Mechanistic Implications of Cyclic ADP-Ribose Hydrolysis and Methanolysis Catalyzed by Calf Spleen NAD+Glycohydrolase

Muller-Steffner, Hélène; Muzard, Murielle; Oppenheimer, Norman J.; Schuber, Francis

doi:10.1006/bbrc.1994.2601

Cited by 24 publications

(21 citation statements)

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“…The involvement of an enzyme-ADP-ribose intermediate in the catalytic mechanism of monofunctional ADP-ribosyl cyclase, bifunctional cyclases/hydrolases, or NAD ϩ glycohydrolases has been suggested by several lines of evidence including: (i) methanolysis of NAD ϩ (29,30,44), (ii) base-exchange reaction between nicotinamide and nicotinic acid (31), (iii) NAD ϩ synthesis from cADPR and nicotinamide (17), and (iv) the conformation of the N 1 -glycosyl linkage of cADPR being in the ␤ configuration in both its crystal form (45) and in aqueous solution (37,46). The data reported in this paper are also consonant with this mechanism because the dimeric structure of (ADPR) 2 implies the transfer of an enzyme-activated ADPribosyl moiety to a pre-existing ADPR molecule behaving as an acceptor substrate.…”

Section: Discussionmentioning

confidence: 99%

CD38 and ADP-ribosyl Cyclase Catalyze the Synthesis of a Dimeric ADP-ribose That Potentiates the Calcium-mobilizing Activity of Cyclic ADP-ribose

Flora

Guida

Franco

et al. 1997

Journal of Biological Chemistry

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CD38, a lymphocyte differentiation antigen, is also a bifunctional enzyme catalyzing the synthesis of cyclic ADP-ribose (cADPR) from NAD ؉ and its hydrolysis to ADP-ribose (ADPR). An additional enzymatic activity of CD38 shared by monofunctional ADP-ribosyl cyclase from Aplysia californica is the exchange of the base group of NAD ؉ (nicotinamide) with various nucleophiles. Both human CD38 (either recombinant or purified from erythrocyte membranes) and Aplysia cyclase were found to catalyze the exchange of ADPR with the nicotinamide group of NAD ؉ leading to the formation of a dimeric ADPR ((ADPR) 2 ). The dimeric structure of the enzymatic product, which was generated by recombinant CD38 and by CD38 ؉ Namalwa cells from as low as 10 M NAD ؉ , was demonstrated using specific enzyme treatments (dinucleotide pyrophosphatase and 5-nucleotidase) and mass spectrometry analyses of the resulting products. The linkage between the two ADPR units of (ADPR) 2 was identified as that between the N 1 of the adenine nucleus of one ADPR unit and the anomeric carbon of the terminal ribose of the second ADPR molecule by enzymatic analyses and by comparison with patterns of cADPR cleavage with Me 2 SO:tert-butoxide. Although (ADPR) 2 itself did not release Ca 2؉ from sea urchin egg microsomal vesicles, it specifically potentiated the Ca 2؉ -releasing activity of subthreshold concentrations of cADPR. Therefore, (ADPR) 2 is a new product of CD38 that amplifies the Ca 2؉

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Section: Discussionmentioning

confidence: 99%

CD38 and ADP-ribosyl Cyclase Catalyze the Synthesis of a Dimeric ADP-ribose That Potentiates the Calcium-mobilizing Activity of Cyclic ADP-ribose

Flora

Guida

Franco

et al. 1997

Journal of Biological Chemistry

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“…Chromatographic analysis of the reaction products of purified recombinant SPN did not reveal any evidence for the formation of cADPR (data not shown). However, ADPribosyl cyclases can also hydrolyze cADPR (32,39), thus lowering the yield of cADPR. ADPR was not detected following incubation of cADPR with either SPN or the E391Q mutant even after 6 h of incubation (Fig.…”

