Myeloperoxidase (MPO) is a
peroxidase enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that in humans is encoded by the ''MPO''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
on
chromosome 17.
MPO is most abundantly expressed in
neutrophil granulocyte
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s (a subtype of
white blood cells), and produces hypohalous acids to carry out their
antimicrobial activity, including hypochlorous acid, the sodium salt of which is the chemical in bleach.
It is a
lysosomal protein stored in
azurophilic granules
An azurophilic granule is a cellular object readily stainable with a Romanowsky stain. In white blood cells and hyperchromatin, staining imparts a burgundy or merlot coloration. Neutrophils in particular are known for containing azurophils load ...
of the neutrophil and released into the
extracellular space
Extracellular space refers to the part of a multicellular organism outside the cells, usually taken to be outside the plasma membranes, and occupied by fluid. This is distinguished from intracellular space, which is inside the cells.
The compos ...
during degranulation.
Neutrophil myeloperoxidase has a
heme pigment, which causes its green color in secretions rich in
neutrophils
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
, such as
mucus
Mucus ( ) is a slippery aqueous secretion produced by, and covering, mucous membranes. It is typically produced from cells found in mucous glands, although it may also originate from mixed glands, which contain both serous and mucous cells. It ...
and
sputum. The green color contributed to its outdated name verdoperoxidase.
Structure
The 150-
kDa MPO protein is a cationic
heterotetramer
A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer c ...
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
heterodimers.
The light chains are
glycosylated and contain the modified iron
protoporphyrin IX active site
In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate ( binding 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
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, ...
pocket at the entrance to the distal heme cavity which carries out its catalytic activity.
Three
isoform
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some is ...
s have been identified, differing only in the size of the heavy chains.
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 (HOCl) from
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3 ...
(H
2O
2) and
chloride
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride s ...
anion
An ion () is an atom or molecule with a net electrical charge.
The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...
(Cl
−) (or
hypobromous acid
Hypobromous acid is a weak, unstable acid with chemical formula of HOBr. It is mainly produced and handled in an aqueous solution. It is generated both biologically and commercially as a disinfectant. Salts of hypobromite are rarely isolated as ...
if Br- is present) during the neutrophil's
respiratory burst. It requires heme as a
cofactor. Furthermore, it oxidizes
tyrosine
-Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...
to tyrosyl radical using
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3 ...
as an
oxidizing agent
An oxidizing agent (also known as an oxidant, oxidizer, electron recipient, or electron acceptor) is a substance in a redox chemical reaction that gains or " accepts"/"receives" an electron from a (called the , , or ). In other words, an oxi ...
.
Hypochlorous acid and tyrosyl radical are
cytotoxic, so they are used by the neutrophil to kill
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...
and other
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a g ...
s.
However, this hypochlorous acid may also cause
oxidative damage in host tissue. Moreover, MPO oxidation of
apoA-I reduces HDL-mediated inhibition of
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
and inflammation.
In addition, MPO mediates protein
nitrosylation and the formation of 3-chlorotyrosine and dityrosine
crosslink
In chemistry and biology a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...
s.
Clinical significance
Myeloperoxidase deficiency
Myeloperoxidase deficiency is a disorder featuring lack in either the quantity or the function of myeloperoxidase–an iron-containing protein expressed primarily in neutrophil granules. There are two types of myeloperoxidase deficiency: primary/in ...
is a hereditary deficiency of the enzyme, which predisposes to
immune deficiency.
Antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...
against MPO have been implicated in various types of
vasculitis
Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused ...
, most prominently three clinically and pathologically recognized forms:
granulomatosis with polyangiitis
Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis (WG), is a rare long-term systemic disorder that involves the formation of granulomas and inflammation of blood vessels (vasculitis). It is a form of vasculitis ...
(GPA), microscopic polyangiitis (MPA); and
eosinophilic granulomatosis with polyangiitis (EGPA). Antibodies are also known as
anti-neutrophil cytoplasmic antibodies
Anti-neutrophil cytoplasmic antibodies (ANCAs) are a group of autoantibodies, mainly of the Immunoglobulin G, IgG type, against antigens in the cytoplasm of neutrophils (the most common type of white blood cell) and monocytes. They are detected ...
(ANCAs), though ANCAs have also been detected in
staining
Staining is a technique used to enhance contrast in samples, generally at the microscopic level. Stains and dyes are frequently used in histology (microscopic study of biological tissues), in cytology (microscopic study of cells), and in th ...
of the perinuclear region.
Recent studies have reported an association between elevated myeloperoxidase levels and the severity of
coronary artery disease
Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...
.
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
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classif ...
and rendering
plaques unstable.
Medical uses
An initial 2003 study suggested that MPO could serve as a sensitive predictor for
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
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
lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...
s, which can otherwise have a similar appearance.
In the case of screening patients for vasculitis,
flow cytometric assays have demonstrated comparable sensitivity to
immunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on microbiological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to spe ...
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 nanotube
A scanning tunneling microscopy image of a single-walled carbon nanotube
Rotating single-walled zigzag carbon nanotube
A carbon nanotube (CNT) is a tube made of carbon with diameters typically measured in nanometers.
''Single-wall carbon na ...
s, 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 (4-ABH) is a more specific inhibitor of MPO.
See also
*
Chloroma
References
External links
*
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EC 1.11.1
Hemoproteins