Myeloperoxidase

 

Myeloperoxidase (MPO) is a heterodimer, occurring in the azurophil granules of mammalian neutrophils catalyzes the hydrogen peroxide-mediated peroxidation of chloride ion to hypochlorite, an effective antibacterial, antifungal, and antiviral agent. MPO is a member of a homologous family of mammalian peroxidases that includes thyroid peroxidase, lactoperoxidase, and eosinophil peroxidase.

 

Reference Protein and Structure

Sequence
P05164 UniProt (1.11.2.2) IPR029609 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
1mhl - CRYSTAL STRUCTURE OF HUMAN MYELOPEROXIDASE ISOFORM C CRYSTALLIZED IN SPACE GROUP P2(1) AT PH 5.5 AND 20 DEG C (2.25 Å) PDBe PDBsum 1mhl
Catalytic CATH Domains
1.10.640.10 CATHdb (see all for 1mhl)
Cofactors
Heme b (1)
Click To Show Structure

Enzyme Reaction (EC:1.11.2.2)

hydrogen peroxide
CHEBI:16240ChEBI
+
hydron
CHEBI:15378ChEBI
+
chloride
CHEBI:17996ChEBI
→
water
CHEBI:15377ChEBI
+
hypochlorous acid
CHEBI:24757ChEBI
Alternative enzyme names: MPO, Verdoperoxidase,

Enzyme Mechanism

Introduction

The myeloperoxidases can oxidise a range of substrates and the mechanism can be broken down into 3 steps, which are repeated for all of them:

  1. Peroxidase (FE3+) + H2O2 = Compound I (FE4+') + H20
  2. Compound I (FE4+') + AH2 = Compound II (FE4+) + AH'
  3. Compound II (FE4+) + AH2 = Peroxidase (FE3+) + AH'
  4. 2AH' = A2H2 or A + AH2

The first step is carried out by a common mechanism through all the heme peroxidases whilst 2-4 vary depending on substrate. The first step is catalysed by residues on the distal side of the heme group. H2O2 enters the active site and binds to the heme Fe, histidine 95 of the small chain, and arginine 239 of the large chain. The oxygen of H2O2 that is bound to the Fe donates a proton to the NE of the histidine. The histidine then in turn donates the proton to the other H2O2 oxygen bound to the arginine. This leaves water bound to arginine and the oxidised Compound I. The mechanism of oxidisation of the substrate varies in steps 2-4.

Catalytic Residues Roles

UniProt PDB* (1mhl)
His261 His95(97)B(C) Acts as a general acid/base catalyst to deprotonate hydrogen peroxide and to protonate the leaving water. proton shuttle (general acid/base)
Arg405 Arg239(127)D Positively-charged residue stabilises build up of negative charge. 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. Fenna R et al. (1995), Arch Biochem Biophys, 316, 653-656. Structure of the Green Heme in Myeloperoxidase. DOI:10.1006/abbi.1995.1086. PMID:7840679.
  2. Arnhold J et al. (2003), Redox Rep, 8, 179-186. Redox properties of myeloperoxidase. DOI:10.1179/135100003225002664. PMID:14599340.
  3. Ghibaudi E et al. (2003), Eur J Biochem, 270, 4403-4412. Unraveling the catalytic mechanism of lactoperoxidase and myeloperoxidase. PMID:14622268.
  4. Davey CA et al. (1996), Biochemistry, 35, 10967-10973. 2.3 Å Resolution X-ray Crystal Structure of the Bisubstrate Analogue Inhibitor Salicylhydroxamic Acid Bound to Human Myeloperoxidase:  A Model for a Prereaction Complex with Hydrogen Peroxide†,‡. DOI:10.1021/bi960577m. PMID:8718890.

Step 1.

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Catalytic Residues Roles

Residue Roles
His95(97)B(C) proton shuttle (general acid/base)
Arg239(127)D electrostatic stabiliser

Chemical Components

Step 1.

Contributors

Anna Waters, Craig Porter, Gemma L. Holliday