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

The diadenosine oligophosphates (Ap(n)A) were discovered in the mid-sixties in the course of studies on aminoacyl-tRNA 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(3)A/Ap(4)A ratio. Cell differentiation and apoptosis have substantial and opposite effects on Ap(3)A/Ap(4)A ratio in cultured cells. A human Ap(3)A hydrolase, Fhit, appeared to be involved in protection of cells against tumourigenesis. Ap(3)A is synthesised by mammalian u synthetase (TrpRS) which in contrast to most other aaRS is unable to synthesise Ap(4)A and is an interferon-inducible protein. Moreover, Ap(3)A appeared to be a preferred substrate for 2-5A synthetase, also interferon-inducible, priming the synthesis of 2' adenylated derivatives of Ap(3)A, which in turn may serve as substrates of Fhit. Tumour suppressor activity of Fhit is assumed to be associated with involvement of the Fhit.Ap(3)A complex in cytokine signalling pathway(s) controlling cell proliferation. The Ap,,A family is potentially a novel class of signal-transducing molecules whose functions are Set to be determined. (C) 1998 Federation of European Biochemical Societies.