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Modeling the Mechanisms and Stabilization of Methionine, Tryptophan and Histidine Oxidation in PTH

TZ John

Recent oxidation events on monoclonal antibody candidates prompted us to investigate the mechanism of oxidation of Met, Trp, and His residues and to search for suitable stabilizers. By using parathyroid hormone (1–34), PTH, as a model protein and various oxidants, aided by liquid chromatography, peptide mapping, and mass spectrometry, we identified and quantified the oxidation of these vulnerable residues. Whereas H2O2 and t-butyl hydroperoxide (t-BHP) primarily oxidized the two Met residues, 2,2′-azobis(2-amidinopropane) dihydrochloride (AAPH), and H2O2+Fe(II) oxidized Met and Trp residues, with AAPH more capable of generating oxidized Trp species than the latter. H2O2+Fe(III) generated results comparable to those with H2O2+Fe(II), except that there was a lesser amount of hydroxylated Phe.