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Catalytic Site Atlas

CSA LITERATURE entry for 1ima

E.C. nameinositol-phosphate phosphatase
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz)
CSA Homologues of 1imaThere are 39 Homologs
CSA Entries With UniProtID P29218
CSA Entries With EC Number
PDBe Entry 1ima
PDBSum Entry 1ima
MACiE Entry 1ima

Literature Report

IntroductionMammalian brain inositol monophosphatase (IMPase) provides inositol for the biosynthesis of the key secondary messenger precursor, phosphatidylinositol 4,5-bisphosphate. Phosphatidylinositol 4,5-bisphosphate is hydrolysed by phosphatidylinositidase C in response to receptor occupation to give diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (Ins 1,4,5-P3), both of which mediate signal transduction through specific interactions with their own targets. DAG activates protein kinase C which modulates the activity of many enzymes through phosphorylation, while Ins 1,4,5-P3 causes the release of calcium ions from an intracellular store. Brain cells vary in their ability to take up inositol and a series of phosphatases exist to sequentially hydrolyse Ins 1,4,5-P3 and other inositol polyphosphates via the bisphosphates to give inositol 1- and 4-monophosphates, substrates for IMPase. The effect of blocking IMPase with inhibitor Li+ cations is depletion of free inositol in brain cells and, thus, several groups have suggested that IMPase might be the target for the lithium ions in manic depression therapy.
MechansimIt has been found that the reaction proceeds with inversion of configuration at phosphorus hence a nucleophile associated with Mg2+ in site 1 is indicated, as opposed to the previously thought site 2.
Note 2 Mg2+ ions bind to the enzyme one before (site 1) and one after (site 2).
A water bound to Mg2+-1, which aided by Glu70 and Thr95 forms an attacking nucleophilic hydroxide ion to cleave the phosphate-inositolate bond.
It has been shown by chemical modification and kinetic studies that 6-OH group of the substrate is essential for catalysis. It is hydrogen bonded to Mg2+-2. This lowers the pKa of a bound water so much that it acts as a proton donor to the inositolate leaving group.

Catalytic Sites for 1ima

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluA7070macie:sideChainActs as a general acid to remove a proton from the hydrate associated with Mg2+-1 to form an attacking nucleophile.
ThrA9595macie:sideChainids formation of hydroxide ion from a magnesium bound water molecule via hydrogen bonding.

Literature References

Atack JR
Structure and mechanism of inositol monophosphatase.
FEBS Lett 1995 361 1-7
PubMed: 7890024
Miller DJ
The 6-OH group of D-inositol 1-phosphate serves as an H-bond donor in the catalytic hydrolysis of the phosphate ester by inositol monophosphatase.
Chembiochem 2000 1 262-271
PubMed: 11828418