Myeloperoxidase

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MPO
PDB 1myp EBI.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MPO , myeloperoxidase
External IDs OMIM: 606989 MGI: 97137 HomoloGene: 55450 GeneCards: MPO
Orthologs
SpeciesHumanMouse
Entrez

4353

17523

Ensembl

ENSG00000005381

ENSMUSG00000009350

UniProt

P05164

P11247

RefSeq (mRNA)

NM_000250

NM_010824

RefSeq (protein)

NP_000241

NP_034954

Location (UCSC) Chr 17: 58.27 – 58.28 Mb Chr 11: 87.68 – 87.7 Mb
PubMed search [3] [4]
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Myeloperoxidase
Identifiers
EC no. 1.11.2.2
Databases
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NCBI proteins

Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene 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 [8] The green color contributed to its outdated name verdoperoxidase.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]

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. [10] [11] Hypochlorous acid and tyrosyl radical are cytotoxic, so they are used by the neutrophil to kill bacteria and other pathogens. [12] [13]

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 dityrosine crosslinks. [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 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. [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 ]

Clinical significance

Myeloperoxidase deficiency is a hereditary deficiency of the enzyme, which predisposes to immune deficiency. [9]

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. [21]

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 atherosclerotic lesion 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]

See also

Related Research Articles

<span class="mw-page-title-main">Catalase</span> Enzyme decomposing hydrogen peroxide

Catalase is a common enzyme found in nearly all living organisms exposed to oxygen which catalyzes the decomposition of hydrogen peroxide to water and oxygen. It is a very important enzyme in protecting the cell from oxidative damage by reactive oxygen species (ROS). Catalase has one of the highest turnover numbers of all enzymes; one catalase molecule can convert millions of hydrogen peroxide molecules to water and oxygen each second.

<span class="mw-page-title-main">Heme</span> Chemical coordination complex of an iron ion chelated to a porphyrin

Heme, or haem, is a ring-shaped iron-containing molecular component of hemoglobin, which is necessary to bind oxygen in the bloodstream. It is composed of four pyrrole rings with 2 vinyl and 2 propionic acid side chains. Heme is biosynthesized in both the bone marrow and the liver.

<span class="mw-page-title-main">Hypochlorous acid</span> Chemical compound

Hypochlorous acid is an inorganic compound with the chemical formula ClOH, also written as HClO, HOCl, or ClHO. Its structure is H−O−Cl. It is an acid that forms when chlorine dissolves in water, and itself partially dissociates, forming hypochlorite anion, ClO−. HClO and ClO− are oxidizers, and the primary disinfection agents of chlorine solutions. HClO cannot be isolated from these solutions due to rapid equilibration with its precursor, chlorine.

<span class="mw-page-title-main">Chronic granulomatous disease</span> Hereditary disease group

Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds used to kill certain ingested pathogens. This leads to the formation of granulomas in many organs. CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.

<span class="mw-page-title-main">Granulomatosis with polyangiitis</span> Medical condition

Granulomatosis with polyangiitis (GPA), also known as Wegener's granulomatosis (WG), after the German physician Friedrich Wegener, is a rare long-term systemic disorder that involves the formation of granulomas and inflammation of blood vessels (vasculitis). It is an autoimmune disease and a form of vasculitis that affects small- and medium-size vessels in many organs but most commonly affects the upper respiratory tract, lungs and kidneys. The signs and symptoms of GPA are highly varied and reflect which organs are supplied by the affected blood vessels. Typical signs and symptoms include nosebleeds, stuffy nose and crustiness of nasal secretions, and inflammation of the uveal layer of the eye. Damage to the heart, lungs and kidneys can be fatal.

<span class="mw-page-title-main">Hypochlorite</span> Ion

In chemistry, hypochlorite, or chloroxide is an anion with the chemical formula ClO−. It combines with a number of cations to form hypochlorite salts. Common examples include sodium hypochlorite and calcium hypochlorite. The Cl-O distance in ClO− is 1.69 Å.

<span class="mw-page-title-main">Myeloperoxidase deficiency</span> Medical condition

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/inherited and secondary/acquired. Lack of functional myeloperoxidase leads to less efficient killing of intracellular pathogens, particularly Candida albicans, as well as less efficient production and release of neutrophil extracellular traps (NETs) from the neutrophils to trap and kill extracellular pathogens. Despite these characteristics, more than 95% of individuals with myeloperoxidase deficiency experience no symptoms in their lifetime. For those who do experience symptoms, the most common symptom is frequent infections by Candida albicans. Individuals with myeloperoxidase deficiency also experience higher rates of chronic inflammatory conditions. Myeloperoxidase deficiency is diagnosed using flow cytometry or cytochemical stains. There is no treatment for myeloperoxidase deficiency itself. Rather, in the rare cases that individuals experience symptoms, these infections should be treated.

