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

Cakir-Kiefer, Céline; Muller-Steffner, Hélène; Oppenheimer, Norman J.; Schuber, Francis

doi:10.1042/0264-6021:3580399

Cited by 20 publications

(15 citation statements)

References 41 publications

(67 reference statements)

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“…In other words, the conformational change of the side chain relieves the contact between Trp-125 and the substrate from 2.40 to 3.42 Å, a more favorable distance for hydrophobic interaction. The conformational change for Trp-125 during the catalysis is consistent with the reduced intrinsic fluorescence changes upon substrate binding (38).…”

Section: A Proposed Nonproductive Site Along the Cadpr Entrysupporting

confidence: 53%

Catalysis-associated Conformational Changes Revealed by Human CD38 Complexed with a Non-hydrolyzable Substrate Analog

Liu

Kriksunov

Moreau

et al. 2007

Journal of Biological Chemistry

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Cyclic ADP-ribose (cADPR) is a calcium mobilization messenger important for mediating a wide range of physiological functions. The endogenous levels of cADPR in mammalian tissues are primarily controlled by CD38, a multifunctional enzyme capable of both synthesizing and hydrolyzing cADPR. In this study, a novel non-hydrolyzable analog of cADPR, N1-cIDPR (N1-cyclic inosine diphosphate ribose), was utilized to elucidate the structural determinants involved in the hydrolysis of cADPR. N1-cIDPR inhibits CD38-catalyzed cADPR hydrolysis with an IC 50 of 0.26 mM. N1-cIDPR forms a complex with CD38 or its inactive mutant in which the catalytic residue Glu-226 is mutated. Both complexes have been determined by x-ray crystallography at 1.7 and 1.76 Å resolution, respectively. The results show that N1-cIDPR forms two hydrogen bonds (2.61 and 2.64 Å ) with Glu-226, confirming our previously proposed model for cADPR catalysis. Structural analyses reveal that both the enzyme and substrate cADPR undergo catalysis-associated conformational changes. From the enzyme side, residues Glu-146, Asp-147, and Trp-125 work collaboratively to facilitate the formation of the Michaelis complex. From the substrate side, cADPR is found to change its conformation to fit into the active site until it reaches the catalytic residue. The binary CD38-cADPR model described here represents the most detailed description of the CD38-catalyzed hydrolysis of cADPR at atomic resolution. Our structural model should provide insights into the design of effective cADPR analogs. Cyclic ADP-ribose (cADPR)3 is a novel cyclic nucleotide derived from NAD. It is metabolized by a family of proteins called ADP-ribosyl cyclases (1, 2). This cyclic nucleotide features a head-to-tail type of glycosidic linkage (N1-C1Ј) between N1 of its adenine and the anomeric carbon (C1Ј) of the terminal ribose (3, 4). Results obtained in the past decade have established the second messenger role of cADPR in mobilizing calcium stores in various cell types (reviewed in Refs. 5, 6). Its calcium signaling function has since been found to be more versatile and has additionally been shown to modulate calcium influx across the plasma membrane (7, 8) as well as regulate calcium homeostasis within the nucleus (9, 10).Human CD38 is a type II transmembrane glycoprotein containing a small N-terminal tail, a single transmembrane helix, and a large extra-membranous portion that possesses ADPribosyl cyclase activity. As a member of the cyclase family, CD38 not only can synthesize cADPR from NAD but also can hydrolyze NAD and cADPR to produce ADP-ribose (2,(11)(12)(13)(14). At acidic conditions, CD38 can also catalyze the formation and hydrolysis of NAADP, another calcium mobilization messenger (15,16). Although the mechanism of how these various activities of CD38 are regulated inside cells remains to be determined, we have previously identified residue Glu-146 as being critically important for controlling the relative synthesizing and hydrolyzing activities (16,17). The enzymatic portion of human ...

