DIADENOSINE OLIGOPHOSPHATES (AP(N)A), A NOVEL CLASS OF SIGNALING MOLECULES

The diadenosine oligophosphates (Ap(n)A) were discovered in the mid-si xties in the course of studies on aminoacyl-tRNA synthetases (aaRS). N ow, more than 30 years later, about 300 papers have been published aro und these substances in attempt to decipher their role in cells. Recen tly, Ap(n)A have emerged as intracellular and extracellular signalling molecules implicated in the maintenance and regulation of vital cellu lar functions and become considered as second messengers. Great variet y of physiological and pathological effects in mammalian cells was fou nd 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 subst antial 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 s ynthesise Ap(4)A and is an interferon-inducible protein. Moreover, Ap( 3)A appeared to be a preferred substrate for 2-5A synthetase, also int erferon-inducible, priming the synthesis of 2' adenylated derivatives of Ap(3)A, which in turn may serve as substrates of Fhit. Tumour suppr essor 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.