and analysis at 1.75-2.0 A resolution
wild-type and mutant E226Q in complex with inhibitor N1-cyclic inosine diphosphate ribose at 1.7 and 1.176 A resolution, respectively
wild-type and mutant E226Q in complex with cyclic ADP-ribose at 1.5 A resolution, with cyclic GDP-ribose at 1.68 A, and with NGD+ at 2.1A. Binding of cyclic ADP-ribose or cyclic GDP-ribose induce structural changes in the dipeptide E146D147 of 2.7 A. Resiudue E226 is critical in catalysis and in positioning of cyclic ADP-ribose
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wild-type and mutant E226Q in complex with NAD+, NGD+, or GDP-ribose. The reaction intermediate is stabilized by polar interactions with the catalytic residue E226 rather than by a covalent linkage
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
partially, solubilization from the membrane fraction, best with CHAPS or Triton X-100
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
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CD157-deficient neutrophils from patients with paroxysmal nocturnal hemoglobinuria are characterized by a severely impaired diapedesis
medicine
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treatment of lymphokine-activated killer cells with interleukin IL-8 results in internalization of CD38, which co-localizes with nonmuscle myosin heavy chain IIA and tyrosine kinase Lck. Blebbistatin blocks the internalization
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Wall, K.A.; Klis, M.; Kornet, J.; Coyle, D.; Ame, J.C.; Jacobson, M.K.; Slama, J.T.
Inhibition of the intrinsic NAD+ glycohydrolase activity of CD38 by carbocyclic NAD analougues
Biochem. J.
335
631-636
1998
Canis lupus familiaris, Homo sapiens, Mus musculus
-
Hara-Yokoyama, M.; Kukimoto, I.; Nishina, H.; Kontani, K.; Hirabayashi, Y.; Irie, F.; Sugiya, H.; Furuyama, S.; Katada, T.
Inhibition of NAD+ glycohydrolase and ADP-ribosyl cyclase activities of leukocyte cell surface antigen CD38 by gangliosides
J. Biol. Chem.
271
12951-12955
1996
Homo sapiens
Zocchi, E.; Franco, L.; Guida, L.; Benatti, U.; Bargellesi, A.; Malavasi, F.; Lee, H.C.; de Flora, A.
A single protein immunologically identified as CD38 displays NAD+ glycohydrolase, ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities at the outer surface of human erythrocytes
Biochem. Biophys. Res. Commun.
196
1459-1465
1993
Homo sapiens
Hara-Yokoyama, M.; Nagatsuka, Y.; Katsumata, O.; Irie, F.; Kontani, K.; Hoshino, S.; Katada, T.; Ono, Y.; Fujita-Yoshigaki, J.; Sugiya, H.; Furuyama, S.; Hirabayashi, Y.
Complex gangliosides as cell surface inhibitors for the ecto-NAD+ glycohydrolase of CD38
Biochemistry
40
888-895
2001
Homo sapiens
Zielinska, W.; Barata, H.; Chini, E.N.
Metabolism of cyclic ADP-ribose: Zinc is an endogenous modulator of the cyclase/NAD glycohydrolase ratio of a CD38-like enzyme from human seminal fluid
Life Sci.
74
1781-1790
2004
Homo sapiens
Balducci, E.; Micossi, L.G.
NAD-dependent inhibition of the NAD-glycohydrolase activity in A549 cells
Mol. Cell. Biochem.
233
127-132
2002
Homo sapiens
Albeniz, I.; Demir, O.; Nurten, R.; Bermek, E.
NAD glycohydrolase activities and ADP-ribose uptake in erythrocytes from normal subjects and cancer patients
Biosci. Rep.
24
41-53
2004
Homo sapiens
Ortolan, E.; Tibaldi, E.V.; Ferranti, B.; Lavagno, L.; Garbarino, G.; Notaro, R.; Luzzatto, L.; Malavasi, F.; Funaro, A.
CD157 plays a pivotal role in neutrophil transendothelial migration
Blood
108
4214-4222
2006
Homo sapiens
Liu, Q.; Kriksunov, I.A.; Graeff, R.; Munshi, C.; Lee, H.C.; Hao, Q.
Structural basis for the mechanistic understanding of human CD38-controlled multiple catalysis
J. Biol. Chem.
281
32861-32869
2006
Homo sapiens
Liu, Q.; Kriksunov, I.A.; Moreau, C.; Graeff, R.; Potter, B.V.; Lee, H.C.; Hao, Q.
Catalysis-associated conformational changes revealed by human CD38 complexed with a non-hydrolyzable substrate analog
J. Biol. Chem.
282
24825-24832
2007
Homo sapiens (P28907)
Rah, S.Y.; Park, K.H.; Nam, T.S.; Kim, S.J.; Kim, H.; Im, M.J.; Kim, U.H.
Association of CD38 with nonmuscle myosin heavy chain IIA and Lck is essential for the internalization and activation of CD38
J. Biol. Chem.
282
5653-5660
2007
Homo sapiens
Liu, Q.; Graeff, R.; Kriksunov, I.A.; Jiang, H.; Zhang, B.; Oppenheimer, N.; Lin, H.; Potter, B.V.; Lee, H.C.; Hao, Q.
Structural basis for enzymatic evolution from a dedicated ADP-ribosyl cyclase to a multifunctional NAD hydrolase
J. Biol. Chem.
284
27637-27645
2009
Aplysia californica, Homo sapiens (P28907), Homo sapiens
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