Myeloperoxidase Explained

Myeloperoxidase
Ec Number:1.11.2.2

Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17.[1] 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.[1] [2] It is a lysosomal protein stored in azurophilic granules of the neutrophil and released into the extracellular space during degranulation.[3] Neutrophil myeloperoxidase has a heme pigment, which causes its green color in secretions rich in neutrophils, such as mucus and sputum.[4] The green color contributed to its outdated name verdoperoxidase.

Myeloperoxidase is 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.

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.[5] Hypochlorous acid and tyrosyl radical are cytotoxic, so they are used by the neutrophil to kill bacteria and other pathogens.[6] [7]

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.[8] In addition, MPO mediates protein nitrosylation and the formation of 3-chlorotyrosine and dityrosine crosslinks. Following phagocytosis, the immune cells repair and remodel tissues, which can be aided by oxidized products of myeloperoxidase function.

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.[9]

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.[10] [11] [12] [13] 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.[13]

Variation in glycosylation and the identity of the heavy chain lead to variations in molecular weight within the 135-200 kDa range.[14] In mice, three isoforms exist, differing only by the heavy chain.[11]

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.[15]

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. This cycle continues for as long as the immune system requires.

Clinical significance

Myeloperoxidase deficiency is a hereditary deficiency of the enzyme, which predisposes to immune deficiency.[16]

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.[17]

Recent studies have reported an association between elevated myeloperoxidase levels and the severity of coronary artery disease.[18] And Heslop et al. reported that elevated MPO levels more than doubled the risk for cardiovascular mortality over a 13-year period.[19] It has also been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable.[20] [21]

Medical tests

An initial 2003 study suggested that MPO could serve as a sensitive predictor for myocardial infarction in patients presenting with chest pain.[22] 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.[19]

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.[23] 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.[24]

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.[25]

