Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO
gene on chromosome 17. MPO is most abundantly expressed in neutrophil
granulocytes, and produces hypohalous acids to carry out their antimicrobial
activity. It is a lysosomal protein stored in azurophilic granules of the
neutrophil and released into the extracellular space during
degranulation. MPO has a heme pigment, which causes its green color in
secretions rich in neutrophils, such as pus and some forms of mucus.
Structure The 150-kDa MPO protein is a cationic
homodimer consisting of two 15-kDa light chains and two variable-weight
glycosylated heavy chains bound to a prosthetic heme group. The light chains
are glycosylated 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. Three isoforms have been identified,
differing only in the size of the heavy chains.
MPO contains a calcium binding site with seven ligands, forming a pentagonal
pyramid conformation. 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 side chain.
Function MPO is a member of the XPO subfamily of
peroxidases and produces hypochlorous acid from hydrogen peroxide and chloride
anion during the neutrophil's respiratory burst. It requires heme as a
cofactor. Furthermore, it oxidizes tyrosine to tyrosyl radical using
hydrogen peroxide as an oxidizing agent. Hypochlorous acid and tyrosyl radical
are cytotoxic, so they are used by the neutrophil to kill bacteria and other
pathogens. However, this hypochlorous acid may also cause oxidative damage in
host tissue. Moreover, MPO oxidation of apoA-I reduces HDL-mediated inhibition
of apoptosis and inflammation. In addition, MPO mediates protein
nitrosylation and the formation of 3-chlorotyrosine and dityrosine
crosslinks. Clinical significance
Myeloperoxidase deficiency is a hereditary deficiency of the enzyme,
which predisposes to immune deficiency. Antibodies against MPO have been
implicated in various types of vasculitis, most prominently three
clinically and pathologically recognized forms: granulomatosis with polyangiitis,
microscopic polyangiitis; and eosinophilic granulomatosis with
polyangiitis. Antibodies are also known as anti-neutrophil cytoplasmic
antibodies, though ANCAs have also been detected in staining of the perinuclear
region. Recent studies have reported an
association between elevated myeloperoxidase levels and the severity
of coronary artery disease. And Heslop et al. reported that elevated MPO levels
more than doubled the risk for cardiovascular mortality over a 13-year
period. It has also been suggested that myeloperoxidase plays a significant role
in the development of the atherosclerotic lesion and rendering
plaques unstable. = Medical uses=
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
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 lymphomas, which can otherwise have a similar appearance. In the case of
screening patients for vasculitis, flow cytometric assays have demonstrated
comparable sensitivity to immunofluorescence tests, with the
additional benefit of simultaneous detection of multiple autoantibodies
relevant to vasculitis. Nonetheless, this method still requires further
testing. Myeloperoxidase is the first and so far
only human enzyme known to break down carbon nanotubes, allaying a concern
among clinicians that using nanotubes for targeted delivery of medicines would
lead to an unhealthy buildup of nanotubes in tissues.
= Inhibitors of MPO= Azide has been used traditionally as an
MPO inhibitor, but 4-aminobenzoic acid hydrazide is a more specific inhibitor
of MPO. See also
Chloroma References