title: A comprehensive picture of non-site specific oxidation of methionine residues by peroxides in protein pharmaceuticals.
abstract: In this article, a comprehensive picture of the oxidation of protein pharmaceuticals by peroxides is developed based on our earlier computational and experimental studies. We propose a new mechanism, the water-mediated mechanism, for the oxidation of methionine residues, and it has been shown to satisfy all available experimental data including new data reported here. Based on the water-mediated mechanism, we found a structural property, average 2-shell water coordination number, that correlates well to the relative rates of oxidation of methionine groups. We used this to study the oxidation of granulocyte colony-stimulating factor (G-CSF) and 1-34 human parathyroid hormone hPTH(1-34). We believe that this comprehensive picture should aid researchers in the pharmaceutical sciences to develop solvent formulations for therapeutic proteins in a more rational way.
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Jhih-Wei
authors.initials: JW
authors.lastname: Chu
authors.forename: Jin
authors.initials: J
authors.lastname: Yin
authors.forename: Bernard R
authors.initials: BR
authors.lastname: Brooks
authors.forename: Daniel I C
authors.initials: DI
authors.lastname: Wang
authors.forename: Margaret Speed
authors.initials: MS
authors.lastname: Ricci
authors.forename: David N
authors.initials: DN
authors.lastname: Brems
authors.forename: Bernhardt L
authors.initials: BL
authors.lastname: Trout
mesh_terms: D001665:Binding Sites / Q000502:physiology; D008715:Methionine / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010545:Peroxides / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*
chemical_list: D010545:Peroxides; D004364:Pharmaceutical Preparations; D011506:Proteins; D008715:Methionine