Inositol 1,3,4,5,6-pentakisphosphate and inositol hexakisphosphate are inhibitors of the soluble inositol 1,3,4,5-tetrakisphosphate 3-phosphatase and the inositol 1,4,5-trisphosphate/1,3,4,5-tetrakisphosphate 5-phosphatase from pig brain.

The influence of highly phosphorylated inositol phosphates on the Ins(1,3,4,5)P4 3-phosphatase enriched from the soluble fraction of pig brain was tested, using [5-32P]Ins(1,3,4,5)P4 as substrate. Both Ins(1,3,4,5,6)P5 and InsP6 were very potent inhibitors of the Ins(1,3,4,5)P4 3-phosphatase. The Ki values were approximately 60 nM and approximately 3 nM for Ins(1,3,4,5,6)P5 and InsP6 respectively. Ins(1,3,4,5,6)P5 and InsP6 also inhibited the Ins(1,4,5)P3/Ins(1,3,4,5)P4 5-phosphatase. Using Ins(1,3,4,5)P4 as substrate, the Ki values were about 35 microM and 15 microM for Ins(1,3,4,5,6)P5 and InsP6 respectively. The concentrations which led to a 50% inhibition of Ins(1,4,5)P3 (0.5 microM) degradation by the 5-phosphatase were about 20 and 10 microM for the pentakis- and hexakis-phosphate respectively. As the intracellular concentrations of Ins(1,3,4,5,6)P5 and InsP6 are high (up to 60 microM) compared with those of the inositol trisphosphates and tetrakisphosphates, it is possible that the highly phosphorylated inositol phosphates act as regulators in the metabolism of Ca(2+)-mobilizing inositol phosphates.