scholarly journals Channelling of substrate promiscuity of the skeletal-muscle ADP-ribosyl cyclase isoform

2004 ◽  
Vol 381 (1) ◽  
pp. 147-154 ◽  
Author(s):  
Ingrid BACHER ◽  
Andreas ZIDAR ◽  
Martin KRATZEL ◽  
Martin HOHENEGGER
Keyword(s):  
Skeletal Muscle ◽  
Nicotinic Acid ◽  
Exchange Reaction ◽  
Second Messengers ◽  
Cyclization Reaction ◽  
Regulation Mechanism ◽  
Base Exchange ◽  
Adp Ribosyl Cyclase ◽  
Highly Sensitive ◽  
Cyclic Adp Ribose

The novel Ca2+-mobilizing second messengers cADPr (cyclic ADP-ribose) and NAADP (nicotinic acid–adenine dinucleotide phosphate) are both synthesized by ADP-ribosyl cyclases. Using HSR (heavy sarcoplasmic reticulum) fractions from rabbit skeletal muscle, NAADP-induced Ca2+ release was observed. In the present paper, we show in HSR membranes the formation of authentic cADPr, cGDPr (cyclic GDP-ribose) and NAADP. The cyclization reaction to form cADPr and cGDPr as well as the base-exchange reaction to form NAADP were strictly dependent on pH. Although the formation of cGDPr is optimized at pH 6, the synthesis of NAADP was most pronounced at a pH below 5. A novel regulation mechanism is provided for nicotinic acid, the co-substrate for NAADP synthesis. Nicotinic acid had virtually no influence on the cyclization reaction, but increased the affinity of NADP at an acidic pH and had the opposite effect at alkaline pH. Nicotinamide, the side product of cADPr synthesis, is an inhibitor of the cyclization reaction (IC50, 0.7±0.1 mM) and was 30-fold more potent at suppressing the base-exchange reaction. Although the synthesis of NAADP was highly sensitive to nicotinamide inhibition, this was not via a competition with the nicotinic-acid-binding site. In contrast with the ecto-ADP-ribosyl cyclase (CD38), the cyclization and base-exchange reaction of the skeletal muscle isoform was inhibited by Cu2+ and Zn2+, while other bivalent cations such as Ca2+, Mg2+ and Mn2+ had virtually no effect. These findings allow for the prediction of a novel ADP-ribosyl cyclase isoform in skeletal muscle HSR, other than CD38. Hence the enzymic prerequisite for cADPr- and NAADP-mediated Ca2+ signalling is present.

scholarly journals A Single Residue in a Novel ADP-ribosyl Cyclase Controls Production of the Calcium-mobilizing Messengers Cyclic ADP-ribose and Nicotinic Acid Adenine Dinucleotide Phosphate

2010 ◽  
Vol 285 (26) ◽  
pp. 19900-19909 ◽  
Author(s):  
Latha Ramakrishnan ◽  
Hélène Muller-Steffner ◽  
Christophe Bosc ◽  
Victor D. Vacquier ◽  
Francis Schuber ◽  
...  
Keyword(s):  
Nicotinic Acid ◽  
Adp Ribosyl Cyclase ◽  
Cyclic Adp Ribose

scholarly journals Sperm express a Ca2+-regulated NAADP synthase

2008 ◽  
Vol 411 (1) ◽  
pp. 63-70 ◽  
Author(s):  
Sridhar R. Vasudevan ◽  
Antony Galione ◽  
Grant C. Churchill
Keyword(s):  
Nicotinic Acid ◽  
Sea Urchin ◽  
Second Messenger ◽  
Cell Types ◽  
Substrate Selectivity ◽  
Base Exchange ◽  
Adp Ribosyl Cyclase ◽  
Wide Range ◽  
Sea Urchin Sperm ◽  
Exchange Activity

NAADP (nicotinic acid–adenine dinucleotide phosphate), the most potent Ca2+-mobilizing second messenger, is active in a wide range of organisms and cell types. Until now, all NAADP-producing enzymes have been thought to be members of the ADP-ribosyl cyclase family. ADP-ribosyl cyclases exhibit promiscuous substrate selectivity, synthesize a variety of products and are regulated in a limited manner, which may be non-physiological. In the present paper, we report the presence of an enzyme on the surface of sea urchin sperm that exhibits bell-shaped regulation by Ca2+ over a range (EC50 of 10 nM and IC50 of 50 μM) that is physiologically relevant. Uniquely, this surface enzyme possesses complete selectivity for nucleotides with a 2′-phosphate group and exhibits only base-exchange activity without any detectable cyclase activity. Taken together, these findings indicate that this novel enzyme should be considered as the first true NAADP synthase.

Preparation of Functionalized Diorganomagnesium Reagents in Toluene via Bromine or Iodine/Magnesium-Exchange Reactions

Synthesis ◽  
2021 ◽  
Author(s):  
Alexandre Desaintjean ◽  
Fanny Danton ◽  
Paul Knochel
Keyword(s):  
Exchange Reaction ◽  
Nitro Group ◽  
General Formula ◽  
Functional Groups ◽  
Exchange Reactions ◽  
Acyl Chlorides ◽  
Aryl Iodides ◽  
Highly Sensitive ◽  
Wide Range ◽  
Magnesium Exchange

A wide range of polyfunctionalized di(hetero)aryl- and dialkenyl-magnesium reagents were prepared in toluene within 10 to 120 min between −78 °C and 25 °C via an I/Mg- or Br/Mg-exchange reaction using reagents of the general formula R2Mg (R = sBu, Mes). Highly sensitive functional groups, such as a triazene or a nitro group, were tolerated in these exchange reactions, enabling the synthesis of various functionalized (hetero)arenes and alkenes derivatives after quenching with several electrophiles including allyl bromides, acyl chlorides, aldehydes, ketones, and aryl iodides.

