Several phosphorylated derivatives of myo-inositol are present in eukariotic cells, the most abundant of these being the fully phosphorylated inositol hexakisphosphate (IP6). IP6 is the precursor of a new class of more polar inositol polyphosphates containing one or two high-energy pyrophosphate bonds.
The best characterized inositol pyrophosphates are the diphosphoinositol pentakisphosphate (IP7 or PP-IP5) and the bis-diphosphoinositol tetrakisphosphate (IP8 or [PP]2-IP4). IP7 and IP8 are present in all eukaryotic cell analyzed thus far, from the amebae Dictyostelium to mammalian neurons, and the enzymes responsible for their synthesis are highly conserved throughout evolution.
The high-energy bonds present in IP7 and IP8 have the potential for unprecedente d molecular actions and their unique structure suggests that inositolpyrophosphates represent a new class of messengers with basic and not yet fully characterized functions. The cloning of the IP6 kinases (IP6K), the enzymes responsible for the synthesis o f inositol pyrophosphates, has provided me with the opportunity of obtaining the molecular tools necessary for studying inositol-pyrophosphate-mediated signalling.
Using recombinant IP6K, I was able to synthesize radiolabelled IP7 of high specific activity. Our recent exciting results demonstrate that IP7 acts as a phosphate donor in a novel mechanism of protein phosphorylation. It is my intention to expand and further characterize the means by which inositol pyrophosphates regulate cell functions by combining biochemical, molecular and genetic approaches.
Moreover, I will spend considerable effort in developing new methodology for the detection of inositol pyrophosphates in vivo. I believe that a simple and reliable technique enabling the analysis of IP7-dependent signalling in eukaryotic cells will dramatically increase the level of interest in the field, opening the opportunity for very unique and potentially groundbreaking discoveries.
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