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Section: A Proposed Nonproductive Site Along the Cadpr Entrysupporting

confidence: 53%

Catalysis-associated Conformational Changes Revealed by Human CD38 Complexed with a Non-hydrolyzable Substrate Analog

Liu

Kriksunov

Moreau

et al. 2007

Journal of Biological Chemistry

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“…Another important characteristic of both analogues is their stability toward hydrolysis. 2′′-NH 2 -cADPR displays an at least 100-fold slower hydrolysis as compared to cADPR (23). cADPcR was stable to enzymic hydrolysis by the hydrolase in rat brain microsomes and by pure extracellular domain of CD38 (34).…”

Section: Discussionmentioning

confidence: 97%

“…2′′-NH 2 -cADPR and 2′′-NH 2 -ADPR ( Figure 1) were obtained from 2′′-NH 2 -NAD + using A. californica ADP-ribosyl cyclase and bovine spleen NAD + glycohydrolase, respectively, as described previously (23). MS: m/z (negative ion ES-MS) 539.2 (M -H) -and 557.2 (M -H) -, respectively, for 2′′-NH 2 -cADPR and 2′′-NH 2 -ADPR; m/z (positive mode) 563.5 (M + Na) + for 2′′-NH 2 -cADPR.…”

Section: Methodsmentioning

confidence: 99%

Novel Hydrolysis-Resistant Analogues of Cyclic ADP-ribose: Modification of the “Northern” Ribose and Calcium Release Activity

et al. 2002

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Three novel analogues modified in the "northern" ribose (ribose linked to N1 of adenine) of the Ca(2+) mobilizing second messenger cyclic adenosine diphosphoribose, termed 2"-NH(2)-cyclic adenosine diphosphoribose, cyclic adenosine diphospho-carbocyclic-ribose, and 8-NH(2)-cyclic adenosine diphospho-carbocyclic-ribose, were synthesized (chemoenzymatically and by total synthesis) and spectroscopically characterized, and the pK(a) values for the 6-amino/imino transition were determined in two cases. The biological activity of these analogues was determined in permeabilized human Jurkat T-lymphocytes. 2"-NH(2)-cyclic adenosine diphosphoribose mediated Ca(2+) release was slightly more potent than that of the endogenous cyclic adenosine diphosphoribose in terms of the concentration-reponse relationship. Both compounds released Ca(2+) from the same intracellular Ca(2+) pool. In addition, the control compound 2"-NH(2)-adenosine diphosphoribose was almost without effect. In contrast, only at much higher concentrations (> or =50 microM) did the "northern" carbocyclic analogue, cyclic adenosine diphospho-carbocyclic-ribose, significantly release Ca(2+) from permeabilized T cells, whereas the previously reported "southern" carbocyclic analogue, cyclic aristeromycin diphosphoribose, was slightly more active than the endogenous cyclic adenosine diphosphoribose. Likewise, 8-NH(2)-cyclic adenosine diphospho-carbocyclic-ribose, expected to antagonize Ca(2+) release as demonstrated previously for 8-NH(2)-cyclic adenosine diphosphoribose, did not inhibit cyclic adenosine diphosphoribose mediated Ca(2+) release. This indicates that the 2"-NH(2)-group substitutes well for the 2"-OH-group it replaces; it may be oriented toward the outside of the putative cyclic adenosine diphosphoribose receptor binding domain and/or it can potentially also engage in H bonding interactions with residues of that domain. In sharp contrast to this, replacement of the endocyclic furanose oxygen atom by CH(2) in a carbocyclic system obviously interferes with a crucial element of interaction between cyclic adenosine diphosphoribose and its receptor in T-lymphocytes.

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“…As happened with the PARPs, CD38 displays a K m for NAD ϩ in the low micromolar range (153), indicating that, a priori, intracellular NAD ϩ levels may not be limiting its catalytic activity. The stoichiometry of the reaction catalyzed by CD38, however, involves a massive amount of NAD ϩ , around 100 molecules, to yield a single cADPribose (154).…”

Section: A Cd38 As a Regulator Of Nad ؉ Availabilitymentioning

confidence: 97%

The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways

et al. 2010

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A century after the identification of a coenzymatic activity for NAD(+), NAD(+) metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD(+) have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD(+)-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects, NAD(+) provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD(+)-dependent pathways may have a major contribution to oxidative metabolism and life span extension. In this review, we will provide an integrated view on: 1) the pathways that control NAD(+) production and cycling, as well as its cellular compartmentalization; 2) the signaling and transcriptional pathways controlled by NAD(+); and 3) novel data that show how modulation of NAD(+)-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.

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

Cited by 20 publications

References 41 publications

Catalysis-associated Conformational Changes Revealed by Human CD38 Complexed with a Non-hydrolyzable Substrate Analog

Catalysis-associated Conformational Changes Revealed by Human CD38 Complexed with a Non-hydrolyzable Substrate Analog

Novel Hydrolysis-Resistant Analogues of Cyclic ADP-ribose: Modification of the “Northern” Ribose and Calcium Release Activity

The Secret Life of NAD+: An Old Metabolite Controlling New Metabolic Signaling Pathways

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