Analogs of diadenosine tetraphosphate (Ap4A).

Abstract

This review summarizes our knowledge of analogs and derivatives of diadenosine 5',5"'-P1,P4-tetraphosphate (Ap4A), the most extensively studied member of the dinucleoside 5',5"'-P1,Pn-polyphosphate (NpnN) family. After a short discussion of enzymes that may be responsible for the accumulation and degradation of Np4)N's in the cell, this review focuses on chemically and/or enzymatically produced analogs and their practical applications. Particular attention is paid to compounds that have aided the study of enzymes involved in the metabolism of Ap4A (Np4N'). Certain Ap4A analogs were alternative substrates of Ap4A-degrading enzymes and/or acted as enzyme inhibitors, some other helped to establish enzyme mechanisms, increased the sensitivity of certain enzyme assays or produced stable enzyme:ligand complexes for structural analysis.

Crystal structures of Salmonella typhimurium propionate kinase and its complex with Ap4A: Evidence for a novel Ap4A synthetic activity

“…Ap 4 A is found in the cytosol of all prokaryotes and eukaryotes in concentrations ranging from 0.05 μ M to approximately 10 μ M 21. There are a few specific enzymes which preferentially use Ap 4 A as the substrate 22–24. In higher eukaryotes, there is a Ap 4 A hydrolase (EC 3.6.1.17) which asymmetrically hydrolyzes Ap 4 A to ATP and AMP.…”

Crystal Structures of Eosinophil-Derived Neurotoxin (EDN) in Complex with the Inhibitors 5‘-ATP, Ap3A, Ap4A, and Ap5A,

“…First, the polyphosphate linkers of these compounds are cleaved readily by a variety of hydrolases and phosphodiesterases both outside and inside the cell, limiting their biological half-lives (63). This can, however, be overcome by replacement of some or all of the phosphate groups with nonhydrolyzable alternatives such as methylene phosphonates or fluorophosphonates (64). Second, the compounds are of limited use in cases where an intracellular action is required: the abundant phosphate groups impart a significant negative charge at physiological pH, preventing the compounds from readily penetrating cell membranes.…”

A diadenosine 5',5''-P1P4 tetraphosphate (Ap4A) hydrolase from Arabidopsis thaliana that is activated preferentially by Mn2+ ions.

“…Bis (5´-nucleosidyl) tetraphosphates are found in both eukaryotic and prokaryotic organisms at submicromolar concentrations (Garrison & Barnes, 1992;Guranowski, 2003). They were initially characterized as toxic side-products of protein synthesis, but more recently have been proposed to play a range of roles in processes such as control of DNA replication and repair, signaling in stress response, and apoptosis (for reviews see McLennan, 2000;2006).…”