Myeloperoxidase(MPO) is aperoxidaseenzymethat in humans is encoded by theMPOgeneonchromosome 17.[5]MPO is most abundantly expressed inneutrophils(a subtype ofwhite blood cells), and produces hypohalous acids to carry out theirantimicrobialactivity, including hypochlorous acid, the sodium salt of which is the chemical in bleach.[5][6]It is alysosomalprotein stored inazurophilic granulesof the neutrophil and released into theextracellular spaceduring degranulation.[7]Neutrophil myeloperoxidase has ahemepigment, which causes its green color in secretions rich inneutrophils,such asmucusandsputum.[8]The green color contributed to its outdated nameverdoperoxidase.
| Myeloperoxidase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||
| EC no. | 1.11.2.2 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDBstructures | RCSB PDBPDBePDBsum | ||||||||
| |||||||||
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
editMPO is a member of the XPO subfamily of peroxidases and produceshypochlorous acid(HOCl) fromhydrogen peroxide(H2O2) andchlorideanion(Cl−) (orhypobromous acidif Br- is present) during the neutrophil'srespiratory burst.It requires heme as acofactor.Furthermore, it oxidizestyrosineto tyrosyl radical using hydrogen peroxide as anoxidizing agent.[10][11]
However, this hypochlorous acid may also cause oxidative damage in host tissue. Moreover, MPO oxidation ofapoA-I reduces HDL-mediated inhibition ofapoptosisand inflammation.[12]In addition, MPO mediates proteinnitrosylationand the formation of 3-chlorotyrosine anddityrosinecrosslinks.[10]
Myeloperoxidase is the first and so far only[needs update]human enzyme known to break downcarbon nanotubes,allaying a concern among clinicians that using nanotubes for targeted delivery of medicines would lead to an unhealthy buildup of nanotubes in tissues.[13]
Role in innate immunity
editNeutrophilsuse myeloperoxidase to produce the substances needed for their respiratory burst.[14]Hypochlorous acid and tyrosyl radical arecytotoxic,so they are used by the neutrophil to killbacteriaand certain types of fungi.[14][15][16]
Structure
editThe 150-kDaMPO protein is a cationicheterotetramerconsisting of two 15-kDa light chains and two variable-weight glycosylated heavy chains bound to a prosthetichemegroup complex with calcium ions, arranged as ahomodimerofheterodimers.Both are proteolytically generated from the precursor peptide encoded by theMPOgene.[17][10][18][19]The light chains areglycosylatedand contain the modified ironprotoporphyrin IXactive site.Together, the light and heavy chains form two identical 73-kDa monomers connected by acystinebridge at Cys153. The protein forms a deep crevice which holds the heme group at the bottom, as well as ahydrophobicpocket at the entrance to the distal heme cavity which carries out its catalytic activity.[19]
Variation in glycosylation and the identity of the heavy chain lead to variations in molecular weight within the 135-200 kDa range.[20][17]In mice, threeisoformsexist, differing only by the heavy chain.[10]
One of the ligands is thecarbonylgroup of Asp 96. Calcium-binding is important for structure of the active site because of Asp 96's close proximity to the catalytic His95side chain.[21]
Reaction mechanism
editThe central heme group acts as theactive 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
editMyeloperoxidase deficiency
editMyeloperoxidase deficiency is a hereditary deficiency of the enzyme, which causes a mildimmune deficiencyagainst certainpathogens.[9][14]People with myeloperoxidase deficiency are most at risk of infection byCandidaspecies, which are pathogenic fungi. The most common species found in humans isCandida albicans.There may be an increased risk of certain other infections, such as withKlebsiella pneumoniae,but recurrentcandidiasisis the only common clinical consequence, if the patient is noticeably affected at all.[14]
Vasculitis
editAntibodiesagainst MPO have been implicated in various types ofvasculitis,most prominently three clinically and pathologically recognized forms:granulomatosis with polyangiitis(GPA), microscopic polyangiitis (MPA); andeosinophilic granulomatosis with polyangiitis(EGPA). Antibodies are also known asanti-neutrophil cytoplasmic antibodies(ANCAs), though ANCAs have also been detected instainingof the perinuclear region.[22]
