Palmitoyl[protein] hydrolase (type 1)

 

Palmitoyl-protein thioesterase I (PPT1) is a lysosomal enzyme which is implicated in the degredation of lipid modified proteins, removing fatty acid groups from cysteine residues. The accumulation of undisgested substrate when a mutant enzyme is present leads to the formation of neuronal storage bodies that are associated with the clinical symptoms of infantile ceroid lipofuscinosis.

 

Reference Protein and Structure

Sequence
P45478 UniProt (3.1.2.22) IPR030294 (Sequence Homologues) (PDB Homologues)
Biological species
Bos taurus (Cattle) Uniprot
PDB
1eh5 - CRYSTAL STRUCTURE OF PALMITOYL PROTEIN THIOESTERASE 1 COMPLEXED WITH PALMITATE (2.5 Å) PDBe PDBsum 1eh5
Catalytic CATH Domains
3.40.50.1820 CATHdb (see all for 1eh5)
Click To Show Structure

Enzyme Reaction (EC:3.1.2.22)

S-palmitoyl-L-cysteine residue
CHEBI:74151ChEBI
+
water
CHEBI:15377ChEBI
→
L-cysteine residue
CHEBI:29950ChEBI
+
hydron
CHEBI:15378ChEBI
+
hexadecanoate
CHEBI:7896ChEBI
Alternative enzyme names: Palmitoyl-(protein) hydrolase, Palmitoyl-protein thioesterase,

Enzyme Mechanism

Introduction

PPT1 contains a catalytic triad composed of Ser115, His 289 and Asp233. Nucleophilic attack by Ser155 on the carbonyl of the substrate palmitate generates a enzyme-substrate tetrahedral intermediate where the main chain NH components of Met41 and Gln116 acts as hydrogen bond donors to stabilise the intermediate oxyanion. Proton donation and subsequent collapse of the intermediate forms an acyl-enzyme intermediate. This is then attacked by a nucleophilic water molcecule, generating a second anionic intermediate, followed by cleavage of the enzyme-acyl bond to generate the products.

Catalytic Residues Roles

UniProt PDB* (1eh5)
His289 His289(262)A The residue acts as a base towards the nucleophilic Ser115. It is activated towards accepting a proton through hydrogen bonding to Asp233. The residue also acts as a proton donor to the initial anionic intermediate.In the free enzyme, the residue is hydrogen bonded to Ser115. proton shuttle (general acid/base), electrostatic stabiliser
Asp233 Asp233(206)A The residue modifies the pH of the basic His 289 residue through hydrogen bonding. electrostatic stabiliser
Ser115 Ser115(88)A The residue is activated towards nucleophilic attack at the substrate by interaction with His 289, forming a tetrahedral intermediate. covalently attached, proton shuttle (general acid/base), electrostatic stabiliser
Gln116 (main-N), Met41 (main-N) Gln116(89)A (main-N), Met41(14)A (main-N) The residue main chain NH component is involved in an oxyanion hole, stabilising the anionic tetrahedral intermediate. electrostatic stabiliser
*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

References

  1. Bellizzi JJ 3rd et al. (2000), Proc Natl Acad Sci U S A, 97, 4573-4578. The crystal structure of palmitoyl protein thioesterase 1 and the molecular basis of infantile neuronal ceroid lipofuscinosis. DOI:10.1073/pnas.080508097. PMID:10781062.
  2. Holmquist M (2000), Curr Protein Pept Sci, 1, 209-235. Alpha Beta-Hydrolase Fold Enzymes Structures, Functions and Mechanisms. DOI:10.2174/1389203003381405. PMID:12369917.

Step 1.

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Catalytic Residues Roles

Residue Roles
Ser115(88)A covalently attached, electrostatic stabiliser, proton shuttle (general acid/base)
His289(262)A proton shuttle (general acid/base), electrostatic stabiliser
Asp233(206)A electrostatic stabiliser
Met41(14)A (main-N) electrostatic stabiliser
Gln116(89)A (main-N) electrostatic stabiliser

Chemical Components

Step 1.

Contributors

James W. Murray, Craig Porter, Gemma L. Holliday