Myeloperoxidase
Introduction
Myeloperoxidase (MPO) is a heme-containing enzyme predominantly expressed in neutrophil granulocytes and to a lesser extent in monocytes. MPO plays a crucial role in the immune system by contributing to the microbicidal activity of phagocytes. This enzyme catalyzes the production of hypochlorous acid (HOCl) from hydrogen peroxide (H₂O₂) and chloride anion (Cl⁻) during the respiratory burst, which is a key mechanism of innate immunity.
Structure and Biochemistry
MPO is a dimeric enzyme, each monomer consisting of a heavy chain (~60 kDa) and a light chain (~12 kDa) linked by a disulfide bond. The enzyme contains a heme prosthetic group, which is essential for its catalytic activity. The heme group is covalently attached to the protein via two ester linkages to aspartic acid and glutamic acid residues.
The active site of MPO contains a heme iron that cycles between different oxidation states during the catalytic process. The enzyme's activity is highly dependent on the presence of chloride ions, which act as substrates for the production of hypochlorous acid.
Function in Immune Response
MPO is primarily involved in the host defense mechanism against pathogens. Upon activation of neutrophils, MPO is released into the phagosome, where it utilizes hydrogen peroxide produced by the NADPH oxidase complex to generate hypochlorous acid. HOCl is a potent antimicrobial agent capable of killing a wide range of pathogens, including bacteria, fungi, and viruses.
The enzyme also participates in the formation of other reactive oxygen species (ROS) and reactive nitrogen species (RNS), which contribute to the oxidative burst that is essential for the destruction of engulfed microbes. MPO-derived oxidants can modify proteins, lipids, and DNA, leading to microbial killing.
Pathophysiology
While MPO plays a protective role in host defense, its activity can also contribute to tissue damage and inflammation. Excessive production of MPO-derived oxidants has been implicated in various inflammatory diseases, including atherosclerosis, rheumatoid arthritis, and neurodegenerative disorders.
In atherosclerosis, MPO-derived oxidants contribute to the oxidation of low-density lipoprotein (LDL), promoting the formation of foam cells and plaque development. Elevated levels of MPO in the blood have been associated with an increased risk of cardiovascular events.
Clinical Significance
MPO has emerged as a potential biomarker for various diseases due to its role in inflammation and oxidative stress. Elevated MPO levels have been detected in patients with cardiovascular diseases, chronic kidney disease, and certain cancers. Measuring MPO activity or concentration in biological fluids can provide valuable diagnostic and prognostic information.
Therapeutic strategies targeting MPO are being explored to mitigate its detrimental effects in inflammatory diseases. Inhibitors of MPO activity, such as 4-aminobenzoic acid hydrazide (ABAH), have shown promise in preclinical studies.
Genetic Variants
Genetic polymorphisms in the MPO gene can influence the enzyme's expression and activity. One well-studied polymorphism is the G-463A variant in the promoter region of the MPO gene, which affects transcriptional activity. Individuals carrying the A allele have reduced MPO expression and activity, which may impact their susceptibility to certain diseases.
Laboratory Analysis
MPO activity can be measured using various biochemical assays. One common method is the guaiacol assay, where the oxidation of guaiacol by MPO in the presence of hydrogen peroxide is monitored spectrophotometrically. Immunoassays, such as enzyme-linked immunosorbent assays (ELISAs), are also used to quantify MPO levels in biological samples.
Therapeutic Implications
Given the dual role of MPO in host defense and tissue damage, therapeutic modulation of MPO activity is a potential strategy for treating inflammatory diseases. MPO inhibitors, antioxidants, and scavengers of MPO-derived oxidants are being investigated for their therapeutic potential.