InsP 6 (inositol hexakisphosphate), the most abundant inositol phosphate in metazoa, is pyrophosphorylated to InsP 7 [5PP-InsP 5 (diphosphoinositol pentakisphosphate)] by cytosolic and nuclear IP6Ks (InsP 6 kinases) and to 1PP-InsP 5 by another InsP 6 /InsP 7 kinase family. MINPP1 (multiple inositol-polyphosphate phosphatase 1), the only known InsP 6 phosphatase, is localized in the ER (endoplasmic reticulum) and lysosome lumina. A mechanism of cytosolic InsP 6 dephosphorylation has remained enigmatic so far. In the present study, we demonstrated that IP6Ks change their kinase activity towards InsP 6 at a decreasing ATP/ADP ratio to an ADP phosphotransferase activity and dephosphorylate InsP 6 . Enantio-selective analysis revealed that Ins(2,3,4,5,6) P 5 is the main InsP 5 product of the IP6K reaction, whereas the exclusive product of MINPP1 activity is the enantiomer Ins(1,2,4,5,6) P 5 . Whereas lentiviral RNAi-based depletion of MINPP1 at falling cellular ATP/ADP ratios had no significant impact on Ins(2,3,4,5,6) P 5 production, the use of the selective IP6K inhibitor TNP [ N 2-(m-trifluorobenzyl), N 6-( p -nitrobenzyl)purine] abolished the production of this enatiomer in different types of cells. Furthermore, by analysis of rat tissue and human blood samples all (main and minor) dephosphorylation products of InsP 6 were detected in vivo . In summary, we identified IP6Ks as novel nuclear and cytosolic InsP 6 - (and InsP 5 -) dephosphorylating enzymes whose activity is sensitively driven by a decrease in the cellular ATP/ADP ratio, thus suggesting a role for IP6Ks as cellular adenylate energy ‘sensors’.