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Myeloperoxidase

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Title: Myeloperoxidase  
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Subject: Eosinophil peroxidase, Azurophilic granule, Peroxidase, Neutrophil granulocyte, MPO
Collection: Ec 1.11.1, Hemoproteins
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Myeloperoxidase

Myeloperoxidase
Identifiers
EC number 1.11.2.2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Myeloperoxidase
Crystallographic structure of human myeloperoxidase.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol
External IDs ChEMBL: GeneCards:
EC number
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
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Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17.[2] MPO is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells), and produces hypohalous acids to carry out their antimicrobial activity.[2][3] It is a lysosomal protein stored in azurophilic granules of the neutrophil and released into the extracellular space during degranulation.[4][5] MPO has a heme pigment, which causes its green color in secretions rich in neutrophils, such as pus and some forms of mucus.[5]

Contents

  • Structure 1
  • Function 2
  • Clinical significance 3
    • Medical uses 3.1
    • Inhibitors of MPO 3.2
  • See also 4
  • References 5

Structure

The 150-kDa MPO protein is a cationic homodimer consisting of two 15-kDa light chains and two variable-weight glycosylated heavy chains bound to a prosthetic heme group.[6][7][8] 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.[8]

Three isoforms have been identified, differing only in the size of the heavy chains.[6]

MPO contains a calcium binding site with seven ligands, forming a pentagonal pyramid conformation. 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.[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 the equivalent from a non-chlorine halide) 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.[6][10] Hypochlorous acid and tyrosyl radical are cytotoxic, so they are used by the neutrophil to kill bacteria and other pathogens.[11] 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.[12] In addition, MPO mediates protein nitrosylation and the formation of 3-chlorotyrosine and dityrosine crosslinks.[6]

Clinical significance

Myeloperoxidase deficiency is a hereditary deficiency of the enzyme, which predisposes to immune deficiency.[13]

Antibodies against MPO have been implicated in various types of vasculitis, most prominently three clinically and pathologically recognized forms: granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis), microscopic polyangiitis (MPA); and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–Strauss syndrome). Antibodies are also known as anti-neutrophil cytoplasmic antibodies (ANCAs), though ANCAs have also been detected in staining of the perinuclear region.[14]

Recent studies have reported an association between elevated myeloperoxidase levels and the severity of coronary artery disease.[15] And Heslop et al. reported that elevated MPO levels more than doubled the risk for cardiovascular mortality over a 13-year period.[16] It has also been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable.[17][18]

Medical uses

An initial 2003 study suggested that MPO could serve as a sensitive predictor for myocardial infarction in patients presenting with chest pain.[19] 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.[16]

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.[20] 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.[21]

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.[22]

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.[23]

See also

References

  1. ^ ​; Blair-Johnson M, Fiedler T, Fenna R (November 2001). "Human myeloperoxidase: structure of a cyanide complex and its interaction with bromide and thiocyanate substrates at 1.9 Å resolution". Biochemistry 40 (46): 13990–7.  
  2. ^ a b "Entrez Gene: Myeloperoxidase". 
  3. ^ Klebanoff SJ (May 2005). "Myeloperoxidase: friend and foe". Journal of Leukocyte Biology 77 (5): 598–625.  
  4. ^ 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.  
  5. ^ a b Tiidus, Peter (2014). Biochemistry Primer for Exercise Science (4th ed.). Cram101.  
  6. ^ a b c d ""Mouse MPO EasyTestTM ELISA Kit"" (PDF). 
  7. ^ Mathy-Hartert M, Bourgeois E, Grülke S, Deby-Dupont G, Caudron I, Deby C, Lamy M, Serteyn D (Apr 1998). "Purification of myeloperoxidase from equine polymorphonuclear leucocytes". Canadian Journal of Veterinary Research = Revue Canadienne De Recherche Vétérinaire 62 (2): 127–32.  
  8. ^ a b Davies MJ (Jan 2011). "Myeloperoxidase-derived oxidation: mechanisms of biological damage and its prevention". Journal of Clinical Biochemistry and Nutrition 48 (1): 8–19.  
  9. ^ 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.  
  10. ^ 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.  
  11. ^ Hampton MB, Kettle AJ, Winterbourn CC (Nov 1998). "Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing". Blood 92 (9): 3007–17.  
  12. ^ 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.  
  13. ^ 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.  
  14. ^ 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.  
  15. ^ 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.  
  16. ^ a b 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.  
  17. ^ Nicholls SJ, Hazen SL (Jun 2005). "Myeloperoxidase and cardiovascular disease". Arteriosclerosis, Thrombosis, and Vascular Biology 25 (6): 1102–11.  
  18. ^ Lau D, Baldus S (Jul 2006). "Myeloperoxidase and its contributory role in inflammatory vascular disease". Pharmacology & Therapeutics 111 (1): 16–26.  
  19. ^ 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.  
  20. ^ Leong A S-Y, Cooper K, Leong, FJ W-M (2003). Manual of Diagnostic Antibodies for Immunohistology. London: Greenwich Medical Media. pp. 325–326.  
  21. ^ Csernok E, Moosig F (Aug 2014). "Current and emerging techniques for ANCA detection in vasculitis". Nature Reviews. Rheumatology 10 (8): 494–501.  
  22. ^ 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.  
  23. ^ Kettle AJ, Gedye CA, Winterbourn CC (Jan 1997). "Mechanism of inactivation of myeloperoxidase by 4-aminobenzoic acid hydrazide". The Biochemical Journal. 321. 321 ( Pt 2): 503–8.  
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