Inositol monophosphatase

Inositol monophosphatase 2
X-ray crystal structure of inositol monophosphatase 2
Identifiers
Symbol	IMPA2
Entrez	3613
HUGO	6051
OMIM	605922
RefSeq	NP_055029
UniProt	O14732
Other data
EC number	3.1.3.25
Locus	Chr. 18 p11.2

Inositol monophosphatase, commonly referred to as IMPase, is an enzyme of the phosphodiesterase family of enzymes. It is involved in the phosphophatidylinositol [PI] 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 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.

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.