Inositol-1,4-bisphosphate 1-phosphatase

 

Inositol polyphosphate 1 -phosphatase (l-ptase) removes the l-position phosphate from inositol 1,4-bisphosphate, yielding inositol 4-phosphate. l-Ptase is a ubiquitous monomeric enzyme that requires Mg2+ for activity and is potently inhibited by Li+, leading to its use in therapeutic targets of lithium treatment for manic-depressive illnesses.

 

Reference Protein and Structure

Sequence
P21327 UniProt (3.1.3.57) IPR000760 (Sequence Homologues) (PDB Homologues)
Biological species
Bos taurus (Cattle) Uniprot
PDB
1inp - CRYSTAL STRUCTURE OF INOSITOL POLYPHOSPHATE 1-PHOSPHATASE AT 2.3 ANGSTROMS RESOLUTION (2.3 Å) PDBe PDBsum 1inp
Catalytic CATH Domains
3.30.540.10 CATHdb 3.40.190.80 CATHdb (see all for 1inp)
Cofactors
Magnesium(2+) (3)
Click To Show Structure

Enzyme Reaction (EC:3.1.3.57)

1D-myo-inositol 1,4-bisphosphate(4-)
CHEBI:58282ChEBI
+
water
CHEBI:15377ChEBI
→
1D-myo-inositol 4-phosphate(2-)
CHEBI:58469ChEBI
+
hydrogenphosphate
CHEBI:43474ChEBI
Alternative enzyme names: Inositol-polyphosphate 1-phosphatase, Inositol polyphosphate 1-phosphatase,

Enzyme Mechanism

Introduction

As with most phosphatases the mechanism involves nucleophilic attack on the phosphate group. The nucleophile is an activated water molecule, which is co-ordinated to two magnesium cofactors and then activated by Thr158. This attacks the phosphate group forming a trigonal bipyramidal intermediate which is stabilised by the magnesium ions, break down of this leads to the the inositol 4-phosphate.

Catalytic Residues Roles

UniProt PDB* (1inp)
Glu79, Asp153, Asp156, Asp317, Ile155 (main-N) Glu79A, Asp153A, Asp156A, Asp317A, Ile155A (main-N) Coordinate the magnesium ions. metal ligand
Asp54, Thr158 Asp54A, Thr158A Part of the hydrogen bonding network that activates the nucleophilic water molecule. proton acceptor, electrostatic stabiliser, proton donor
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

overall reactant used, proton transfer, proton relay, bimolecular nucleophilic addition, overall product formed, unimolecular elimination by the conjugate base, inferred reaction step, native state of enzyme regenerated

References

  1. York JD et al. (1994), Biochemistry, 33, 13164-13171. Crystal structure of inositol polyphosphate 1-phosphatase at 2.3-A resolution. DOI:10.2210/pdb1inp/pdb. PMID:7947723.
  2. Faisal Tarique K et al. (2014), Acta Crystallogr D Biol Crystallogr, 70, 2019-2031. Structural elucidation of a dual-activity PAP phosphatase-1 from Entamoeba histolytica capable of hydrolysing both 3'-phosphoadenosine 5'-phosphate and inositol 1,4-bisphosphate. DOI:10.1107/S1399004714010268. PMID:25004978.
  3. Patel S et al. (2002), J Mol Biol, 315, 677-685. Crystal structure of an enzyme displaying both inositol-polyphosphate-1-phosphatase and 3′-phosphoadenosine-5′-phosphate phosphatase activities: a novel target of lithium therapy. DOI:10.1006/jmbi.2001.5271. PMID:11812139.

Step 1. The Asp54/Thr158 network deprotonates a water molecule activating it for nucleophilic attack on the phosphate. The penta-covalent intermediate formed is stabilized by the magnesium ions.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Thr158A enhance reactivity, electrostatic stabiliser
Glu79A metal ligand
Asp153A metal ligand
Ile155A (main-N) metal ligand
Asp156A metal ligand
Asp317A metal ligand
Thr158A proton relay, increase nucleophilicity
Asp54A electrostatic stabiliser
Thr158A proton acceptor
Asp54A proton acceptor
Thr158A proton donor

Chemical Components

overall reactant used, proton transfer, proton relay, ingold: bimolecular nucleophilic addition

Step 2. The intermediate collapses yielding inositol 4-phosphate.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Glu79A metal ligand
Asp153A metal ligand
Ile155A (main-N) metal ligand
Asp156A metal ligand
Asp317A metal ligand

Chemical Components

overall product formed, ingold: unimolecular elimination by the conjugate base

Step 3. Inferred step- product is protonated and the enzyme is regenerated in its native state.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Thr158A proton relay, proton acceptor
Asp54A proton donor
Thr158A proton donor

Chemical Components

inferred reaction step, proton transfer, proton relay, native state of enzyme regenerated
Download: Image, Marvin File

Step 1. The Asp54/Thr158 network deprotonates a water molecule activating it for nucleophilic attack on the phosphate. The penta-covalent intermediate formed is stabilized by the magnesium ions.

Step 2. The intermediate collapses yielding inositol 4-phosphate.

Step 3. Inferred step- product is protonated and the enzyme is regenerated in its native state.

Products.

Contributors

Anna Waters, Craig Porter, Gemma L. Holliday, James Willey, Marko Babić