Cellular effects and metabolic stability of <i>N</i>1‐cyclic inosine diphosphoribose and its derivatives

Kirchberger, Tanja; Wagner, Gerd K.; Xu, Jianfeng; Cordiglieri, Chiara; Wang, P.; Gasser, Andreas; Fliegert, Ralf; Bruhn, Sören; Flügel, Andreas; Lund, Fren; Zhang, Lee; Potter, Barry V. L.; Guse, Andreas H.

doi:10.1038/sj.bjp.0706869

Cited by 16 publications

(18 citation statements)

References 44 publications

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“…However, the latter seems unlikely, as incubation of 8-bromo N 1-cIDPR with CD38 revealed no change in the nucleotide profile when analyzed by HPLC after 18 h (data not shown). Similar stability was observed by Kirchberger et al when studying the metabolic stability of N 1-cIDPR derivatives [45]. Despite this, we note vide infra that 8-bromo N 1-cIDPR does bind with an IC 50 actually better than N 1-cIDPR, but that the diaminobutane derivative binds very poorly.…”

Section: Resultssupporting

confidence: 87%

CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5′-Diphosphate Ribose Template

et al. 2013

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Few inhibitors exist for CD38, a multifunctional enzyme catalyzing the formation and metabolism of the Ca2+-mobilizing second messenger cyclic adenosine 5′-diphosphoribose (cADPR). Synthetic, non-hydrolyzable ligands can facilitate structure-based inhibitor design. Molecular docking was used to reproduce the crystallographic binding mode of cyclic inosine 5′-diphosphoribose (N1-cIDPR) with CD38, revealing an exploitable pocket and predicting the potential to introduce an extra hydrogen bond interaction with Asp-155. The purine C-8 position of N1-cIDPR (IC50 276 µM) was extended with an amino or diaminobutane group and the 8-modified compounds were evaluated against CD38-catalyzed cADPR hydrolysis. Crystallography of an 8-amino N1-cIDPR:CD38 complex confirmed the predicted interaction with Asp-155, together with a second H-bond from a realigned Glu-146, rationalizing the improved inhibition (IC50 56 µM). Crystallography of a complex of cyclic ADP-carbocyclic ribose (cADPcR, IC50 129 µM) with CD38 illustrated that Glu-146 hydrogen bonds with the ligand N6-amino group. Both 8-amino N1-cIDPR and cADPcR bind deep in the active site reaching the catalytic residue Glu-226, and mimicking the likely location of cADPR during catalysis. Substantial overlap of the N1-cIDPR “northern” ribose monophosphate and the cADPcR carbocyclic ribose monophosphate regions suggests that this area is crucial for inhibitor design, leading to a new compound series of N1-inosine 5′-monophosphates (N1-IMPs). These small fragments inhibit hydrolysis of cADPR more efficiently than the parent cyclic compounds, with the best in the series demonstrating potent inhibition (IC50 = 7.6 µM). The lower molecular weight and relative simplicity of these compounds compared to cADPR make them attractive as a starting point for further inhibitor design.

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Section: Resultssupporting

confidence: 87%

CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5′-Diphosphate Ribose Template

et al. 2013

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“…The only difference is an oxo group at position 6 of the purine ring replacing the imino group of cADPR. N1-cIDPR is also a functional mimic of cADPR that can activate calcium signals that are almost identical to those triggered by cADPR in cells (30).…”

mentioning

confidence: 99%

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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“…cADPR is readily hydrolyzed by CD38 NADase at the unstable N 1 link to produce ADP‐ribose (ADPR), another Ca 2+ second messenger . Chemical modifications, such as in cIDPR and cIDPRE, provided relatively stable analogues . Incubation of compounds 3 – 5 for 18 h with CD38 NADase did not result in any metabolism (Figure S2).…”

Section: Discussionmentioning

confidence: 87%

Calcium‐Mobilizing Behaviors of Neutral Cyclic ADP‐Ribose Mimics that Integrate Modifications to the Nucleobase, Northern Ribose and Pyrophosphate

Wang

Zhang

et al. 2018

ChemBioChem

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Cyclic adenosine diphosphate ribose (cADPR) is an endogenous Ca mobilizer involved in diverse cellular processes. Mimics of cADPR play a crucial role in investigating the molecular mechanism(s) of cADPR-mediated signaling. Here, compound 3, a mimic of cADPR in which a neutral triazole moiety and an ether linkage were introduced to substitute the pyrophosphate and "northern" ribose components, respectively, was synthesized for the first time. The pharmacological activities in Jurkat cells indicated that this mimic is capable of penetrating plasma membrane and inciting Ca release from the endoplasmic reticulum (ER) through the action of ryanodine receptors (RyRs) and triggering Ca influx. Furthermore, a uridine moiety was introduced in place of adenine and the new cADPR mimics 4 and 5 were synthesized. The results of biological investigation showed that these mimics also targeted RyRs and retained moderate Ca agonistic activities. The results indicated that the neutral cADPR mimics had the same targets for inducing Ca signaling.

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Cellular effects and metabolic stability of N1‐cyclic inosine diphosphoribose and its derivatives

Cited by 16 publications

References 44 publications

CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5′-Diphosphate Ribose Template

CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5′-Diphosphate Ribose Template

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

Calcium‐Mobilizing Behaviors of Neutral Cyclic ADP‐Ribose Mimics that Integrate Modifications to the Nucleobase, Northern Ribose and Pyrophosphate

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