Atherosclerosis and heart disease
editMyeloperoxidase is known to contribute toatherosclerosisand diseases related to it, includingcoronary artery disease.MPO oxidizesLDL cholesterol,and as a result, theLDL receptorin liver cells becomes unable to bind to LDL and remove it from the blood stream. However, in its oxidized state, LDL can still contribute tofoam cellformation and other atherosclerotic processes. Thus, elevated levels of MPO are a risk factor for atherosclerosis.[23]
Medical tests
editThis section needs to beupdated.(January 2025) |
An initial 2003 study suggested that MPO could serve as a sensitive predictor formyocardial infarctionin patients presenting withchest pain.[24]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.[25]
Immunohistochemicalstaining for myeloperoxidase used to be administered in the diagnosis ofacute myeloid leukemiato demonstrate that the leukemic cells were derived from themyeloidlineage. Myeloperoxidase staining is still important in the diagnosis ofmyeloid sarcoma,contrasting with the negative staining oflymphomas,which can otherwise have a similar appearance.[26]In the case of screening patients for vasculitis,flow cytometric assayshave demonstrated comparable sensitivity toimmunofluorescencetests, with the additional benefit of simultaneous detection of multiple autoantibodies relevant to vasculitis. Nonetheless, this method still requires further testing.[27]
Inhibitors of MPO
editAzidehas been used traditionally as an MPO inhibitor, but 4-aminobenzoic acid hydrazide (4-ABH) is a more specific inhibitor of MPO.[28]
See also
editReferences
edit- ^abcGRCh38: Ensembl release 89: ENSG00000005381–Ensembl,May 2017
- ^abcGRCm38: Ensembl release 89: ENSMUSG00000009350–Ensembl,May 2017
- ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ab"Entrez Gene: Myeloperoxidase".
- ^Klebanoff SJ (May 2005)."Myeloperoxidase: friend and foe".Journal of Leukocyte Biology.77(5):598–625.doi:10.1189/jlb.1204697.PMID15689384.S2CID12489688.
- ^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.
- ^abcd"Mouse MPO EasyTestTM ELISA Kit"(PDF).Archived fromthe original(PDF)on 2016-03-03.Retrieved2015-08-06.
- ^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.PMC443356.PMID8390491.
- ^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.PMC2838938.PMID20043647.
- ^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.PMC6714564.PMID20364135.
- Clay Dillow (April 6, 2010)."Scientists Devise A Means For Human Bodies To Break Down Carbon Nanotubes".Popular Science.
- ^abcdAratani Y (2018-02-15)."Myeloperoxidase: Its role for host defense, inflammation, and neutrophil function".Archives of Biochemistry and Biophysics.640:47–52.doi:10.1016/j.abb.2018.01.004.ISSN0003-9861.PMID29336940.
- ^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.PMID9787133.
- ^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.PMID32961264.S2CID221865058.
- ^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.
- ^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.PMC1189459.PMID9553712.
- ^abDavies 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.PMC3022070.PMID21297906.
- ^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.
- ^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.PMID25629443.S2CID20296651.
- ^Frangie C, Daher J (2022-05-06)."Role of myeloperoxidase in inflammation and atherosclerosis (Review)".Biomedical Reports.16(6): 53.doi:10.3892/br.2022.1536.ISSN2049-9434.PMC9112398.PMID35620311.
- ^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.PMID14573731.S2CID22084078.
- ^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.PMID20223364.
- ^Leong AS, Cooper K, Leong, FJ (2003).Manual of Diagnostic Antibodies for Immunohistology.London: Greenwich Medical Media. pp.325–326.ISBN1-84110-100-1.
- ^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.PMID24890776.S2CID25292707.
- ^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.PMC1218097.PMID9020887.
