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  Biomolecules 2015, 5, 378-411; doi:10.3390/biom5020378 biomolecules ISSN 2218-273X www.mdpi.com/journal/biomolecules/ Review Mass Spectrometry-Based Methods for Identifying Oxidized Proteins in Disease: Advances and Challenges Ivan Verrastro, Sabah Pasha, Karina Tveen Jensen, Andrew R. Pitt and Corinne M. Spickett * School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, B4 7ET, UK; E-Mails: verrasti@aston.ac.uk (I.V.); pashas@aston.ac.uk (S.P.); k.tveen-jensen@aston.ac.uk (K.T.J.); a.r.pitt@aston.ac.uk (A.R.P.) * Author to whom correspondence should be addressed; E-Mail: c.m.spickett@aston.ac.uk; Tel.: +44-121-2044085.  Academic Editors: Michael Breitenbach and Peter Eckl  Received: 2 February 2015 / Accepted: 23 March 2015 / Published: 14 April 2015  Abstract:Manyinflammatorydiseaseshaveanoxidativeaetiology,whichleadsto oxidativedamagetobiomolecules,includingproteins.Itisnowincreasinglyrecognized thatoxidativepost-translationalmodifications(oxPTMs)ofproteinsaffectcellsignalling andbehaviour,andcancontributetopathology.Moreover,oxidizedproteinshave potentialasbiomarkersforinflammatorydiseases.Althoughmanyassaysforgeneric proteinoxidationandbreakdownproductsofproteinoxidationareavailable,only advancedtandemmassspectrometryapproacheshavethepowertolocalizespecific oxPTMsinidentifiedproteins.Whilemuchworkhasbeencarriedoutusinguntargeted ordiscoverymassspectrometryapproaches,identificationofoxPTMsindiseasehas benefittedfromthedevelopmentofsophisticatedtargetedorsemi-targetedscanning routines,combinedwithchemicallabelingandenrichmentapproaches.Nevertheless, manypotentialpitfallsexistwhichcanresultinincorrectidentifications.Thisreview explainsthelimitations,advantagesandchallengesofalloftheseapproachesto detectingoxidativelymodifiedproteins,andprovidesanupdateonrecentliteraturein which they have been used to detect and quantify protein oxidation in disease. Keywords:oxidativepost-translationalmodification;inflammation;cardiovascular  disease;proteincarbonyls;nitrotyrosine;chlorotyrosine;LC-MS/MS;precursorion scanning; neutral loss scanning; multiple reaction monitoring OPEN ACCESS      Biomolecules 2015, 5 379 1. Introduction to Protein Oxidation Manydiseaseshaveanoxidativeaetiologyresultingfromactivationoftheimmune system,mitochondrialdysfunctionorenvironmentally-inducedoxidativestress. Oxidativemodificationofproteinscanhavemultipleeffects,suchaslossofenzymatic activity,functionalalterations,lossofstructuralintegrity,andproteinaggregation[1]. Variousdifferentreactiveandoxidizingspeciesexistandvaryintheirreactivityto proteinresiduesandsites.Metal-catalysedoxidationdependsontheformationof  hydroxylradicalsthroughFentonchemistry;hydroxylradicalsarehighlyreactiveand abletomodifyalmostanysitethroughhydrogenabstractionandperoxideformation, oftenleadingtobackbonefragmentation.Themostsusceptiblesidechainsinproteins arethesulfur-containingcysteineandmethioninesidechains;thereactivityofcysteine withhydrogenperoxidedependsonthepKaofthethiolgroupasthethiolateanionisa betternucleophile.Cysteinecanalsoreactwithreactivenitrogenspeciestoform nitrosothiols(Figure1).Otherresiduesthatarecommonlyoxidizedincludehistidine, proline,lysineandarginine,wherehydroxylationorformationofaldehydesorketones mayoccur.Reactivenitrogencompoundsderivedfromperoxynitriteareoftenboth nitratingandoxidizing.Sitessusceptibletonitrationincludetyrosine(forming 3-nitrotyrosine)andtryptophan.Hypohalitescanalsoreactwitharomaticresiduesto form halogenated products such as 3-chloro and 3-bromotyrosine [2]. OH OH OH OH OH HO CH 2 C OH Cl NO 2 N H 5-Hydroxytryptophan CH 2 CH 2 CH  2 CH 2 CH 2 O 2 N CH 2 C C C C C C 3-Hydroxytyrosine 3-Chlorotyrosine 3-Nitrotyrosine Dityrosine N H OH S O OH O S O S OH R C 5-Nitrotryptophan S CH 2 S CH 2 CH 3 O O
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