Effects of Calmodulin Antagonists on Serine Phospholipid Base-Exchange Reaction in Rabbit Platelets1

1986 ◽  
Vol 99 (3) ◽  
pp. 615-625 ◽  
Author(s):  
Motokazu FUJIWARA ◽  
Shigehiro MORIKAWA ◽  
Shinkichi TANIGUCHI ◽  
Keiichiro MORI ◽  
Motohatsu FUJIWARA ◽  
...  
Keyword(s):  
Exchange Reaction ◽  
Calmodulin Antagonists ◽  
Base Exchange

Mechanisms of calcium signaling by cyclic ADP-ribose and NAADP

1997 ◽  
Vol 77 (4) ◽  
pp. 1133-1164 ◽  
Author(s):  
H. C. Lee
Keyword(s):  
Nitric Oxide ◽  
Nicotinic Acid ◽  
Live Cells ◽  
Release Mechanism ◽  
Major Mechanism ◽  
Signaling Mechanisms ◽  
Signaling Function ◽  
Cyclic Adp Ribose ◽  
Inositol 1,4,5 Trisphosphate ◽  
External Signals

Cells possess various mechanisms for transducing external signals to intracellular responses. The discovery of inositol 1,4,5-trisphosphate (IP3) as a messenger for mobilizing internal Ca2+ stores has centralized Ca2+ mobilization among signaling mechanisms. Results reviewed in this article establish that, in addition to IP3, the internal Ca2+ stores can be mobilized by at least two other molecules, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), via totally independent mechanisms. Cyclic ADP-ribose is a newly discovered cyclic nucleotide derived from NAD, but, unlike adenosine 3',5'-cyclic monophosphate, its main signaling function is modulation of Ca(2+)-induced Ca2+ release, a major mechanism of Ca2+ mobilization in addition to the IP3 pathway. Evidence shows that cADPR may in fact be responsible for mediating the Ca(2+)-mobilizing activity of the gaseous messenger nitric oxide. Cells responsive to cADPR are widespread and include species from plant to mammal, indicating the generality of cADPR as a signaling molecule. In addition to cADPR, NAADP, a metabolite of NADP, can also mobilize Ca2+ stores. The release mechanism and the stores on which NAADP acts are distinct from cADPR and IP3. Nicotinic acid adenine dinucleotide phosphate may play a role in generating Ca2+ oscillations, since liberation of NAADP in live cells by photolyzing its caged analog produces long lasting Ca2+ oscillations. These two new Ca2+ agonists are intimately related, since the same metabolic enzymes can, under appropriate conditions, synthesize either one, suggesting a unified mechanism may regulate both pathways. Elucidation of these two new Ca2+ mobilization pathways is likely to have an important impact on our understanding of cellular signaling mechanisms.

scholarly journals Snake venom NAD glycohydrolases: primary structures, genomic location, and gene structure

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6154 ◽  
Author(s):  
Ivan Koludarov ◽  
Steven D. Aird
Keyword(s):  
Snake Venom ◽  
Active Site ◽  
Disulfide Bonds ◽  
Venom Gland ◽  
Catalytic Residue ◽  
Nad Glycohydrolase ◽  
Adp Ribosyl Cyclase ◽  
Genomic Location ◽  
Cyclic Adp Ribose ◽  
Very High

NAD glycohydrolase (EC 3.2.2.5) (NADase) sequences have been identified in 10 elapid and crotalid venom gland transcriptomes, eight of which are complete. These sequences show very high homology, but elapid and crotalid sequences also display consistent differences. As in Aplysia kurodai ADP-ribosyl cyclase and vertebrate CD38 genes, snake venom NADase genes comprise eight exons; however, in the Protobothrops mucrosquamatus genome, the sixth exon is sometimes not transcribed, yielding a shortened NADase mRNA that encodes all six disulfide bonds, but an active site that lacks the catalytic glutamate residue. The function of this shortened protein, if expressed, is unknown. While many vertebrate CD38s are multifunctional, liberating both ADP-ribose and small quantities of cyclic ADP-ribose (cADPR), snake venom CD38 homologs are dedicated NADases. They possess the invariant TLEDTL sequence (residues 144–149) that bounds the active site and the catalytic residue, Glu228. In addition, they possess a disulfide bond (Cys121–Cys202) that specifically prevents ADP-ribosyl cyclase activity in combination with Ile224, in lieu of phenylalanine, which is requisite for ADPR cyclases. In concert with venom phosphodiesterase and 5′-nucleotidase and their ecto-enzyme homologs in prey tissues, snake venom NADases comprise part of an envenomation strategy to liberate purine nucleosides, and particularly adenosine, in the prey, promoting prey immobilization via hypotension and paralysis.

scholarly journals Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) and Cyclic ADP-Ribose (cADPR) Mediate Ca2+ Signaling in Cardiac Hypertrophy Induced by β-Adrenergic Stimulation

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0149125 ◽  
Author(s):  
Rukhsana Gul ◽  
Dae-Ryoung Park ◽  
Asif Iqbal Shawl ◽  
Soo-Yeul Im ◽  
Tae-Sik Nam ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Nicotinic Acid ◽  
Adrenergic Stimulation ◽  
Cyclic Adp Ribose
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