<span class="mw-page-title-main">Anti-neutrophil cytoplasmic antibody</span> Group of autoantibodies

Anti-neutrophil cytoplasmic antibodies (ANCAs) are a group of autoantibodies, mainly of the IgG type, against antigens in the cytoplasm of neutrophils and monocytes. They are detected as a blood test in a number of autoimmune disorders, but are particularly associated with systemic vasculitis, so called ANCA-associated vasculitides (AAV).

Respiratory burst is the rapid release of the reactive oxygen species (ROS), superoxide anion and hydrogen peroxide, from different cell types.

NADPH oxidase is a membrane-bound enzyme complex that faces the extracellular space. It can be found in the plasma membrane as well as in the membranes of phagosomes used by neutrophil white blood cells to engulf microorganisms. Human isoforms of the catalytic component of the complex include NOX1, NOX2, NOX3, NOX4, NOX5, DUOX1, and DUOX2.

Microscopic polyangiitis is an autoimmune disease characterized by a systemic, pauci-immune, necrotizing, small-vessel vasculitis without clinical or pathological evidence of granulomatous inflammation.

<span class="mw-page-title-main">Hemopexin</span>

Hemopexin, also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the HPX gene and belongs to the hemopexin family of proteins. Hemopexin is the plasma protein with the highest binding affinity for heme.

<span class="mw-page-title-main">Proteinase 3</span> Mammalian protein found in Homo sapiens

Proteinase 3, also known as PRTN3, is an enzyme that in humans is encoded by the PRTN3 gene.

<span class="mw-page-title-main">Sulfite oxidase</span>

Sulfite oxidase is an enzyme in the mitochondria of all eukaryotes, with exception of the yeasts. It oxidizes sulfite to sulfate and, via cytochrome c, transfers the electrons produced to the electron transport chain, allowing generation of ATP in oxidative phosphorylation. This is the last step in the metabolism of sulfur-containing compounds and the sulfate is excreted.

p-ANCA Type of autoantibody

p-ANCA, or MPO-ANCA, or perinuclear anti-neutrophil cytoplasmic antibodies, are antibodies that stain the material around the nucleus of a neutrophil. They are a special class of anti-neutrophil cytoplasmic antibodies.

<span class="mw-page-title-main">Animal heme-dependent peroxidases</span>

Animal heme-dependent peroxidases is a family of peroxidases. Peroxidases are found in bacteria, fungi, plants and animals. On the basis of sequence similarity, a number of animal heme peroxidases can be categorized as members of a superfamily: myeloperoxidase (MPO); eosinophil peroxidase (EPO); lactoperoxidase (LPO); thyroid peroxidase (TPO); prostaglandin H synthase (PGHS); and peroxidasin.

Haloperoxidases are peroxidases that are able to mediate the oxidation of halides by hydrogen peroxide. Both halides and hydrogen peroxide are widely available in the environment.

<span class="mw-page-title-main">Systemic vasculitis</span> Medical condition

Necrotizing vasculitis, also called systemic necrotizing vasculitis, is a general term for the inflammation of veins and arteries that develops into necrosis and narrows the vessels.

Ronald Jonathan Falk, MD, FACP, FASN is the Nan and Hugh Cullman Eminent Professor and Chair of the Department of Medicine at the University of North Carolina-Chapel Hill (UNC). He is a clinical nephrologist and internationally recognized expert in anti-neutrophil cytoplasmic autoantibody (ANCA)-induced vasculitis and autoimmune kidney disease. His career as a translational physician-scientist spans more than three decades. His clinical practice and translational research focus on characterizing the cell, tissue and physiologic changes in the development of specific autoimmune kidney diseases and developing new approaches for studying autoimmunity, inflammation and basic neutrophil/monocyte biology. He was Chief of the UNC Division of Nephrology and Hypertension from 1993-2015. He co-founded the UNC Kidney Center in 2005 and continues as Co-Director. Falk is a Past-President of the American Society of Nephrology (ASN). Since 2015, he has served as Chair of the Department of Medicine at UNC.

<span class="mw-page-title-main">Eosinophil peroxidase</span> Protein-coding gene in the species Homo sapiens

