The myeloperoxidase system of human phagocytes generates Nε-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation

Anderson, Melissa M.; Requena, Jesús R.; Crowley, Jan R.; Thorpe, Suzanne R.; Heinecke, Jay W.

doi:10.1172/jci3042

Cited by 328 publications

(236 citation statements)

References 62 publications

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“…Loss of methanesulfenic acid from the precursor the ion at m/z 3273.1 was evident. Peptide bond fragmentations (y-type) are also shown; y [17][18][19]21 indicate the presence of dehydroalanine, suggesting that formation of this product ion is very favorable in MALDI (high energy) processes.…”

Section: Low Energy Cid/maldi Psd Analysis Of A8 -Lys Sulfinamide Adductmentioning

confidence: 95%

“…The respiratory burst produces superoxide anions which dismutate to hydrogen peroxide (H 2 O 2 ) that is converted by myeloperoxidase (MPO) and Cl Ϫ to the powerful twoelectron (non-radical) oxidant hypochlorous acid (HOCl), which can chemically modify lipids, proteins and kill invading pathogens [14]. MPO-generated and exogenous HOCl react identically [15][16][17] and protein thiols and Met are preferred substrates [18]. HOCl also initiates LDL lipid peroxidation and formation of 3-chlorotyrosine and dityrosine [19].…”

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confidence: 99%

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Electrospray low energy CID and MALDI PSD fragmentations of protonated sulfinamide cross-linked peptides

Raftery

Geczy

2002

J. Am. Soc. Mass Spectrom.

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Murine S100A8 (A8) is a major cytoplasmic neutrophil protein and is converted to novel oxidation products containing Cys-amino-Lys sulfinamide cross-links and Met-sulfoxide by the neutrophil oxidant HOCl. Seven products were separated using RP-HPLC, with electrospray ionization mass spectrometry (ESI-MS) masses after deconvolution of 10,354, 10,388, Ϯ1, and 20,707, Ϯ3 Da, and all were resistant to reduction by dithiothreitol. The major products with masses of 10,354 Da contained Cys 41 -Lys 34/35 intramolecular cross-links. Additional isomeric products with identical masses (10,354 Da) were isolated and peptide mapping and ESI/MS indicated that Cys 41 forms covalent sulfinamide cross-links with either Lys 6 , Lys 76 , Lys 83 , or Lys 87 present in A8. Electrospray low energy collisionally induced (CID) spectra of multiply-charged AspN digest peptides with sulfinamide cross-links contained characteristic fragmentations that corresponded to simple cleavage of the nitrogen™sulfur bond with charge retention on either of the fragment ions, allowing conformation of cross-linked peptides. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) post source decay spectra of [M ϩ H] ϩ ions of the same sulfinamide-containing cross-linked peptides fragment similarly, but additional facile fragmentation reactions corresponding to formation of a protonated peptide containing de-hydroalanine were attributed to cleavage of the carbon™sulfur bond. In addition, lose of methanesulfenic acid from Met-sulfoxide was observed. A sulfinamide-containing adduct was isolated after incubation of the A8/HOCl reaction mixture with Lys or ␣ N-acetyl Lys with masses of 10,500 or 10,542 Da. ESI/MS/MS and MALDI/ post decay source (PSD) analysis of A8 32-57 -sulfinamide showed the same characteristic fragmentations as those in the sulfinamide cross-linked peptides, confirming the Cys 41 -Lys sulfinamide cross-link and suggesting that peptide-peptide sulfinamides may all fragment similarly, allowing ready identification of these cross-links in proteins from more complex biological materials. (J Am Soc Mass Spectrom 2002, 13, 709 -718)

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Section: Low Energy Cid/maldi Psd Analysis Of A8 -Lys Sulfinamide Adductmentioning

confidence: 95%

mentioning

confidence: 99%

Electrospray low energy CID and MALDI PSD fragmentations of protonated sulfinamide cross-linked peptides

