Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17. MPO is most abundantly expressed in neutrophil granulocytes (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 The green color contributed to its outdated name verdoperoxidase.
EC number
The EC number of myeloperoxidase (MPO) is 1.11.2.2. 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.
Reaction pathway
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.
Structure
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.
Three isoforms 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
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.