Eosinophil peroxidase is an enzyme found within the eosinophil granulocytes, innate immune cells of humans and mammals. This oxidoreductase protein is encoded by the gene EPX, expressed within these myeloid cells. EPO shares many similarities with its orthologous peroxidases, myeloperoxidase (MPO), lactoperoxidase (LPO), and thyroid peroxidase (TPO). The protein is concentrated in secretory granules within eosinophils. Eosinophil peroxidase is a heme peroxidase, its activities including the oxidation of halide ions to bacteriocidal reactive oxygen species, the cationic disruption of bacterial cell walls, and the post-translational modification of protein amino acid residues.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000005381 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000009350 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 "Entrez Gene: Myeloperoxidase".
  6. ↑ Klebanoff SJ (May 2005). "Myeloperoxidase: friend and foe". Journal of Leukocyte Biology. 77 (5): 598–625. doi: 10.1189/jlb.1204697 . PMID   15689384. S2CID   12489688.
  7. ↑ 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. PMID   6192815.
  8. ↑ 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. ISBN   9781260467529.
  9. 1 2 Kutter 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. PMID   11111115. S2CID   36776058.
  10. 1 2 3 4 "Mouse MPO EasyTestTM ELISA Kit" (PDF). Archived from the original (PDF) on 2016-03-03. Retrieved 2015-08-06.
  11. ↑ Heinecke JW, Li W, Francis GA, Goldstein JA (Jun 1993). "Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins". The Journal of Clinical Investigation. 91 (6): 2866–72. doi:10.1172/JCI116531. PMC   443356 . PMID   8390491.
  12. ↑ Hampton MB, Kettle AJ, Winterbourn CC (Nov 1998). "Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing". Blood. 92 (9): 3007–17. doi:10.1182/blood.V92.9.3007. PMID   9787133.
  13. ↑ Davies MJ (February 2021). "Myeloperoxidase: Mechanisms, reactions and inhibition as a therapeutic strategy in inflammatory diseases". Pharmacology & Therapeutics. 218: 107685. doi:10.1016/j.pharmthera.2020.107685. PMID   32961264. S2CID   221865058.
  14. ↑ Shao B, Oda MN, Oram JF, Heinecke JW (Mar 2010). "Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein". Chemical Research in Toxicology. 23 (3): 447–54. doi:10.1021/tx9003775. PMC   2838938 . PMID   20043647.
  15. ↑ Kagan VE, Konduru NV, Feng W, Allen BL, Conroy J, Volkov Y, Vlasova II, Belikova NA, Yanamala N, Kapralov A, Tyurina YY, Shi J, Kisin ER, Murray AR, Franks J, Stolz D, Gou P, Klein-Seetharaman J, Fadeel B, Star A, Shvedova AA (May 2010). "Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation". Nature Nanotechnology. 5 (5): 354–9. Bibcode:2010NatNa...5..354K. doi:10.1038/nnano.2010.44. PMC   6714564 . PMID   20364135.
  16. 1 2 Davey 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. PMID   8718890.
  17. ↑ Mathy-Hartert M, Bourgeois E, Grülke S, Deby-Dupont G, Caudron I, Deby C, et al. (April 1998). "Purification of myeloperoxidase from equine polymorphonuclear leucocytes". Canadian Journal of Veterinary Research. 62 (2): 127–132. PMC   1189459 . PMID   9553712.
  18. 1 2 Davies MJ (January 2011). "Myeloperoxidase-derived oxidation: mechanisms of biological damage and its prevention". Journal of Clinical Biochemistry and Nutrition. 48 (1): 8–19. doi:10.3164/jcbn.11-006FR. PMC   3022070 . PMID   21297906.
  19. ↑ 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. PMID   33007547. S2CID   222145838.
  20. ↑ 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. PMID   11237766.
  21. ↑ Flint SM, McKinney EF, Smith KG (Mar 2015). "Emerging concepts in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis". Current Opinion in Rheumatology. 27 (2): 197–203. doi:10.1097/BOR.0000000000000145. PMID   25629443. S2CID   20296651.
  22. ↑ Zhang R, Brennan ML, Fu X, Aviles RJ, Pearce GL, Penn MS, Topol EJ, Sprecher DL, Hazen SL (Nov 2001). "Association between myeloperoxidase levels and risk of coronary artery disease". JAMA. 286 (17): 2136–42. doi: 10.1001/jama.286.17.2136 . PMID   11694155.
  23. 1 2 Heslop CL, Frohlich JJ, Hill JS (Mar 2010). "Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography". Journal of the American College of Cardiology. 55 (11): 1102–9. doi: 10.1016/j.jacc.2009.11.050 . PMID   20223364.
  24. ↑ Nicholls SJ, Hazen SL (Jun 2005). "Myeloperoxidase and cardiovascular disease". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (6): 1102–11. doi: 10.1161/01.ATV.0000163262.83456.6d . PMID   15790935.
  25. ↑ 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. PMID   16476484.
  26. ↑ Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ, Goormastic M, Pepoy ML, McErlean ES, Topol EJ, Nissen SE, Hazen SL (Oct 2003). "Prognostic value of myeloperoxidase in patients with chest pain". The New England Journal of Medicine. 349 (17): 1595–604. doi: 10.1056/NEJMoa035003 . PMID   14573731. S2CID   22084078.
  27. ↑ Leong AS, Cooper K, Leong, FJ (2003). Manual of Diagnostic Antibodies for Immunohistology. London: Greenwich Medical Media. pp. 325–326. ISBN   1-84110-100-1.
  28. ↑ Csernok E, Moosig F (Aug 2014). "Current and emerging techniques for ANCA detection in vasculitis". Nature Reviews. Rheumatology. 10 (8): 494–501. doi:10.1038/nrrheum.2014.78. PMID   24890776. S2CID   25292707.
  29. ↑ Kettle AJ, Gedye CA, Winterbourn CC (Jan 1997). "Mechanism of inactivation of myeloperoxidase by 4-aminobenzoic acid hydrazide". The Biochemical Journal. 321. 321 (2): 503–8. doi:10.1042/bj3210503. PMC   1218097 . PMID   9020887.
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