Raftery

Geczy

2002

J. Am. Soc. Mass Spectrom.

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“…The best characterized role of myeloperoxidase is in host defense (Klebanoff and Clark 1978;Hurst and Barrette 1989;Gaut et al 2001) where the enzyme converts hydrogen peroxide generated from the oxidative burst to the potent microbicidal oxidant hypochlorous acid (HOCl; Harrison and Schultz 1976). HOCl chlorinates electron-rich substrates (Klebanoff and Clark 1978;Hurst and Barrette 1989), generates protein carbonyls (Yan et al 1997), and converts free amino acids to reactive aldehydes (Stetmaszynska and Zgliczynski 1978;Anderson et al 1997) that contribute to formation of AGEs (Anderson et al 1999). Myeloperoxidase also oxidizes nitrite to reactive nitrogen species (Eiserich et al 1998;Byun et al 1999) and converts tyrosine to tyrosyl radical, a reactive intermediate that promotes o,o¢-dityrosine formation and initiates lipid peroxidation (Heinecke et al 1993;Savenkova et al 1994).…”

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confidence: 99%

Neuronal expression of myeloperoxidase is increased in Alzheimer's disease

Green

Mendez

Jacob

et al. 2004

Journal of Neurochemistry

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290

196

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Myeloperoxidase, a heme protein expressed by professional phagocytic cells, generates an array of oxidants which are proposed to contribute to tissue damage during inflammation. We now report that enzymatically active myeloperoxidase and its characteristic amino acid oxidation products are present in human brain. Further, expression of myeloperoxidase is increased in brain tissue showing Alzheimer's neuropathology. Consistent with expression in phagocytic cells, myeloperoxidase immunoreactivity was present in some activated microglia in Alzheimer brains. However, the majority of immunoreactive material in brain localized with amyloid plaques and, surprisingly, neurons including granule and pyramidal neurons of the hippocampus. Confirming neuronal localization of the enzyme, several neuronal cell lines as well as primary neuronal cultures expressed myeloperoxidase protein. Myeloperoxidase mRNA was also detected in neuronal cell lines. These results reveal the unexpected presence of myeloperoxidase in neurons. The increase in neuronal myeloperoxidase expression we observed in Alzheimer disease brains raises the possibility that the enzyme contributes to the oxidative stress implicated in the pathogenesis of the neurodegenerative disorder.

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“…Myeloperoxidase-derived chlorinating agents also generate secondary oxidants such as monochloramines, dichloramines (14 -16), and amino acid-derived aldehydes (17)(18)(19).…”

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Production of Brominating Intermediates by Myeloperoxidase

Henderson¹,

Byun²,

Williams³

et al. 2001

Journal of Biological Chemistry

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118

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The existence of interhalogen compounds was proposed more than a century ago, but no biological roles have been attributed to these highly oxidizing intermediates. In this study, we determined whether the peroxidases of white blood cells can generate the interhalogen gas bromine chloride (BrCl ؊ -Br ؊ system generated a gas that converted cyclohexene into 1-bromo-2-chlorocyclohexane, implicating BrCl in the reaction. Moreover, human neutrophils used myeloperoxidase, H 2 O 2 , and Br ؊ to brominate deoxycytidine by a taurine-sensitive pathway, suggesting that transhalogenation reactions may be physiologically relevant. 5-Bromouracil incorporated into nuclear DNA is a well known mutagen. Our observations therefore raise the possibility that transhalogenation reactions initiated by phagocytes provide one pathway for mutagenesis and cytotoxicity at sites of inflammation.

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The myeloperoxidase system of human phagocytes generates Nε-(carboxymethyl)lysine on proteins: a mechanism for producing advanced glycation end products at sites of inflammation

Cited by 328 publications

References 62 publications

Electrospray low energy CID and MALDI PSD fragmentations of protonated sulfinamide cross-linked peptides

Electrospray low energy CID and MALDI PSD fragmentations of protonated sulfinamide cross-linked peptides

Neuronal expression of myeloperoxidase is increased in Alzheimer's disease

Production of Brominating Intermediates by Myeloperoxidase

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