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Synthesis of terminal ribose analogues of adenosine 5'-diphosphate ribose (ADPR) as probes for the Transient Receptor Potential (TRP) cation channel TRPM2.

08:00 EDT 12th April 2019 | BioPortfolio

Summary of "Synthesis of terminal ribose analogues of adenosine 5'-diphosphate ribose (ADPR) as probes for the Transient Receptor Potential (TRP) cation channel TRPM2."

TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a non-selective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5'-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail we designed synthetic routes to novel analogues of ADPR and 2'-deoxy-ADPR that were modified only by removal of a single hydroxyl group from of the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2″-based analogues proved to be unstable. The C1″- and C3″-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1"-α-methylfuranoside-2", 3"-isopropylidene derivative was evaluated. Removal of either C1" or C3" hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications, and blocking all three hydroxyl groups resulted in ADPR antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation.

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This article was published in the following journal.

Name: The Journal of organic chemistry
ISSN: 1520-6904
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Medical and Biotech [MESH] Definitions

An ester formed between the aldehydic carbon of RIBOSE and the terminal phosphate of ADENOSINE DIPHOSPHATE. It is produced by the hydrolysis of nicotinamide-adenine dinucleotide (NAD) by a variety of enzymes, some of which transfer an ADP-ribosyl group to target proteins.

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Enzymes that catalyze the transfer of multiple ADP-RIBOSE groups from nicotinamide-adenine dinucleotide (NAD) onto protein targets, thus building up a linear or branched homopolymer of repeating ADP-ribose units i.e., POLY ADENOSINE DIPHOSPHATE RIBOSE.

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An acetyl ester of ADENOSINE DIPHOSPHATE RIBOSE formed during NAD-dependent deacetylation of proteins by SIRTUINS. The acetate group resides on the ribose ring where nicotinamide was cleaved from NAD during the reaction. Several isomers of O-acetyl-ADP-ribose have been isolated from the reaction.

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