Synthesis of diphosphoinositol pentakisphosphate by a newly identified family of higher inositol polyphosphate kinases

Inositol (1,4,5) trisphosphate (Ins(1,4,5)P 3 ) is a well-known messenger molecule that releases calcium from intracellular stores. Homologues with up to six phosphates have been characterized and recently, homologues with seven or eight phosphate groups, including pyrophosphates, have been identified. These homologues are diphosphoinositol pentakisphosphate (PP-InsP 5 /InsP 7 ) and bis(diphospho)inositol tetrakisphosphate (bis-PP-InsP 4 /InsP 8 ) [1], the rapid turnover of which [2] is regulated by calcium [2] and adrenergic receptor activity [3]. It has been proposed that the high-energy pyrophosphates might participate in protein phosphorylation [4]. We have purified InsP 6 kinase [5] and PP-InsP 5 kinase [6], both of which display ATP synthase activity, transferring phosphate to ADP. Here, we report the cloning of two mammalian InsP 6 kinases and a yeast InsP 6 kinase. Furthermore, we show that the yeast protein, ArgRIII, is an inositol-polyphosphate kinase that can convert InsP 3 to InsP 4 , InsP 5 and InsP 6 . We have identified a new family of highly conserved inositol-polyphosphate kinases that contain a newly identified, unique consensus sequence.