Deconstruction of activity-dependent covalent modification of heme in human neutrophil myeloperoxidase by multistage mass spectrometry (MS(4))

Biochemistry
Kieran F GeogheganFelix F Vajdos

Abstract

Myeloperoxidase (MPO) is known to be inactivated and covalently modified by treatment with hydrogen peroxide and agents similar to 3-(2-ethoxypropyl)-2-thioxo-2,3-dihydro-1H-purin-6(9H)-one (1), a 254.08 Da derivative of 2-thioxanthine. Peptide mapping by liquid chromatography and mass spectrometry detected modification by 1 in a labile peptide-heme-peptide fragment of the enzyme, accompanied by a mass increase of 252.08 Da. The loss of two hydrogen atoms was consistent with mechanism-based oxidative coupling. Multistage mass spectrometry (MS(4)) of the modified fragment in an ion trap/Orbitrap spectrometer demonstrated that 1 was coupled directly to heme. Use of a 10 amu window delivered the full isotopic envelope of each precursor ion to collision-induced dissociation, preserving definitive isotopic profiles for iron-containing fragments through successive steps of multistage mass spectrometry. Iron isotope signatures and accurate mass measurements supported the structural assignments. Crystallographic analysis confirmed linkage between the methyl substituent of the heme pyrrole D ring and the sulfur atom of 1. The final orientation of 1 perpendicular to the plane of the heme ring suggested a mechanism consisting of two conse...Continue Reading

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Citations

May 6, 2014·BioMed Research International·Safa Abdul-GhaniM-Saadeh Suleiman
Nov 17, 2012·Journal of Proteomics·Parveen SharmaAnthony O Gramolini
Jul 1, 2016·The Journal of Physical Chemistry. B·Hector D Arbelo-LopezTroy Wymore
Aug 5, 2018·The Journal of Pharmacology and Experimental Therapeutics·Martin L MarroJean B Regard
Dec 21, 2017·Analytical Biochemistry·Louisa V Forbes, Anthony J Kettle

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