The enzyme Inositol phosphate-phosphatase (IMPase, EC 3.1.3.25) is a member of the phosphodiesterase family of enzymes. It is involved in the phosphophatidylinositol signaling pathway, which affects a wide array of cell functions, including but not limited to, cell growth, apoptosis, secretion, and information processing. Inhibition of inositol monophosphatase may be key in the action of lithium in treating bipolar disorder, specifically manic depression. The catalyzed reaction:
myo-inositol phosphate + H2O ⇌ {\displaystyle \rightleftharpoons } myo-inositol + phosphate
Nomenclature 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. IMPase has three hydrophilic hollow active sites, each of which bind water and magnesium molecules. These binding sites appear to be conserved in other phosphodiesterases such as fructose 1,6-bisphosphatase (FBPase) and inositol polyphosphate 1-phosphatase.
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. Another magnesium ion then cooperatively binds to binding site 2, which has of carboxylates of Asp90, Asp93, Asp220, and three water molecules, one of which is shared by binding site 1. Then, a third magnesium weakly and non-cooperatively to the third binding site, which has 5 water molecules and residue Glu70. After all three magnesium ions have bound, the inositol monophosphatase can bind, the negatively charge phosphate group stabilized by the three positively charged magnesium ions. Finally an activated water molecule acts a nucleophile and hydrolyzes the substrate, giving inositol and inorganic phosphate.
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. The enzyme acts on five of the six isomers of inositol monophosphate. For example it converts inositol 3-phosphate to inositol and orthophosphate:
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 4,5-bisphosphate (PIP2), resulting in a membrane associated product, diacylglycerol, and a water-soluble product, inositol triphosphate. Diacylglycerol acts as a second messenger, activating several protein kinases and produces extended downstream signaling. Inositol triphosphate is also a second messenger which activates receptors on the endoplasmic reticulum to release calcium ion stores into the cytoplasm, 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. Furthermore, not only is PIP2 a precursor to several signaling molecules, it can be phosphorylated at the 3’ position to become PIP3, which is involved in cell proliferation, apoptosis and cell movement. In this pathway, IMPase is the common, final step in recycling IP3 to produce PIP2. IMPase does this by dephosphorylating inositol monophosphate to produce inorganic phosphate and myo-inositol, the precursor to PIP2. Because of IMPase's crucial role in this signaling pathway, it is a potential drug target for inhibition and modulation.
Inositol monophosphatase in the de novo synthesis of myo-inositol There are at least 2 known steps in the de novo synthesis of myo-inositol from glucose 6-phosphate. In the first step, glucose 6-phosphate is converted to D-inositol 1 monophosphate by the enzyme glucose 6 phosphate cyclase. Inositol monophosphatase catalyzes the final step in which D-inositol 1 monophosphate is dephosphorylated to form myo-inositol.
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