Diadenosine oligophosphates (Ap_nA), a novel class of signalling molecules?

Abstract

The diadenosine oligophosphates (Ap n A) were discovered in the mid-sixties in the course of studies on aminoacyltRNA synthetases (aaRS). Now, more than 30 years later, about 300 papers have been published around these substances in attempt to decipher their role in cells. Recently, Ap n A have emerged as intracellular and extracellular signalling molecules implicated in the maintenance and regulation of vital cellular functions and become considered as second messengers. Great variety of physiological and pathological effects in mammalian cells was found to be associated with alterations of Ap n A levels (n from 2 to 6) and Ap Q A/Ap R A ratio. Cell differentiation and apoptosis have substantial and opposite effects on Ap Q A/Ap R A ratio in cultured cells. A human Ap Q A hydrolase, Fhit, appeared to be involved in protection of cells against tumourigenesis. Ap Q A is synthesised by mammalian u synthetase (TrpRS) which in contrast to most other aaRS is unable to synthesise Ap R A and is an interferon-inducible protein. Moreover, Ap Q A appeared to be a preferred substrate for 2-5A synthetase, also interferoninducible, priming the synthesis of 2P adenylated derivatives of Ap Q A, which in turn may serve as substrates of Fhit. Tumour suppressor activity of Fhit is assumed to be associated with involvement of the FhitWAp Q A complex in cytokine signalling pathway(s) controlling cell proliferation. The Ap n A family is potentially a novel class of signal-transducing molecules whose functions are yet to be determined.z 1998 Federation of European Biochemical Societies.

Identification of 2′-Phosphodiesterase, Which Plays a Role in the 2-5A System Regulated by Interferon

“…2B). These hypothetical genes might be related to metabolism of other ribonucleotide analogs, such as diadenosine oligophosphates (43).…”

Hint1 is a haplo-insufficient tumor suppressor in mice

“…In Escherichia coli, cell division is associated with an increase in the concentration of Ap 4 A. In mammalian cells, Ap 3 A and Ap 4 A have been implicated in inhibition of ATP-sensitive potassium channels and regulation of intracellular levels of Ca 2 þ (Kisselev et al, 1998), and when added to the medium at 10 mM, Ap 4 A induced apoptosis in cultures of human HL60, U937, Jurkat, and mouse VMRO cells (Vartanian et al, 1999).…”

Molecular Cloning of a Novel Isoform of Diphosphoinositol Polyphosphate Phosphohydrolase: A Potential Target of Lithium Therapy

“…In addition to dephosphorylating diphosphoinositol polyphosphates, DIPP also actively hydrolyzes diadenosine 5Ј ,5ЈЈЈ-P -hexaphosphate (Ap 6 A) (Yang et al 1999), a group of putative signaling molecules implicated in regulating a diverse array of cellular functions (Kisselev et al 1998;Miras-Portugal et al 1998). It has been reported that the levels of diadenosine polyphosphates were increased in response to heat shock and oxidative stress (Baker and Jacobson 1986).…”