Section: Spn Is Deficient In Both Cadprmentioning

confidence: 99%

Characterization of Streptococcus pyogenes β-NAD+ Glycohydrolase

Ghosh

Anderson

Chandrasekaran

et al. 2010

Journal of Biological Chemistry

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The Gram-positive pathogen Streptococcus pyogenes injects a ␤-NAD ؉ glycohydrolase (SPN) into the cytosol of an infected host cell using the cytolysin-mediated translocation pathway. In this compartment, SPN accelerates the death of the host cell by an unknown mechanism that may involve its ␤-NAD ؉ -dependent enzyme activities. SPN has been reported to possess the unique characteristic of not only catalyzing hydrolysis of ␤-NAD ؉ , but also carrying out ADP-ribosyl cyclase and ADP- The enzymes that cleave the nicotinamide-ribosyl bond of ␤-NAD ϩ to produce numerous small molecules are able to modulate various aspects of cellular function, including signal transduction, vascular activity, gene expression, calcium homeostasis, and cell death (reviewed in Refs. 1, 2). All of these enzymes hydrolyze ␤-NAD ϩ to produce nicotinamide and adenosine diphosphoribose (ADPR) 3 (see Fig. 1 and Table 2). Interestingly, most enzymes within this class are multifunctional and can be further classified on the basis of the additional reactions that they can catalyze following the release of nicotinamide (see Fig. 1 and Table 2). The ADP-ribosyl cyclases (EC 3.2.2.6) convert enzyme-bound ADPR to cyclic ADPR (cADPR) (reviewed in Refs. Only the strict ␤-NAD ϩ glycohydrolases (EC 3.2.2.5) are not capable of further catalysis of the products of the initial reaction, and, as a general rule, the cyclases and transferases do not catalyze each other's reactions (Fig. 1).An exception to the above rule, the Streptococcus pyogenes ␤-NAD ϩ glycohydrolase (SPN, also known as Nga) is the only enzyme reported to possess all three activities (6 -9). These activities can contribute to S. pyogenes virulence as, after SPN is exported, the enzyme is injected across the host cell membrane into the cytosol by a process called cytolysin-mediated translocation (10, 11). Once in the cytosol, SPN likely contributes to the pathogenesis of the numerous different diseases that S. pyogenes can cause, including pharyngitis, impetigo, necrotizing faciitis rheumatic fever, or acute glomerulonephritis (12). The contribution of SPN to pathogenesis has been demonstrated in several model systems. For example, mutants of S. pyogenes engineered to lack SPN were avirulent in animal models of streptococcal infection (13), and cytosolic SPN was highly cytotoxic to yeast and to cultured epithelial cells (10,11,14). However, the mechanism for pathogenesis by SPN remains unknown. Given the number and diversity of the different diseases that S. pyogenes can cause, an understanding of the contribution of SPN to pathogenesis of any streptococcal disease requires a detailed characterization of its kinetic and catalytic properties.Until recently, characterization of the kinetic properties of SPN has been hindered due to difficulties in expression of recombinant SPN owing to its toxicity. Toxicity is so severe that expression plasmids containing the gene for SPN cannot be * This work was supported, in whole or in part, by National Institutes of Health Grant AI064721 (to M. G. C.)...

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“…This latter condition is important because it takes into account the fact that ADP-ribose is overwhelmingly the major product of the pathway catalysed by CD38. No transient accumulation of cADPR was measurable during the entire reaction course, up to a complete transformation of NAD + (see, for example, [24]). Situations where the dissociation of one of the reaction products is rate limiting have been well documented in enzymology.…”

Section: Commitment To Catalysis Of the Cd38-cadpr Complexmentioning

confidence: 99%

“…This was not possible in the present study because of the binding constant of cADPR (see below), the efficiency of its hydrolysis and the high quantities of enzyme needed. One must therefore rely on extrapolations using the kinetic parameters we have determined previously [24] for the NAD + glycohydrolase-catalysed hydrolysis of cADPR : K m l 2n15 mM and k cat l 106 s −" . These data indicate a fairly weak binding of the cyclic metabolite to the enzyme in comparison with that of NAD + (K m l 26 µM).…”

Section: Commitment To Catalysis Of the Cd38-cadpr Complexmentioning

confidence: 99%

Kinetic competence of the cADP-ribose‒CD38 complex as an intermediate in the CD38/NAD+ glycohydrolase-catalysed reactions: implication for CD38 signalling

et al. 2001

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Mechanistic Implications of Cyclic ADP-Ribose Hydrolysis and Methanolysis Catalyzed by Calf Spleen NAD+Glycohydrolase

Cited by 24 publications

References 0 publications

CD38 and ADP-ribosyl Cyclase Catalyze the Synthesis of a Dimeric ADP-ribose That Potentiates the Calcium-mobilizing Activity of Cyclic ADP-ribose

CD38 and ADP-ribosyl Cyclase Catalyze the Synthesis of a Dimeric ADP-ribose That Potentiates the Calcium-mobilizing Activity of Cyclic ADP-ribose

Characterization of Streptococcus pyogenes β-NAD+ Glycohydrolase

Kinetic competence of the cADP-ribose‒CD38 complex as an intermediate in the CD38/NAD+ glycohydrolase-catalysed reactions: implication for CD38 signalling

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