Myeloperoxidase

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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
Myeloperoxidase.png
Crystallographic structure of human myeloperoxidase.[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol MPO
External IDs OMIM606989 MGI97137 HomoloGene55450 ChEMBL: 2439 GeneCards: MPO Gene
EC number 1.11.2.2
RNA expression pattern
PBB GE MPO 203948 s at tn.png
PBB GE MPO 203949 at tn.png
More reference expression data
Orthologs
Species Human Mouse
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:
56.35 – 56.36 Mb
Chr 11:
87.79 – 87.8 Mb
PubMed search [1] [2]

Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene.[2] Myeloperoxidase is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells).[3] It is a lysosomal protein stored in azurophilic granules of the neutrophil. MPO has a heme pigment, which causes its green color in secretions rich in neutrophils, such as pus and some forms of mucus.

Structure[edit]

The 150-kDa MPO protein is a dimer consisting of two 15-kDa light chains and two variable-weight glycosylated heavy chains bound to a prosthetic heme group. Three isoforms have been identified, differing only in the size of the heavy chains.[4] It 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.

Function[edit]

MPO 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.[5]

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

Inhibitors of MPO[edit]

Azide has been used traditionally as an MPO inhibitor, but 4-aminobenzoic acid hydrazide (4-ABH) is a more specific inhibitor of MPO.[6]

Genetics[edit]

The human gene is located on chromosome 17 (17q23.1).[2]

Role in disease[edit]

Myeloperoxidase deficiency is a hereditary deficiency of the enzyme, which predisposes to immune deficiency.[7]

Antibodies against MPO have been implicated in various types of vasculitis, most prominently crescentic glomerulonephritis and Churg-Strauss syndrome. They are detected as perinuclear ANCAs (p-ANCAs), as opposed to the cytoplasmic ANCAs (c-ANCAs) against proteinase-3 (PR3), which are strongly associated with Wegener's granulomatosis.

Recent studies have reported an association between elevated myeloperoxidase levels and the severity of coronary artery disease.[8] And Heslop et al. reported that elevated MPO levels more than doubled the risk for cardiovascular mortality over a 13-year period.[9] It has also been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable.[10][11]

Medical uses[edit]

An initial 2003 study suggested that MPO could serve as a sensitive predictor for myocardial infarction in patients presenting with chest pain.[12] 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.[9]

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. However, the use of myeloperoxidase staining in this setting has been supplanted by the widespread use of flow cytometry.[citation needed] 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.[13]

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.[14]

See also[edit]

References[edit]

  1. ^ PDB 1D7W; 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. doi:10.1021/bi0111808. PMID 11705390. 
  2. ^ a b "Entrez Gene: Myeloperoxidase". 
  3. ^ Klebanoff SJ (May 2005). "Myeloperoxidase: friend and foe". J. Leukoc. Biol. 77 (5): 598–625. doi:10.1189/jlb.1204697. PMID 15689384. 
  4. ^ Mathy-Hartert M, Bourgeois E, Grülke S, Deby-Dupont G, Caudron I, Deby C, Lamy M, Serteyn D (April 1998). "Purification of myeloperoxidase from equine polymorphonuclear leucocytes". Can. J. Vet. Res. 62 (2): 127–32. PMC 1189459. PMID 9553712. 
  5. ^ Heinecke JW, Li W, Francis GA, Goldstein JA (June 1993). "Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins". J. Clin. Invest. 91 (6): 2866–72. doi:10.1172/JCI116531. PMC 443356. PMID 8390491. 
  6. ^ Kettle AJ, Gedye CA, Winterbourn CC (January 1997). "Mechanism of inactivation of myeloperoxidase by 4-aminobenzoic acid hydrazide". Biochem. J. 321. ( Pt 2): 503–8. PMC 1218097. PMID 9020887. 
  7. ^ Kutter D, Devaquet P, Vanderstocken G, Paulus JM, Marchal V, Gothot A (2000). "Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit ?". Acta Haematol. 104 (1): 10–5. doi:10.1159/000041062. PMID 11111115. 
  8. ^ Zhang R, Brennan ML, Fu X, Aviles RJ, Pearce GL, Penn MS, Topol EJ, Sprecher DL, Hazen SL (November 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. 
  9. ^ a b Heslop CL, Frohlich JJ, Hill JS (March 2010). "Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography". J. Am. Coll. Cardiol. 55 (11): 1102–9. doi:10.1016/j.jacc.2009.11.050. PMID 20223364. 
  10. ^ Nicholls SJ, Hazen SL (June 2005). "Myeloperoxidase and cardiovascular disease". Arterioscler. Thromb. Vasc. Biol. 25 (6): 1102–11. doi:10.1161/01.ATV.0000163262.83456.6d. PMID 15790935. 
  11. ^ Lau D, Baldus S (July 2006). "Myeloperoxidase and its contributory role in inflammatory vascular disease". Pharmacol. Ther. 111 (1): 16–26. doi:10.1016/j.pharmthera.2005.06.023. PMID 16476484. 
  12. ^ 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 (October 2003). "Prognostic value of myeloperoxidase in patients with chest pain". N. Engl. J. Med. 349 (17): 1595–604. doi:10.1056/NEJMoa035003. PMID 14573731. 
  13. ^ Leong A S-Y, Cooper K, Leong, FJ W-M (2003). Manual of Diagnostic Antibodies for Immunohistology. London: Greenwich Medical Media. pp. 325–326. ISBN 1-84110-100-1. 
  14. ^ 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 (April 2010). "Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation". Nat Nanotechnol 5 (5): 354–9. doi:10.1038/nnano.2010.44. PMID 20364135. Lay summarypopsci.com.