Neurolysin

 

Neurolysin is a zinc metalloprotease which plays a key role in processing ogliopeptides in the nervous system thus degrading peptide hormones and terminating signals. Rat neurolysin shows the classic sequence motif shared by all zinc binding proteases: His-Glu-X-X-His. It also shows structural homology to thermolysin, a well studied member of the class, but little structural identity towards neprilysin despite a similar physiological role.

 

Reference Protein and Structure

Sequence
P42676 UniProt (3.4.24.16) IPR001567 (Sequence Homologues) (PDB Homologues)
Biological species
Rattus norvegicus (Norway rat) Uniprot
PDB
1i1i - NEUROLYSIN (ENDOPEPTIDASE 24.16) CRYSTAL STRUCTURE (2.3 Å) PDBe PDBsum 1i1i
Catalytic CATH Domains
1.10.1370.10 CATHdb 3.40.390.10 CATHdb (see all for 1i1i)
Cofactors
Zinc(2+) (1)
Click To Show Structure

Enzyme Reaction (EC:3.4.24.16)

water
CHEBI:15377ChEBI
+
Pro-Tyr
CHEBI:74799ChEBI
→
proline
CHEBI:26271ChEBI
+
L-tyrosine
CHEBI:17895ChEBI
Alternative enzyme names: Endo-oligopeptidase B (proline-endopeptidase), Endopeptidase 24.16, Neurotensin endopeptidase,

Enzyme Mechanism

Introduction

Glu498 and the Zinc ion act together to activate water by deprotonation so that it can act as a nucleophile and attack the peptide bond. This will form a tetrahedral intermediate, which is stabilised by the oxyanion hole, made up of the Zinc ion and the OH group of Tyr613. Subsequent protonation of the leaving group by Glu498 results in the collapse of the intermediate and the formation of products.

Catalytic Residues Roles

UniProt PDB* (1i1i)
Glu498 Glu475P(A) Acts to deprotonate water for nucleophilic attack on the substrate peptide. Subsequently protonates the leaving group to allow collapse of the tetrahedral intermediate.
Tyr636 Tyr613P(A) Stabilises the tetrahedral intermediate through hydrogen bonding of its OH group with the oxyanion. electrostatic stabiliser
His497, His501, Glu526 His474P(A), His478P(A), Glu503P(A) Forms the Zinc binding site of the enzyme
*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. Brown CK et al. (2001), Proc Natl Acad Sci U S A, 98, 3127-3132. Structure of neurolysin reveals a deep channel that limits substrate access. DOI:10.1073/pnas.051633198. PMID:11248043.
  2. Teixeira PF et al. (2018), J Mol Biol, 430, 348-362. Mechanism of Peptide Binding and Cleavage by the Human Mitochondrial Peptidase Neurolysin. DOI:10.1016/j.jmb.2017.11.011. PMID:29183787.
  3. Oliveira V et al. (2003), FEBS Lett, 541, 89-92. A structure-based site-directed mutagenesis study on the neurolysin (EC 3.4.24.16) and thimet oligopeptidase (EC 3.4.24.15) catalysis. DOI:10.1016/S0014-5793(03)00310-7.
  4. Sigman JA et al. (2003), FEBS Lett, 545, 224-228. pH dependence studies provide insight into the structure and mechanism of thimet oligopeptidase (EC 3.4.24.15). DOI:10.1016/S0014-5793(03)00548-9.

Step 1.

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Catalytic Residues Roles

Residue Roles
Tyr613P(A) electrostatic stabiliser
Glu503P(A) proton shuttle (general acid/base)

Chemical Components

Step 1.

Contributors

Peter Sarkies, Gemma L. Holliday, Charity Hornby