Research Group

Adolfo Saiardi Research Group

The hexagonal inositol molecule serves as a module for the generation of a high level molecular diversity through the combinatorial attachment and removal of phosphate groups. Although, likely many of the observed inositol polyphosphates species merely represent metabolic intermediates, undoubtedly evolution has exploited this great diversity of structures by generating many important signalling molecules. Several phosphorylated derivatives of inositol are present in eukaryotic cells.

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The best characterized of them is the calcium releasing factor I(1,4,5)P3 (IP3), which represents a classical example of signal transduction mechanism; for IP3:

 

  • we know the stimuli that dynamically modulate its intracellular concentration;
  • we know the molecular mechanism of action;
  • we know the physiological consequence.

For none of the other inositol polyphosphates a specific function can be definitively and undoubtedly attributed, as none of them satisfies all the three criteria. Our objective is to characterize the physiological role of inositol polyphosphates that are still "orphan" of some (of all) of the three criteria described above. We are particularly interested to study the function of inositols containing high-energy pyrophosphate bonds. In fact, inositol ring is altered in a vast combinatorial array of possibilities, not only by adding phosphates, but also by the presence of two (pyro) or even three phosphate groups attached to different positions of ring. 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 cells analyzed thus far, from amoeba to mammalian neurons, and the enzymes responsible for their synthesis are highly conserved throughout evolution. Adolfow2_0.jpgThe high-energy bonds present in IP7 and IP8 have the potential for unprecedented molecular actions and their unique structure suggests that inositol pyrophosphates may represent a new class of second messengers with basic and not yet fully characterized functions. Our recent discovery that the high-energy phosphate of the pyrophosphate moiety can be directly donated to pre-phosphorylated proteins, providing a novel kind of protein post-transductional modification (protein pyrophosphorylation), may potentially open an entirely new and unexplored field in signal transduction.

Undoubtedly, evolution used the inositol module to create different signaling entities metabolically interconnected. The aim of my laboratory is to understand how an ancient inositol polyphosphates module with limited functions has evolved to become the sophisticated system of signaling molecules present in our cells.