Inositol polyphosphate phosphatase (IPPase) (IPPase)

Inositol polyphosphate phosphatase and related Mg²⁺-dependent phosphomonoesterases (InterPro: IPR000457) constitute a family of enzymes, including inositol monophosphatase (IMPA1/IMPA2) and inositol polyphosphate 1-phosphatase (INPP1), that are essential for the phosphoinositide signaling cycle (UniProt: P29218, P49441). These enzymes catalyze the dephosphorylation of various inositol phosphates to regenerate free myo-inositol, a precursor required for the resynthesis of phosphatidylinositol 4,5-bisphosphate (PIP2) (PubMed: 15181247). This family is the primary pharmacological target of lithium, which is the gold-standard treatment for bipolar disorder (StatPearls: Lithium). Lithium acts as an uncompetitive inhibitor of these enzymes, preventing the recycling of inositol and thereby dampening overactive signaling pathways, a mechanism known as the inositol depletion hypothesis (PubMed: 11597598). Beyond mood stabilization, these enzymes are involved in calcium homeostasis and are being explored as targets for neurodegenerative conditions (PubMed: 25830690). However, therapeutic use of drugs targeting this family is often limited by a narrow therapeutic index and risks of renal and thyroid toxicity (StatPearls: Lithium Toxicity).

Other names

Inositol monophosphataseIMPaseMyo-inositol monophosphataseINPP1IMPA1IMPA2Inositol-1,4-bisphosphate 1-phosphataseInositol polyphosphate phosphatase and related Mg²⁺-dependent phosphomonoesterases

Uncompetitive inhibition of phosphatase activity, leading to the depletion of cellular myo-inositol and subsequent dampening of phosphoinositide-mediated signaling.