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  • Title: Oxidation of human growth hormone by oxygen-centered radicals: formation of Leu-101 hydroperoxide and Tyr-103 oxidation products.
    Author: Steinmann D, Ji JA, Wang YJ, Schöneich C.
    Journal: Mol Pharm; 2012 Apr 02; 9(4):803-14. PubMed ID: 22397317.
    Abstract:
    Human growth hormone (hGH) was exposed to oxygen-centered radicals generated through the thermolysis of AAPH in the presence of dioxygen. Such conditions mimic oxidative processes which protein pharmaceuticals can encounter during formulation in the presence of polysorbates. We detected the oxidation of Met to Met sulfoxide, the formation of protein carbonyls, the oxidation of Tyr to dityrosine and several additional Tyr oxidation products, the conformation-dependent oxidation of Trp, and the site-specific formation of protein hydroperoxides. The sensitivity of Met oxidation correlates with their solvent accessible surface, i.e. the yields of MetSO decreased in the order Met-14 > Met-125 > Met-170. Trp oxidation in native hGH was negligible, but was enhanced through denaturation. Dityrosine formed predominantly intramolecularly but did not contribute significantly to protein cross-linking. Hydroperoxides formed selectively on Leu-101 and were generated specifically by alkoxyl radicals, generated through the decomposition of peroxyl radicals. Tyr-103 was converted into a series of oxidation products characterized by mass shifts of Tyr + 14 Da and Tyr + 16 Da.
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