See also

Notes and References

  1. Web site: Entrez Gene: Myeloperoxidase .
  2. Klebanoff SJ . Myeloperoxidase: friend and foe . Journal of Leukocyte Biology . 77 . 5 . 598–625 . May 2005 . 15689384 . 10.1189/jlb.1204697 . 12489688 . free .
  3. Kinkade JM, Pember SO, Barnes KC, Shapira R, Spitznagel JK, Martin LE . Differential distribution of distinct forms of myeloperoxidase in different azurophilic granule subpopulations from human neutrophils . Biochemical and Biophysical Research Communications . 114 . 1 . 296–303 . Jul 1983 . 6192815 . 10.1016/0006-291x(83)91627-3.
  4. Book: Le T, Bhushan V, Sochat M, Damisch K, Abrams J, Kallianos K, Boqambar H, Qiu, C, Coleman C . First Aid for the USMLE Step 1 . 2021 . McGraw Hill . New York . 9781260467529 . 109 . 2021.
  5. Heinecke JW, Li W, Francis GA, Goldstein JA . Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins . The Journal of Clinical Investigation . 91 . 6 . 2866–72 . Jun 1993 . 8390491 . 443356 . 10.1172/JCI116531 .
  6. Hampton MB, Kettle AJ, Winterbourn CC . Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing . Blood . 92 . 9 . 3007–17 . Nov 1998 . 9787133 . 10.1182/blood.V92.9.3007 .
  7. Davies MJ . Myeloperoxidase: Mechanisms, reactions and inhibition as a therapeutic strategy in inflammatory diseases . Pharmacology & Therapeutics . 218 . 107685 . February 2021 . 32961264 . 10.1016/j.pharmthera.2020.107685 . 221865058 .
  8. Shao B, Oda MN, Oram JF, Heinecke JW . Myeloperoxidase: an oxidative pathway for generating dysfunctional high-density lipoprotein . Chemical Research in Toxicology . 23 . 3 . 447–54 . Mar 2010 . 20043647 . 10.1021/tx9003775 . 2838938.
  9. 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 . Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation . Nature Nanotechnology . 5 . 5 . 354–9 . May 2010 . 20364135 . 10.1038/nnano.2010.44 . 6714564 . 2010NatNa...5..354K .
  10. Davey CA, Fenna RE . 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 . August 1996 . 8718890 . 10.1021/bi960577m .
  11. Web site: Mouse MPO EasyTestTM ELISA Kit. 2015-08-06. https://web.archive.org/web/20160303172034/http://bioaimscientific.com/sites/default/files/manual/MouseMPOELISA.pdf. 2016-03-03. dead.
  12. Mathy-Hartert M, Bourgeois E, Grülke S, Deby-Dupont G, Caudron I, Deby C, Lamy M, Serteyn D . 6 . Purification of myeloperoxidase from equine polymorphonuclear leucocytes . Canadian Journal of Veterinary Research . 62 . 2 . 127–132 . April 1998 . 9553712 . 1189459 .
  13. Davies MJ . Myeloperoxidase-derived oxidation: mechanisms of biological damage and its prevention . Journal of Clinical Biochemistry and Nutrition . 48 . 1 . 8–19 . January 2011 . 21297906 . 3022070 . 10.3164/jcbn.11-006FR .
  14. Shaw SA, Vokits BP, Dilger AK, Viet A, Clark CG, Abell LM, Locke GA, Duke G, Kopcho LM, Dongre A, Gao J, Krishnakumar A, Jusuf S, Khan J, Spronk SA, Basso MD, Zhao L, Cantor GH, Onorato JM, Wexler RR, Duclos F, Kick EK . 6 . Discovery and structure activity relationships of 7-benzyl triazolopyridines as stable, selective, and reversible inhibitors of myeloperoxidase . Bioorganic & Medicinal Chemistry . 28 . 22 . 115723 . November 2020 . 33007547 . 10.1016/j.bmc.2020.115723 . 222145838 .
  15. Shin K, Hayasawa H, Lönnerdal B . Mutations affecting the calcium-binding site of myeloperoxidase and lactoperoxidase . Biochemical and Biophysical Research Communications . 281 . 4 . 1024–9 . Mar 2001 . 11237766 . 10.1006/bbrc.2001.4448 .
  16. Kutter D, Devaquet P, Vanderstocken G, Paulus JM, Marchal V, Gothot A . Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit ? . Acta Haematologica . 104 . 1 . 10–5 . 2000 . 11111115 . 10.1159/000041062 . 36776058 .
  17. Flint SM, McKinney EF, Smith KG . Emerging concepts in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis . Current Opinion in Rheumatology . 27 . 2 . 197–203 . Mar 2015 . 25629443 . 10.1097/BOR.0000000000000145 . 20296651 .
  18. Zhang R, Brennan ML, Fu X, Aviles RJ, Pearce GL, Penn MS, Topol EJ, Sprecher DL, Hazen SL . Association between myeloperoxidase levels and risk of coronary artery disease . JAMA . 286 . 17 . 2136–42 . Nov 2001 . 11694155 . 10.1001/jama.286.17.2136 . free .
  19. Heslop CL, Frohlich JJ, Hill JS . 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 . Mar 2010 . 20223364 . 10.1016/j.jacc.2009.11.050 . free .
  20. Nicholls SJ, Hazen SL . Myeloperoxidase and cardiovascular disease . Arteriosclerosis, Thrombosis, and Vascular Biology . 25 . 6 . 1102–11 . Jun 2005 . 15790935 . 10.1161/01.ATV.0000163262.83456.6d . free .
  21. Lau D, Baldus S . Myeloperoxidase and its contributory role in inflammatory vascular disease . Pharmacology & Therapeutics . 111 . 1 . 16–26 . Jul 2006 . 16476484 . 10.1016/j.pharmthera.2005.06.023 .
  22. 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 . Prognostic value of myeloperoxidase in patients with chest pain . The New England Journal of Medicine . 349 . 17 . 1595–604 . Oct 2003 . 14573731 . 10.1056/NEJMoa035003 . 22084078 . free .
  23. Book: Leong AS, Cooper K, Leong, FJ . Manual of Diagnostic Antibodies for Immunohistology . Greenwich Medical Media . London . 2003 . 325–326 . 1-84110-100-1 .
  24. Csernok E, Moosig F . Current and emerging techniques for ANCA detection in vasculitis . Nature Reviews. Rheumatology . 10 . 8 . 494–501 . Aug 2014 . 24890776 . 10.1038/nrrheum.2014.78 . 25292707 .
  25. Kettle AJ, Gedye CA, Winterbourn CC . Mechanism of inactivation of myeloperoxidase by 4-aminobenzoic acid hydrazide . The Biochemical Journal . 321 . 2. 503–8 . Jan 1997 . 9020887 . 1218097 . 10.1042/bj3210503. 321 .

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