|PDB structures||RCSB PDB PDBe PDBsum|
Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17. MPO is most abundantly expressed in neutrophils (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 of the neutrophil and released into the extracellular space during degranulation. Neutrophil myeloperoxidase has a heme pigment, which causes its green color in secretions rich in neutrophils, such as mucus and sputum. The green color contributed to its outdated name verdoperoxidase.
The EC number of myeloperoxidase (MPO) is 126.96.36.199. The first digit, 1, places the enzyme into a class the class which catalyzes oxidoreductase reactions. The second digit, 11, classifies the enzyme as a peroxidase. The final digits, 2 and 2 identify specifically myeloperoxidase.
The major reaction myeloperoxidase catalyzes is the conversion of hydrogen peroxide and chloride ions into hypochlorous acid. To achieve this, myeloperoxidase uses hydrogen peroxide as an electron acceptor (for breakdown) and chloride ions as substrates. This all occurs within a neutrophil cell, which is important for innate immune function. The first part of the reaction pathway is when the heme group of the myeloperoxidase is converted to an activated heme called Compound I when hydrogen peroxide donates an oxygen to myeloperoxidase. 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. The myeloperoxidase activity within the phagosome of the neutrophil is conducive to the breakdown of pathogens, as hypochlorous acid is an effective antimicrobial agent.
The 150-kDa 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 heterodimers. 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.
Myeloperoxidase's main functions are within the immune system, functioning to essentially destroy pathogens. The way this works is that they are released from granules within the neutrophil into the phagosome for breakdown of pathogens. It does this by, as described before, catalysis of hydrogen peroxide into hypochlorous acid. This hypochlorous acid, along with destruction of pathogens, can also initiate and regulate inflammatory response. Inflammatory response affects metabolic pathways when activating immune cells. In order to provide energy necessary for inflammatory response, glycolysis is upregulated to provide ATP for phagocytosis. Following phagocytosis, the immune cells repair and remodel tissues, which can be aided by oxidized products of myeloperoxidase function.
MPO is a member of the XPO subfamily of peroxidases and produces hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion (Cl−) (or hypobromous acid if Br- is present) 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.
Structure effect on function
As described before, the structure of myeloperoxidase is integral to its function. The central heme group acts as the active site for chloride ions and hydrogen peroxide. This is also the site of electron transfer, which allows myeloperoxidase to convert the two into hypochlorous acid. This allows the main function of myeloperoxidase, breakdown of pathogens, to occur.
There are many variations of the myeloperoxidase 3D structure, however they all follow a specific pattern. The myeloperoxidase enzyme typically weighs within the 135-200 kDa range, depending on the varying heavy chains it can be bound to. The enzyme is a heterotetramer with two light chains (15 kDa) and two glycosylated heavy chains which cause variability in weight. These heavy chains are bound to a heme group complex with calcium ions, arranged as a homodimer of heterodimers. The light and heavy chain monomers are connected by a cystine bridge at Cys153.
The heme group containing a central iron atom functions as the active site for myeloperoxidase. This heme group is active in the oxidoreductase activity on hydrogen peroxide. This is also where substrate (Cl- ions) and hydrogen peroxide may bind. This results in a reaction with the heme iron, and the chloride ions help form hypochlorous acid. Amino acid residues participate in the transfer of electrons during the reaction catalyzed by myeloperoxidase.
Organisms containing Myeloperoxidase
Myeloperoxidase is currently found in many different organisms including mammals, birds, fish, reptiles, and amphibians. Myeloperoxidase deficiency is a well-documented disease among humans resulting in impaired immune function.
Antibodies 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.
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.
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 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
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