Myeloperoxidase (MPO) is a peroxidaseenzyme that in humans is encoded by the MPOgene on chromosome 17.[5] 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.[5][6] It is a lysosomal protein stored in azurophilic granules of the neutrophil and released into the extracellular space during degranulation.[7] Neutrophil myeloperoxidase has a heme pigment, which causes its green color in secretions rich in neutrophils, such as mucus and sputum.[8] The green color contributed to its outdated name verdoperoxidase.
Myeloperoxidase is found in many different organisms including mammals, birds, fish, reptiles, and amphibians.[citation needed] Myeloperoxidase deficiency is a well-documented disease among humans resulting in impaired immune function.[9]
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.[14] In addition, MPO mediates protein nitrosylation and the formation of 3-chlorotyrosine and dityrosinecrosslinks.[10] Following phagocytosis, the immune cells repair and remodel tissues, which can be aided by oxidized products of myeloperoxidase function.[citation needed]
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.[15]
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. Both are proteolytically generated from the precursor peptide encoded by the MPO gene.[16][10][17][18] The light chains are glycosylated and contain the modified iron protoporphyrin IXactive 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.[18]
Variation in glycosylation and the identity of the heavy chain lead to variations in molecular weight within the 135-200 kDa range.[19][16] In mice, three isoforms exist, differing only by the heavy chain.[10]
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.[20]
Reaction mechanism
The central heme group acts as the active site. The reaction starts when hydrogen peroxide donates an oxygen to the heme group, converting it to an activated form called "Compound I". 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.[how?] This cycle continues for as long as the immune system requires.[citation needed]
Recent studies have reported an association between elevated myeloperoxidase levels and the severity of coronary artery disease.[22] And Heslop et al. reported that elevated MPO levels more than doubled the risk for cardiovascular mortality over a 13-year period.[23] It has also been suggested that myeloperoxidase plays a significant role in the development of the atheroscleroticlesion and rendering plaques unstable.[24][25]
Medical tests
An initial 2003 study suggested that MPO could serve as a sensitive predictor for myocardial infarction in patients presenting with chest pain.[26] 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.[23]
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.[27] 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.[28]
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.[29]
^Kinkade JM, Pember SO, Barnes KC, Shapira R, Spitznagel JK, Martin LE (Jul 1983). "Differential distribution of distinct forms of myeloperoxidase in different azurophilic granule subpopulations from human neutrophils". Biochemical and Biophysical Research Communications. 114 (1): 296–303. doi:10.1016/0006-291x(83)91627-3. PMID6192815.
^Le T, Bhushan V, Sochat M, Damisch K, Abrams J, Kallianos K, Boqambar H, Qiu, C, Coleman C (2021). First Aid for the USMLE Step 1 (2021 ed.). New York: McGraw Hill. p. 109. ISBN9781260467529.
^ abKutter D, Devaquet P, Vanderstocken G, Paulus JM, Marchal V, Gothot A (2000). "Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit ?". Acta Haematologica. 104 (1): 10–5. doi:10.1159/000041062. PMID11111115. S2CID36776058.
^ abDavey CA, Fenna RE (August 1996). "2.3 A resolution X-ray crystal structure of the bisubstrate analogue inhibitor salicylhydroxamic acid bound to human myeloperoxidase: a model for a prereaction complex with hydrogen peroxide". Biochemistry. 35 (33): 10967–10973. doi:10.1021/bi960577m. PMID8718890.
^Shaw SA, Vokits BP, Dilger AK, Viet A, Clark CG, Abell LM, et al. (November 2020). "Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase". Bioorganic & Medicinal Chemistry. 28 (22): 115723. doi:10.1016/j.bmc.2020.115723. PMID33007547. S2CID222145838.
^Shin K, Hayasawa H, Lönnerdal B (Mar 2001). "Mutations affecting the calcium-binding site of myeloperoxidase and lactoperoxidase". Biochemical and Biophysical Research Communications. 281 (4): 1024–9. doi:10.1006/bbrc.2001.4448. PMID11237766.
^Lau D, Baldus S (Jul 2006). "Myeloperoxidase and its contributory role in inflammatory vascular disease". Pharmacology & Therapeutics. 111 (1): 16–26. doi:10.1016/j.pharmthera.2005.06.023. PMID16476484.
^Leong AS, Cooper K, Leong, FJ (2003). Manual of Diagnostic Antibodies for Immunohistology. London: Greenwich Medical Media. pp. 325–326. ISBN1-84110-100-1.
