Myeloperoxidase ( MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17.
Myeloperoxidase is found in many different organisms including mammals, birds, fish,
Structure
The MPO protein is a cationic heterotetramer consisting of two 15-kDa light chains and two variable-weight glycosylated heavy chains bound to a prosthetic
heme group complex with calcium ions, arranged as a
homodimer of
. Both are proteolytically generated from the precursor peptide encoded by the
MPO gene.
The light chains are
and contain the modified iron protoporphyrin IX
active site. Together, the light and heavy chains form two identical 73-kDa monomers connected by a
cystine bridge at Cys153. The protein forms a deep crevice which holds the heme group at the bottom, as well as a
hydrophobic pocket at the entrance to the distal heme cavity which carries out its catalytic activity.
Variation in glycosylation and the identity of the heavy chain lead to variations in molecular weight within the 135-200 kDa range.
One of the ligands is the carbonyl group of Asp 96. Calcium-binding is important for structure of the active site because of Asp 96's close proximity to the catalytic His95 Substituent.
Reaction mechanism
The central heme group acts as the
active site. The reaction starts when hydrogen peroxide donates an oxygen to the heme group, converting it to an activated form called "Compound I". This compound then oxidizes the chloride ions to form the hypochlorous acid and Compound II, which can be reduced back down to its original heme state. This cycle continues for as long as the immune system requires.
Function
MPO is a member of the XPO subfamily of peroxidases and produces hypochlorous acid (HOCl) from hydrogen peroxide (H
2O
2) and
chloride anion (Cl
−) (or
hypobromous acid if Br- is present) during the
neutrophil's defensive respiratory burst. It requires heme as a cofactor. Furthermore, it oxidizes
tyrosine to tyrosyl radical using hydrogen peroxide as an
oxidizing agent.
However, this hypochlorous acid may also cause oxidative damage in host tissue. Moreover, MPO oxidation of apolipoprotein A-I reduces HDL-mediated inhibition of apoptosis and inflammation.
Myeloperoxidase is the first and so far only human enzyme known to break down , allaying a concern among clinicians that using nanotubes for targeted delivery of medicines would lead to an unhealthy buildup of nanotubes in tissues.[
]
Role in innate immunity
Neutrophil use myeloperoxidase to produce the substances needed for their respiratory burst.
Hypochlorous acid and tyrosyl radical are
cytotoxic, so they are used by the neutrophil to kill
bacteria and certain types of fungi.
Clinical significance
Myeloperoxidase deficiency
Myeloperoxidase deficiency is a hereditary deficiency of the enzyme, which causes a mild immune deficiency against certain
Pathogen.
People with myeloperoxidase deficiency are most at risk of infection by
Candida species, which are pathogenic fungi. The most common species found in humans is
Candida albicans. There may be an increased risk of certain other infections, such as with
Klebsiella pneumoniae, but recurrent
candidiasis is the only common clinical consequence, if the patient is noticeably affected at all.
Vasculitis
Antibody against MPO have been implicated in various types of
vasculitis, most prominently three clinically and pathologically recognized forms: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA); and eosinophilic granulomatosis with polyangiitis (EGPA). Antibodies are also known as anti-neutrophil cytoplasmic antibodies (ANCAs), though ANCAs have also been detected in
staining of the perinuclear region.
Atherosclerosis and heart disease
Myeloperoxidase is known to contribute to
atherosclerosis and diseases related to it, including coronary artery disease. MPO oxidizes LDL cholesterol, and as a result, the
LDL receptor in liver cells becomes unable to bind to LDL and remove it from the blood stream. However, in its oxidized state, LDL can still contribute to
foam cell formation and other atherosclerotic processes. Thus, elevated levels of MPO are a risk factor for atherosclerosis.
Medical tests
An initial 2003 study suggested that MPO could serve as a sensitive predictor for myocardial infarction in patients presenting with
chest pain.
Since then, there have been over 100 published studies documenting the utility of MPO testing. The 2010 Heslop et al. study reported that measuring both MPO and CRP (C-reactive protein; a general and cardiac-related marker of inflammation) provided added benefit for risk prediction than just measuring CRP alone.
Immunohistochemical staining for myeloperoxidase used to be administered in the diagnosis of acute myeloid leukemia to demonstrate that the leukemic cells were derived from the myeloid lineage. Myeloperoxidase staining is still important in the diagnosis of myeloid sarcoma, contrasting with the negative staining of , which can otherwise have a similar appearance.
Inhibitors
Azide has been used traditionally as an MPO inhibitor, but 4-aminobenzoic acid hydrazide (4-ABH) is a more specific inhibitor of MPO.
See also
External links
