Inositol-phosphate phosphatase

This enzyme belongs to the family of hydrolases, specifically those acting on phosphoric monoester bonds. The systematic name is '''myo-inositol-phosphate phosphohydrolase'''. Other names in common use include: • myo-inositol-1(or 4)-monophosphatase, • inositol 1-phosphatase, • L-myo-inositol-1-phosphate phosphatase, • myo-inositol 1-phosphatase, • inositol phosphatase, • inositol monophosphate phosphatase, • inositol-1(or 4)-monophosphatase, • myo-inositol-1(or 4)-phosphate phosphohydrolase, • myo-inositol monophosphatase, and • myo-inositol-1-phosphatase. == Structure ==

The enzyme is a dimer comprising 277 amino acid residues per subunit. Each dimer exists in 5 layers of alternating α-helices and β-sheets, totaling to 9 α-helices and β-sheets per subunit. == Catalytic mechanism ==

It was previously reported that the hydrolysis of inositol monophosphate was catalyzed by IMPase through a 2-magnesium ion mechanism. However a recent 1.4 A resolution crystal structure shows 3 magnesium ions coordinating in each active binding site of the 2 dimers, supporting a 3-magnesium ion mechanism. The mechanism for hydrolysis is now thought to proceed as such: the enzyme is activated by a magnesium ion binding to binding site I, containing three water molecules, and stabilized by the negative charges on the carboxylates of Glu70 and Asp90, and the carbonyl of Ile92. == Function ==

Inositol monophosphatase plays an important role in maintaining intracellular levels of myo-inositol, a molecule that forms the structural basis of several secondary messengers in eukaryotic cells. IMPase dephosphorylates the isomers of inositol monophosphate to produce inositol, mostly in the form of the stereoisomer, myo-inositol. Inositol monophosphatase is able to regulate inositol homeostasis because it lies at the convergence of two pathways that generate inositol: • The phosphatidylinositol signaling pathway • The de novo biosynthesis of inositol from glucose 6-phosphate Inositol monophosphatase in the phosphatidylinositol signaling pathway In this pathway, G-coupled protein receptors and tyrosine kinase receptors are activated, resulting in the activation of phospholipase C, which hydrolyzes phosphatidylinositol biphosphate (PIP2), resulting in a membrane associated product, diacylglycerol, and a water-soluble product, inositol triphosphate. creating a complex signaling system that can be involved in modulating fertilization, proliferation, contraction, cell metabolism, vesicle and fluid secretion, and information processing in neuronal cells. Overall, diacylglycerol and inositol triphosphate signaling has implications for neuronal plasticity, impacting hippocampal long term potentiation, stress-induced cognitive impairment, and neuronal growth cone spreading. == Clinical significance ==

Inositol monophosphatase has historically been believed to be a direct target of lithium, the primary treatment for bipolar disorder. Scientific support for this hypothesis exists but is limited; the complete role of lithium and inositol monophosphatase in treating bipolar disorder or reducing myo-inositol levels is not well understood. In support of the inositol depletion hypothesis, researchers have shown that lithium binds uncompetitively to purified bovine inositol monophosphatase at the site of one of the magnesium ions. Rodents administered lithium showed a decrease in inositol levels, in line with the hypothesis. Valproate, another mood-stabilizing drug given to bipolar disorder patients, has also been shown to mimic the effects of lithium on myo-inositol. However, some clinical studies have found that bipolar disorder patients that had been administered lithium showed lower myo-inositol levels, while others found no effect on myo-inositol levels. Furthermore, lithium also binds to inositol polyphosphate 1-phosphatase (IPP), an enzyme also present in the phosphoinositide pathway, and could lower inositol levels through this mechanism More research is required to fully explain the role that lithium and IMPase play in bipolar disorder patients. Such an inhibitor would need to cross the blood–brain barrier in order to reach the inositol monophosphatase in neurons. == References ==