Inositol monophosphatase
Encyclopedia
Inositol monophosphatase , commonly referred to as IMPase, is an enzyme
found in all cells and is thought to be key in bipolar disorder
(manic depression). Carbamazepine is an IMPase inhibitor used in the clinic.
The enzyme itself is a dimer
comprising 277 amino acid
residues per subunit which dephosphorylates
inositol phosphate to inositol
as part of the phosphatidylinositol signalling pathway. Each dimer exists as a five-layered sandwich of three pairs of α-helices
and two β-sheets
. IMPase’s two active sites are located in large, hydrophilic caverns at the base of the two central helices where several segments of secondary structure
intersect.
Two kinetically distinct metal-binding environments have been found by metal titration experiments which show that two magnesium
ion
s are involved in the catalytic mechanism. It is thought that one magnesium ion is responsible for the stabilisation of a negative charge on nucleophilic water and the second is involved in stabilising the negative charge on the phosphate leaving group
. IMPase is unusual in its mechanism for the dephosphorylation of inositol-1-phosphate as, unlike most phosphatases, it does not proceed by a phospho-enzyme intermediate. Two mechanisms have been proposed, dependent on the location of the water in the active site. The first suggests that the nucleophile (OH- from water) attacks opposite the leaving group in the substrate, resulting in inversion of stereochemistry
at the phosphorus, whilst the second proposes that the nucleophile attacks the phosphorus at the face thus causing the stereochemistry to be retained.
In bipolar disorder sufferers, it has been found that the phosphatidylinositol
signalling pathway is hyperactive and through the inhibition of IMPase - a key enzyme in the pathway - the cycle can be halted resulting in the symptomatic relief of the disorder. It is known that lithium ions, usually from lithium carbonate
drug therapy, are good inhibitors of the active sites of IMPase. Lithium is, however, an extremely toxic metal and the toxic dose is only marginally greater than the therapeutic dose. Therefore, a great deal of research is currently being undertaken to develop a novel inhibitor of IMPase without the risk of lithium. However, as the IMPase which needs to be inhibited is only that present in the brain, the new inhibitor must have a good bioavailability
and be able to easily cross the blood-brain barrier
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
found in all cells and is thought to be key in bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
(manic depression). Carbamazepine is an IMPase inhibitor used in the clinic.
The enzyme itself is a dimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
comprising 277 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues per subunit which dephosphorylates
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
inositol phosphate to inositol
Inositol
Inositol or cyclohexane-1,2,3,4,5,6-hexol is a chemical compound with formula 6126 or 6, a sixfold alcohol of cyclohexane. It exists in nine possible stereoisomers, of which the most prominent form, widely occurring in nature, is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol...
as part of the phosphatidylinositol signalling pathway. Each dimer exists as a five-layered sandwich of three pairs of α-helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
and two β-sheets
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
. IMPase’s two active sites are located in large, hydrophilic caverns at the base of the two central helices where several segments of secondary structure
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
intersect.
Two kinetically distinct metal-binding environments have been found by metal titration experiments which show that two magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s are involved in the catalytic mechanism. It is thought that one magnesium ion is responsible for the stabilisation of a negative charge on nucleophilic water and the second is involved in stabilising the negative charge on the phosphate leaving group
Leaving group
In chemistry, a leaving group is a molecular fragment that departs with a pair of electrons in heterolytic bond cleavage. Leaving groups can be anions or neutral molecules. Common anionic leaving groups are halides such as Cl−, Br−, and I−, and sulfonate esters, such as para-toluenesulfonate...
. IMPase is unusual in its mechanism for the dephosphorylation of inositol-1-phosphate as, unlike most phosphatases, it does not proceed by a phospho-enzyme intermediate. Two mechanisms have been proposed, dependent on the location of the water in the active site. The first suggests that the nucleophile (OH- from water) attacks opposite the leaving group in the substrate, resulting in inversion of stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
at the phosphorus, whilst the second proposes that the nucleophile attacks the phosphorus at the face thus causing the stereochemistry to be retained.
In bipolar disorder sufferers, it has been found that the phosphatidylinositol
Phosphatidylinositol
Phosphatidylinositol is a negatively charged phospholipid and a minor component in the cytosolic side of eukaryotic cell membranes....
signalling pathway is hyperactive and through the inhibition of IMPase - a key enzyme in the pathway - the cycle can be halted resulting in the symptomatic relief of the disorder. It is known that lithium ions, usually from lithium carbonate
Lithium carbonate
Lithium carbonate is a chemical compound of lithium, carbon, and oxygen with the formula Li2CO3. This colorless salt is widely used in the processing of metal oxides and has received attention for its use in psychiatry. It is found in nature as the rare mineral zabuyelite.-Properties:Like almost...
drug therapy, are good inhibitors of the active sites of IMPase. Lithium is, however, an extremely toxic metal and the toxic dose is only marginally greater than the therapeutic dose. Therefore, a great deal of research is currently being undertaken to develop a novel inhibitor of IMPase without the risk of lithium. However, as the IMPase which needs to be inhibited is only that present in the brain, the new inhibitor must have a good bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
and be able to easily cross the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
.